clinical oncology news digital edition - june 2012

There is a significant drop in bone density with two years of use of the

aromatase inhibitor exemestane (Aro-masin, Pfizer) at a dosage of 25 mg per day, according to a new study.

In a substudy of a randomized con-trolled trial of healthy postmenopaus-al women taking exemestane to pre-vent breast cancer, the medication was associated with an average 6.1% reduc-tion in bone mineral density (BMD) at the distal radius using quantitative

Significant Bone Changes with Exemestane Unclear whether bone density drop leads to increased fractures

All patients with metastatic non-small cell lung cancer (NSCLC)

should be offered palliative care along with standard cancer therapy, begin-ning at the time of diagnosis, according to a provisional clinical opinion (PCO) issued by the American Society of Clin-ical Oncology (ASCO).

The statement, published Feb. 6 in the Journal of Clinical Oncology (2012;30:880-887, PMID: 22312101), was initiated by a recent Phase III ran-domized clinical trial that demonstrat-ed the benefits of concurrent palliative

Metastatic NSCLC: Palliative Care at DiagnosisASCO provisional opinion says palliative care at diagnosis leads to better patient outcomes

San Francisco—A growing body of evi-dence demonstrates that stomach cancer is an extremely heterogeneous disease, so much so that researchers are questioning whether clinical trials need to be restruc-tured to reflect the myriad differences.

“Gastric cancer isn’t one disease but many diseases,” said Manish Shah, MD, the director of Gastrointestinal Oncology at Weill Cornell Medical College in New York City, speaking at the 2012 Gastroin-testinal Cancers Symposium (ASCO-GI).

“This is supported by epidemiology, risk factors, response to therapy and even molecular analyses.”

Teasing Out the Differences

Although gastric cancer is more prev-alent in Asia, there is more advanced disease in the United States and the West in general.

“Then there is the question of whether there is different underlying biology. That

There appears to be a signifi cant disconnect between the cardiac

effects of cancer drugs and how they are reported in clinical trials. The problem may be so prev-alent that some oncologists are calling for revamping how cardiovascular side effects are reported during clinical trials of newer chemother-apeutic agents.

“There are s ig-nals that many of the tyrosine kinase inhib-itors are an issue,” said Ronald Witteles, MD, an assistant professor of car-diovascular medicine at Stan-ford University School of Medi-cine in Stanford, Calif. “However, there is no way to know how widespread the

The Underreported Cardiac Toxicity of Anticancer Drugs

Heterogeneity of Gastric Cancers Poses Challenges

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Anticancer agents causing permanent damage

Doxorubicin Daunorubicin

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Anticancer agents causing reversible damage

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see CARDIOTOXICITY, page 17

see CHANGES, page 10 see CHALLENGES, page 29

To order cancer therapeutic

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go to http://www.clinicaloncology.com/

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3 A more pragmatic approach to Phase II trials.

12 Clinical Conundrums: A quiz for the practicing hematologist/oncologist.

25 Addressing the needs of young adults with cancer.

14 An introduction to the Taussig Cancer Institute.

15 One institution’s 29-year experience with intraoperative radiation therapy.

22 Adjuvant chemotherapy for non-small cell lung cancer.

EXPERT COMMENTARIES FROM CLEVELAND CLINIC

Nathan Pennell, MD, PhD

Kevin Stephans, MD

SOLID TUMORS

23 A new biomarker to guide treatment for esophagogastric cancer treatment.

New Drugs for Malignancy, An Issue of Hematology/

Oncology Clinics of North America

Franco Muggia, MD

See page 31.

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Independent News on Advances in Cancer Care

CLINICALoNCoLoGY.CoM • June 2012 • Vol. 7, No. 6

Oncology Edition

2 CliniCAl OnCOlOgy nEwS • JunE 2012CLINICAL ONCOLOGY NEWS

EDITORIAL BOARD

Solid TumorsBone Metastases

Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Andrew Seidman, MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Maura N. Dickler, MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer

Edward Chu, MDUniversity of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Cathy Eng, MDUniversity of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma

Ephraim Casper, MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Genitourinary Cancer

Ronald M. Bukowski, MDTaussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Maurie Markman, MDCancer Treatment Centers of America Philadelphia, PA

Lung, and Head and Neck Cancers

Edward S. Kim, MDUniversity of Texas, MD Anderson Cancer Center Houston, TX

Lung Cancer, Emesis

Richard J. Gralla, MDHofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Prostate Cancer

Michael A. Carducci, MDAEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Hematologic MalignanciesJennifer R. Brown, MD, PhDDana-Farber Cancer Institute, Harvard Medical School Boston, MA

Harry Erba, MD, PhDUniversity of Michigan Ann Arbor, MI

Shaji Kumar, MDMayo Clinic Rochester, MN

Richard Stone, MDDana-Farber Cancer Institute, Harvard Medical School Boston, MA

Community OncologyJohn W. Finnie, MDMercy Medical Center St. Louis, MO

Michael J. Fisch, MD, MPHUniversity of Texas, MD Anderson Cancer Center Houston, TX

Steven Vogl, MDMedical Oncologist New York, NY

Symptom Control and Palliative Care

William S. Breitbart, MDMemorial Sloan-Kettering Cancer Center New York, NY

Steven D. Passik, PhDVanderbilt University Medical Center Nashville, TN

Joseph V. Pergolizzi Jr., MDJohns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MDBeth Israel Medical Center New York, NY

Charles F. von Gunten, MDUniversity of California, San Diego, CA

Infection Control

Susan K. Seo, MDMemorial Sloan-Kettering Cancer Center New York, NY

Oncology Nursing

Betty Ferrell, RN, PhDCity of Hope National Medical Center Duarte, CA

Michele Neskey, MMSc, PA-CUniversity of Texas, MD Anderson Cancer Center Houston, TX

Pharmacy

Cindy o’Bryant, PharmDUniversity of Colorado Cancer Center Denver, CO

Sara S. Kim, PharmDThe Mount Sinai Medical Center New York, NY

Bioethics

Joseph P. DeMarco, PhDCleveland State University Cleveland, OH

Paul J. Ford, PhDCleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Policy and Management

Mary Lou Bowers, MBAThe Pritchard Group Rockville, MD

Rhonda M. Gold, RN, MSNThe Pritchard Group Rockville, MD

Editorial Philosophy

The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Additionally, all news articles that appear in Clinical Oncology news are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

Mission Statement

The mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the

issues that oncologists and hematologists care about most. we strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.

We should add the need for more pragmatic clinical trials that address, even if not definitively, issues of consid-erable relevance to individual patient management, but for which there is lit-tle recognized interest from either the “scientific community” or potential financial sponsors.

Consider, for example, the recent report on the biological activity of sin-gle-agent, nanoparticle albumin-bound paclitaxel in the second-line treatment of epithelial ovarian cancer.1 This non-randomized study, conducted by the

Gynecologic Oncology Group, revealed an objective response rate of 23%, sim-ilar to that previously reported with the far less expensive generic paclitaxel.2,3

But is it possible that this agent is actually superior to paclitaxel in that treatment with nanoparticle albumin-bound paclitaxel achieves a similar degree of objective clinical benefit (e.g., degree of tumor shrinkage and delay in time to progression) but with a measur-ably more favorable toxicity profile that includes a substantially reduced risk for peripheral neuropathy?

Unfortunately, in the complete absence of data from a randomized trial, the answer to this specific question will

simply be unknown because any sug-gested “superior” outcomes may sole-ly reflect the inadvertent selection bias resulting from the favorable baseline clinical features inherent in all nonran-domized studies.

And although a definitive answer to this question would admittedly require a rather large Phase III trial, a 100- or 120-patient randomized Phase II study that directly compares the nanoparticle agent with generic paclitaxel may pro-vide sufficient data to adequately inform both individual patient decision making

as well as deliberations by third-party insurers asked to pay the cost associated with the more expensive antineoplastic.

As the question being addressed does not relate to drug approval or mar-keting, there would be no regulato-ry requirement for a study confirming superiority based on improved surviv-al. Rather, the specific issues addressed by the study relate solely to the decision to both use and pay for the agent in its clinical indication; and the data would be directed at the physician, payer and patient audiences.

It also can be strongly argued that pragmatic, randomized Phase II tri-als should be simple in design, address

only a single well-defined question, be easy to explain to prospective research subjects and strictly avoid the largely, if not completely, unnecessary mandates required for regulatory approval—for example, placebo control and indepen-dent radiology review.

And wherever clinically appropriate, a crossover design should be strongly considered, permitting patients enter-ing the trial the opportunity to receive and potentially benefit from the inves-tigative regimen. Patients progress-ing on weekly paclitaxel in the above

example might cross over to nanoparti-cle paclitaxel, the argument being that the unique drug formulation may over-come a clinically meaningful degree of paclitaxel resistance. Of course, there can never be any guarantee to patients that crossover will be possible—clin-ical circumstances at the time of dis-ease progression may demand alterna-tive options that are ultimately in the patient’s best interests.

In pragmatic, randomized Phase II studies, the acceptable end points might include differences in the objec-tive response rate, progression-free survival, clinically relevant toxicity—peripheral neuropathy or stomatitis/

mucositis—or even time to worsening of cancer-related symptoms.

Finally, although pragmatic, random-ized Phase II trials will almost never serve as a definitive test, they may pro-vide genuinely meaningful data in a sub-stantial number of clinical settings that truly inform the decision-making pro-cess both for the treating physician and, most importantly, the patient.

References

1. Coleman RL, Brady WE, McMeekin DS, et al. A phase II evaluation of nanoparticle, albumin-bound (nab) paclitaxel in the treat-ment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a Gynecologic Oncolo-gy Group study. Gynecol Oncol. 2001;122:111-115, PMID: 21497382.

2. Markman M, Blessing J, Rubin SC, et al. Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol Oncol. 2006;101:436-440, PMID: 16325893.

3. Markman M, Hall J, Spitz D, et al. Phase II trial of weekly single-agent paclitaxel in paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol. 2002;20:2365-2369, PMID: 11981009.

Randomized Phase II trials:

A Pragmatic Way To Inform Clinical PracticeThe crisis in clinical cancer research has been well described. From the extremely small percentage of patients that elect to enter a cancer trial, to the time required for the activation of studies, to the high failure rate by cooperative groups to complete accrual, and the increasingly questionable ethical justification of “placebo” or “no crossover” studies, there is much in clinical cancer research that desperately requires fixing.

EDITORIAL BOARD COMMENTARY

Maurie Markman, MDSenior Vice President of Clinical Affairs and national Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor

Gabriel Miller at

[email protected]

Comments or feedback

‘It can be strongly argued that pragmatic, randomized Phase II trials should be

simple in design, address only a single well-defined question, be easy to explain

to prospective research subjects and strictly avoid the largely, if not completely,

unnecessary mandates required for regulatory approval—for example, placebo

control and independent radiology review.’

McMahon Publishing is a 40-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Clinical Oncology news (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp. Office, 83 Peaceable Street, Redding CT 06896 Copyright© 2012 McMahon Publishing, New York, NY. All rights reserved.

POSTMASTER: Please send address changes to Clinical Oncology news, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

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CliniCAl OnCOlOgy nEwS • JunE 2012 3PRN

Evidence-based Medicine

Bone metastases from solid tumors

IndicationZOMETA (zoledronic acid) 4 mg/5 mL Injection is indicated for the treatment of hypercalcemia of malignancy (HCM) and patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Safe and efficacious use of ZOMETA has not been established for use in hyperparathyroidism or non-tumor-related hypercalcemia.

Important Safety InformationZOMETA is contraindicated in patients with hypersensitivity to zoledronic acid or any components of ZOMETA. Hypersensitivity reactions, including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock, have been reported. Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient.Patients with HCM must be adequately rehydrated prior to use of ZOMETA and loop diuretics (if applicable). Loop diuretics should be used with caution in combination with ZOMETA to avoid hypocalcemia. ZOMETA should be used with caution with other nephrotoxic drugs. Carefully monitor serum calcium, phosphate, magnesium, and serum creatinine following initiation of ZOMETA. Short-term supplemental therapy may be necessary.In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. Consider individual patient risk/benefit profile before starting ZOMETA therapy in HCM patients with severe renal impairment. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment. Preexisting renal insufficiency and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose.Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection, including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible, as recovery may be prolonged. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.ZOMETA should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant or plans to breast-feed while taking this drug, the patient should be apprised of the potential harm to the fetus or baby.In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including ZOMETA. Discontinue use if severe symptoms develop, as a subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. There have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates.Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including ZOMETA. These fractures may occur with minimal or no trauma. A number of case reports noted that patients were also receiving treatment with glucocorticoids at time of fracture. Causality with bisphosphonates has not been established. Any patient with a history of bisphosphonate exposure who presents with hip, thigh, or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Drug discontinuation in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit/risk assessment.Insufficient data exist on how to safely use ZOMETA in HCM patients with hepatic impairment.Acute-phase reaction symptoms can occur in HCM patients, with fever most commonly reported (44% with ZOMETA vs. 33% with pamidronate). Patients may occasionally experience flu-like syndrome (fever, chills, flushing, bone pain and/or arthralgias and myalgias). The most common adverse events (≥10%) in HCM clinical trials, regardless of causality, with ZOMETA 4 mg (n=86) were as follows: fever (44%), nausea (29%), constipation (27%), anemia (22%), dyspnea (22%), diarrhea (17%), abdominal pain (16%), progression of cancer (16%), insomnia (15%), vomiting (14%), anxiety (14%), urinary tract infection (14%), hypophosphatemia (13%), confusion (13%), agitation (13%), moniliasis (12%), hypokalemia (12%), coughing (12%), skeletal pain (12%), hypotension (11%), and hypomagnesemia (11%). In controlled HCM clinical trials, adverse events (5-10% frequency) occurring in greater incidence with ZOMETA than pamidronate include: asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, non-specific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Injection site reactions (redness, swelling) have been infrequently reported.The most common adverse events (≥15%) in bone metastases clinical trials, regardless of causality, with ZOMETA 4 mg (n=1031) were as follows: bone pain (55%), nausea (46%), fatigue (39%), anemia (33%), pyrexia (32%), vomiting (32%), constipation (31%), dyspnea (27%), diarrhea (24%), weakness (24%), myalgia (23%), anorexia (22%), cough (22%), arthralgia (21%), lower-limb edema (21%), malignant neoplasm aggravated (20%), headache (19%), dizziness (excluding vertigo) (18%), insomnia (16%), decreased weight (16%), back pain (15%), and paresthesia (15%). Patients should also be made aware of the potential for abdominal pain. Ocular adverse events may occur with bisphosphonates, including ZOMETA. Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.Caution is advised when bisphosphonates, including ZOMETA, are administered with aminoglycosides, loop diuretics, and potentially nephrotoxic drugs. Patients with multiple myeloma and bone metastases due to solid tumors should be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.Please see full Prescribing Information.Please see brief summary of full Prescribing Information on the following pages.

References: 1. ZOMETA Prescribing Information. Novartis Pharmaceuticals Corporation. 2. Aredia Prescribing Information. Novartis Pharmaceuticals Corporation. 3. Actonel Prescribing Information. Procter & Gamble Pharmaceuticals. 4. Boniva Prescribing Information. Roche Laboratories Inc. 5. Didronel Prescribing Information. Procter & Gamble Pharmaceuticals. 6. Fosamax Prescribing Information. Merck & Co. 7. Skelid Prescribing Information. sanofi -aventis US LLC. 8. Xgeva Prescribing Information. Amgen Inc.

© 2012 Novartis April 2012 ZOM-1040045

Please see full Prescribing Information.Please see brief summary of full Prescribing Information on the following pages.

Highlights from the Important Safety Information• There have been reports of renal toxicity with ZOMETA. Renal toxicity may be greater in patients with renal impairment. Treatment in patients with severe renal impairment is not recommended. Do not use doses greater than 4 mg and monitor serum creatinine before each dose

• Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including ZOMETA. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status

• A causal relationship between bisphosphonate use and ONJ has not been established

Proven effi cacyacross multiple malignancies1

* ZOMETA (zoledronic acid) 4 mg/5 mL Injection should be used in prostate patients with bone metastases that have progressed after treatment with at least one hormonal therapy.

SRE=skeletal-related event.

Indicated across more advanced malignancies than any other approved bone-remodeling agent1-8

Across multiple advanced malignancies, helps reduce and delay multiple SREs1

• Pathologic fracture• Surgery to bone• HCM

• Spinal cord compression• Radiation to bone

MCCON482.indd 1 5/23/12 8:26 PM

Zometa® (zoledronic acid) InjectionReady-to-Use Solution for Intravenous Infusion (For Single Use)Concentrate for Intravenous InfusionInitial U.S. Approval: 2001BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE

1.1 Hypercalcemia of MalignancyZometa is indicated for the treatment of hypercalcemia of malignancy defined as analbumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3.0 mmol/L]using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL - patient albumin (g/dL)).1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patientswith documented bone metastases from solid tumors, in conjunction with standardantineoplastic therapy. Prostate cancer should have progressed after treatment withat least one hormonal therapy.1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not beenestablished.

4 CONTRAINDICATIONS4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, andvery rare cases of anaphylactic reaction/shock have been reported [see AdverseReactions (6.2)].

5 WARNINGS AND PRECAUTIONS5.1 Drugs with Same Active Ingredient or in the Same Drug Class Zometa contains the same active ingredient as found in Reclast® (zoledronic acid).Patients being treated with Zometa should not be treated with Reclast or other bisphosphonates.5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior toadministration of Zometa. Loop diuretics should not be used until the patient is ade-quately rehydrated and should be used with caution in combination with Zometa inorder to avoid hypocalcemia. Zometa should be used with caution with othernephrotoxic drugs.Standard hypercalcemia-related metabolic parameters, such as serum levels of cal-cium, phosphate, and magnesium, as well as serum creatinine, should be carefullymonitored following initiation of therapy with Zometa. If hypocalcemia, hypophos-phatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary.5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions,in particular renal adverse reactions, may be greater in patients with impaired renalfunction. Safety and pharmacokinetic data are limited in patients with severe renalimpairment and the risk of renal deterioration is increased [see Adverse Reactions(6.1)]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa.Factors predisposing to renal deterioration, such as dehydration or the use of othernephrotoxic drugs, should be identified and managed, if possible.Zometa treatment in patients with hypercalcemia of malignancy with severe renalimpairment should be considered only after evaluating the risks and benefits of treat-ment. In the clinical studies, patients with serum creatinine greater than 400 μmol/L orgreater than 4.5 mg/dL were excluded.Zometa treatment is not recommended in patients with bone metastases with severerenal impairment. In the clinical studies, patients with serum creatinine greater than265 μmol/L or greater than 3.0 mg/dL were excluded and there were only 8 of 564patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatininegreater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinineclearance less than 30 mL/min [see Clinical Pharmacology (12.3) in the full pre-scribing information].5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patientstreated with intravenous bisphosphonates, including Zometa. Many of these patientswere also receiving chemotherapy and corticosteroids which may be risk factors forONJ. Postmarketing experience and the literature suggest a greater frequency ofreports of ONJ based on tumor type (advanced breast cancer, multiple myeloma),and dental status (dental extraction, periodontal disease, local trauma includingpoorly fitting dentures). Many reports of ONJ involved patients with signs of localinfection including osteomyelitis.Cancer patients should maintain good oral hygiene and should have a dental exami-nation with preventive dentistry prior to treatment with bisphosphonates.While on treatment, these patients should avoid invasive dental procedures if possi-ble. For patients who develop ONJ while on bisphosphonate therapy, dental surgerymay exacerbate the condition. For patients requiring dental procedures, there are nodata available to suggest whether discontinuation of bisphosphonate treatment

reduces the risk of ONJ. Clinical judgment of the treating physician should guide themanagement plan of each patient based on individual benefit/risk assessment [seeAdverse Reactions (6.2)].5.5 Musculoskeletal PainIn postmarketing experience, severe and occasionally incapacitating bone, joint,and/or muscle pain has been reported in patients taking bisphosphonates. This cate-gory of drugs includes Zometa. The time to onset of symptoms varied from one dayto several months after starting the drug. Discontinue use if severe symptomsdevelop. Most patients had relief of symptoms after stopping. A subset had recur-rence of symptoms when rechallenged with the same drug or another bisphospho-nate [see Adverse Reactions (6.2)].5.6 Atypical subtrochanteric and diaphyseal femoral fracturesAtypical subtrochanteric and diaphyseal femoral fractures have been reported inpatients receiving bisphosphonate therapy, including Zometa. These fractures canoccur anywhere in the femoral shaft from just below the lesser trochanter to justabove the supracondylar flare and are transverse or short oblique in orientationwithout evidence of comminution. These fractures occur after minimal or no trauma.Patients may experience thigh or groin pain weeks to months before presenting witha completed femoral fracture. Fractures are often bilateral; therefore the contralateralfemur should be examined in bisphosphonate-treated patients who have sustained afemoral shaft fracture. Poor healing of these fractures has also been reported. Anumber of case reports noted that patients were also receiving treatment with gluco-corticoids (such as prednisone or dexamethasone) at the time of fracture. Causalitywith bisphosphonate therapy has not been established.Any patient with a history of bisphosphonate exposure who presents with thigh orgroin pain in the absence of trauma should be suspected of having an atypical frac-ture and should be evaluated. Discontinuation of Zometa therapy in patients sus-pected to have an atypical femur fracture should be considered pending evaluationof the patient, based on an individual benefit risk assessment. It is unknown whetherthe risk of atypical femur fracture continues after stopping therapy.5.7 Patients with AsthmaWhile not observed in clinical trials with Zometa, there have been reports of broncho-constriction in aspirin sensitive patients receiving bisphosphonates.5.8 Hepatic ImpairmentOnly limited clinical data are available for use of Zometa to treat hypercalcemia ofmalignancy in patients with hepatic insufficiency, and these data are not adequate toprovide guidance on dosage selection or how to safely use Zometa in these patients.5.9 Use in PregnancyBisphosphonates, such as Zometa, are incorporated into the bone matrix, fromwhere they are gradually released over periods of weeks to years. There may be arisk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes preg-nant after completing a course of bisphosphonate therapy. Zometa may cause fetal harm when administered to a pregnant woman. In reproduc-tive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times thehuman systemic exposure resulted in pre- and post-implantation losses, decreasesin viable fetuses and fetal skeletal, visceral, and external malformations. There areno adequate and well controlled studies in pregnant women. If this drug is used dur-ing pregnancy, or if the patient becomes pregnant while taking this drug, the patientshould be apprised of the potential hazard to a fetus [see Use in Specific Popula-tions (8.1)].

6 ADVERSE REACTIONS6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reac-tion rates observed in the clinical trials of a drug cannot be directly compared torates in the clinical trials of another drug and may not reflect the rates observed inpractice.Hypercalcemia of MalignancyThe safety of Zometa was studied in 185 patients with hypercalcemia of malignancy(HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion(n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). Thepopulation was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung,head and neck, and renal cancer as the most common forms of malignancy. NOTE:pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safetyof pamidronate 90 mg given as a 2-hour intravenous infusion compared to the samedose given as a 24-hour intravenous infusion has not been adequately studied incontrolled clinical trials.Renal ToxicityAdministration of Zometa 4 mg given as a 5-minute intravenous infusion has beenshown to result in an increased risk of renal toxicity, as measured by increases inserum creatinine, which can progress to renal failure. The incidence of renal toxicityand renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenousinfusion over no less than 15 minutes [see Warnings And Precautions (5) andDosage And Administration (2) in the full prescribing information].The most frequently observed adverse events were fever, nausea, constipation, ane-mia, and dyspnea (see Table 4).

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Table 4 provides adverse events that were reported by 10% or more of the 189patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials.Adverse events are listed regardless of presumed causality to study drug.

Table 4: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

Zometa Pamidronate 4 mg 90 mg n (%) n (%)Patients Studied

Total No. of Patients Studied 86 (100) 103 (100)Total No. of Patients with any AE 81 (94) 95 (92)

Body as a Whole Fever 38 (44) 34 (33)Progression of Cancer 14 (16) 21 (20)

Cardiovascular Hypotension 9 (11) 2 (2)

Digestive Nausea 25 (29) 28 (27)Constipation 23 (27) 13 (13)Diarrhea 15 (17) 17 (17)Abdominal Pain 14 (16) 13 (13)Vomiting 12 (14) 17 (17)Anorexia 8 (9) 14 (14)

Hemic and Lymphatic System Anemia 19 (22) 18 (18)

Infections Moniliasis 10 (12) 4 (4)

Laboratory Abnormalities Hypophosphatemia 11 (13) 2 (2)Hypokalemia 10 (12) 16 (16)Hypomagnesemia 9 (11) 5 (5)

Musculoskeletal Skeletal Pain 10 (12) 10 (10)

Nervous Insomnia 13 (15) 10 (10)Anxiety 12 (14) 8 (8)Confusion 11 (13) 13 (13)Agitation 11 (13) 8 (8)

Respiratory Dyspnea 19 (22) 20 (19)Coughing 10 (12) 12 (12)

Urogenital Urinary Tract Infection 12 (14) 15 (15)

The following adverse events from the two controlled multicenter HCM trials(n=189) were reported by a greater percentage of patients treated with Zometa 4 mgthan with pamidronate 90 mg and occurred with a frequency of greater than or equalto 5% but less than 10%. Adverse events are listed regardless of presumed causalityto study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocyto -penia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehy-dration, arthralgias, headache and somnolence.Rare cases of rash, pruritus, and chest pain have been reported following treatmentwith Zometa. Acute Phase Reaction-like EventsSymptoms consistent with acute phase reaction (APR) can occur with intravenousbisphosphonate use. Fever has been the most commonly associated symptom,occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treatedwith Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome con-sisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias.Mineral and Electrolyte AbnormalitiesElectrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia andhypomagnesemia, can occur with bisphosphonate use.Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium,serum phosphorus, and serum magnesium observed in two clinical trials of Zometain patients with HCM are shown in Table 5 and 6.

Table 5: Grade 3 Laboratory Abnormalities forSerum Creatinine, Serum Calcium, Serum Phosphorus,

and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3Laboratory Parameter Zometa Pamidronate 4 mg 90 mg n/N (%) n/N (%)Serum Creatinine1 2/86 (2%) 3/100 (3%)Hypocalcemia2 1/86 (1%) 2/100 (2%)Hypophosphatemia3 36/70 (51%) 27/81 (33%)Hypomagnesemia4 0/71 — 0/84 —

Table 6: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus,

and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 4Laboratory Parameter Zometa Pamidronate 4 mg 90 mg n/N (%) n/N (%)Serum Creatinine1 0/86 — 1/100 (1%)Hypocalcemia2 0/86 — 0/100 —Hypophosphatemia3 1/70 (1%) 4/81 (5%)Hypomagnesemia4 0/71 — 1/84 (1%)1Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limitof Normal)

2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)4Grade 3 (less than 0.8 mEq/L); Grade 4 (less than 0.5 mEq/L)

Injection Site ReactionsLocal reactions at the infusion site, such as redness or swelling, were observedinfrequently. In most cases, no specific treatment is required and the symptomssubside after 24-48 hours.Ocular Adverse EventsOcular inflammation such as uveitis and scleritis can occur with bisphosphonateuse, including Zometa. No cases of iritis, scleritis or uveitis were reported duringthese clinical trials. However, cases have been seen in postmarketing use [seeAdverse Reactions (6.2)].Multiple Myeloma and Bone Metastases of Solid TumorsThe safety analysis includes patients treated in the core and extension phases of thetrials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate90 mg, or placebo in the three controlled multicenter bone metastases trials, includ-ing 969 patients completing the efficacy phase of the trial, and 619 patients thatcontinued in the safety extension phase. Only 347 patients completed the extensionphases and were followed for 2 years (or 21 months for the other solid tumorpatients). The median duration of exposure for safety analysis for Zometa 4 mg(core plus extension phases) was 12.8 months for breast cancer and multiplemyeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors.Table 7 describes adverse events that were reported by 10% or more of patients.Adverse events are listed regardless of presumed causality to study drug.

Table 7: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System

Zometa Pamidronate Placebo 4 mg 90 mg n (%) n (%) n (%)Patients Studied

Total No. of Patients 1031 (100) 556 (100) 455 (100)Total No. of Patients with any AE 1015 (98) 548 (99) 445 (98)

Blood and Lymphatic Anemia 344 (33) 175 (32) 128 (28)Neutropenia 124 (12) 83 (15) 35 (8)Thrombocytopenia 102 (10) 53 (10) 20 (4)

Gastrointestinal Nausea 476 (46) 266 (48) 171 (38)Vomiting 333 (32) 183 (33) 122 (27)Constipation 320 (31) 162 (29) 174 (38)Diarrhea 249 (24) 162 (29) 83 (18)Abdominal Pain 143 (14) 81 (15) 48 (11)Dyspepsia 105 (10) 74 (13) 31 (7)Stomatitis 86 (8) 65 (12) 14 (3)Sore Throat 82 (8) 61 (11) 17 (4)

General Disorders and Administration Site Fatigue 398 (39) 240 (43) 130 (29)Pyrexia 328 (32) 172 (31) 89 (20)Weakness 252 (24) 108 (19) 114 (25)Edema Lower Limb 215 (21) 126 (23) 84 (19)Rigors 112 (11) 62 (11) 28 (6)

Infections Urinary Tract Infection 124 (12) 50 (9) 41 (9)Upper Respiratory Tract Infection 101 (10) 82 (15) 30 (7)

MetabolismAnorexia 231 (22) 81 (15) 105 (23)Weight Decreased 164 (16) 50 (9) 61 (13)Dehydration 145 (14) 60 (11) 59 (13)Appetite Decreased 130 (13) 48 (9) 45 (10)

(continued)

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Table 7: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System

Zometa Pamidronate Placebo 4 mg 90 mg n (%) n (%) n (%)Musculoskeletal

Bone Pain 569 (55) 316 (57) 284 (62)Myalgia 239 (23) 143 (26) 74 (16)Arthralgia 216 (21) 131 (24) 73 (16)Back Pain 156 (15) 106 (19) 40 (9)Pain in Limb 143 (14) 84 (15) 52 (11)

Neoplasms Malignant Neoplasm Aggravated 205 (20) 97 (17) 89 (20)

Nervous Headache 191 (19) 149 (27) 50 (11)Dizziness (excluding vertigo) 180 (18) 91 (16) 58 (13)Insomnia 166 (16) 111 (20) 73 (16)Paresthesia 149 (15) 85 (15) 35 (8)Hypoesthesia 127 (12) 65 (12) 43 (10)

Psychiatric Depression 146 (14) 95 (17) 49 (11)Anxiety 112 (11) 73 (13) 37 (8)Confusion 74 (7) 39 (7) 47 (10)

Respiratory Dyspnea 282 (27) 155 (28) 107 (24)Cough 224 (22) 129 (23) 65 (14)

Skin Alopecia 125 (12) 80 (14) 36 (8)Dermatitis 114 (11) 74 (13) 38 (8)

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium,serum phosphorus, and serum magnesium observed in three clinical trials ofZometa in patients with bone metastases are shown in Tables 8 and 9.

Table 8: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium

in Three Clinical Trials in Patients with Bone Metastases Grade 3Laboratory Parameter Zometa Pamidronate Placebo 4 mg 90 mg n/N (%) n/N (%) n/N (%)Serum Creatinine1* 7/529 (1%) 4/268 (2%) 4/241 (2%)Hypocalcemia2 6/973 (<1%) 4/536 (<1%) 0/415 —Hypophosphatemia3 115/973 (12%) 38/537 (7%) 14/415 (3%)Hypermagnesemia4 19/971 (2%) 2/535 (<1%) 8/415 (2%)Hypomagnesemia5 1/971 (<1%) 0/535 — 1/415 (<1%)1Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limitof Normal)

*Serum creatinine data for all patients randomized after the 15-minute infusion amendment

2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)4Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L)5Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)

Table 9: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in

Three Clinical Trials in Patients with Bone Metastases Grade 4Laboratory Parameter Zometa Pamidronate Placebo 4 mg 90 mg n/N (%) n/N (%) n/N (%)Serum Creatinine1* 2/529 (<1%) 1/268 (<1%) 0/241 —Hypocalcemia2 7/973 (<1%) 3/536 (<1%) 2/415 (<1%)Hypophosphatemia3 5/973 (<1%) 0/537 — 1/415 (<1%)Hypermagnesemia4 0/971 — 0/535 — 2/415 (<1%)Hypomagnesemia5 2/971 (<1%) 1/535 (<1%) 0/415 —1Grade 3 (greater than 3x Upper Limit of Normal); Grade 4 (greater than 6x Upper Limitof Normal)

*Serum creatinine data for all patients randomized after the 15-minute infusion amendment

2Grade 3 (less than 7 mg/dL); Grade 4 (less than 6 mg/dL)3Grade 3 (less than 2 mg/dL); Grade 4 (less than 1 mg/dL)4Grade 3 (greater than 3 mEq/L); Grade 4 (greater than 8 mEq/L)5Grade 3 (less than 0.9 mEq/L); Grade 4 (less than 0.7 mEq/L)

Among the less frequently occurring adverse events (less than 15% of patients), rig-ors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for moreevents with bisphosphonate administration (Zometa 4 mg and pamidronate groups)compared to the placebo group.Less common adverse events reported more often with Zometa 4 mg than pamidronateincluded decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite wasreported in slightly more patients in the Zometa 4 mg group (13%) compared withthe pamidronate (9%) and placebo (10%) groups, but the clinical significance ofthese small differences is not clear.Renal ToxicityIn the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (less than 1.4 mg/dL) or anincrease of 1.0 mg/dL for patients with an abnormal baseline creatinine (greater thanor equal to 1.4 mg/dL). The following are data on the incidence of renal deteriorationin patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 10).

Table 10: Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine*

Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer Zometa 4 mg Pamidronate 90 mg n/N (%) n/N (%)Normal 27/246 (11%) 23/246 (9%)Abnormal 2/26 (8%) 2/22 (9%)Total 29/272 (11%) 25/268 (9%)Solid Tumors Zometa 4 mg Placebo n/N (%) n/N (%)Normal 17/154 (11%) 10/143 (7%)Abnormal 1/11 (9%) 1/20 (5%)Total 18/165 (11%) 11/163 (7%)Prostate Cancer Zometa 4 mg Placebo n/N (%) n/N (%)Normal 12/82 (15%) 8/68 (12%)Abnormal 4/10 (40%) 2/10 (20%)Total 16/92 (17%) 10/78 (13%)*Table includes only patients who were randomized to the trial after a protocol amend-ment that lengthened the infusion duration of Zometa to 15 minutes.

The risk of deterioration in renal function appeared to be related to time on study,whether patients were receiving Zometa (4 mg over 15 minutes), placebo, orpamidronate.In the trials and in postmarketing experience, renal deterioration, progression torenal failure and dialysis have occurred in patients with normal and abnormal base-line renal function, including patients treated with 4 mg infused over a 15-minuteperiod. There have been instances of this occurring after the initial Zometa dose.6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use ofZometa. Because these reports are from a population of uncertain size and are sub-ject to confounding factors, it is not possible to reliably estimate their frequency orestablish a causal relationship to drug exposure.Osteonecrosis of the JawCases of osteonecrosis (primarily involving the jaws) have been reported predomi-nantly in cancer patients treated with intravenous bisphosphonates including Zometa.Many of these patients were also receiving chemotherapy and corticosteroids whichmay be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ incertain cancers, such as advanced breast cancer and multiple myeloma. The major-ity of the reported cases are in cancer patients following invasive dental procedures,such as tooth extraction. It is therefore prudent to avoid invasive dental proceduresas recovery may be prolonged [see Warnings And Precautions (5)].Musculoskeletal PainSevere and occasionally incapacitating bone, joint, and/or muscle pain has beenreported with bisphosphonate use [see Warnings And Precautions (5)].Atypical subtrochanteric and diaphyseal femoral fracturesAtypical subtrochanteric and diaphyseal femoral fractures have been reported withbisphosphonate therapy, including Zometa [see Warnings and Precautions (5.6)].Ocular Adverse EventsCases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammationincluding orbital edema have been reported during postmarketing use. In somecases, symptoms resolved with topical steroids.Hypersensitivity ReactionsThere have been rare reports of allergic reaction with intravenous zoledronic acidincluding angioedema, and bronchoconstriction. Very rare cases of anaphylacticreaction/shock have also been reported.

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Additional adverse reactions reported in postmarketing use include:CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: Increased sweating; Musculoskeletal: musclecramps; Cardiovascular: hypertension, bradycardia, hypotension (associated withsyncope or circulatory collapse primarily in patients with underlying risk factors);Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disordersand Administration Site: weight increase, influenza-like illness (pyrexia, asthenia,fatigue or malaise) persisting for greater than 30 days; Laboratory Abnormalities:hyperkalemia, hypernatremia.

7 DRUG INTERACTIONSIn-vitro studies indicate that zoledronic acid is approximately 22% bound to plasmaproteins. In-vitro studies also indicate that zoledronic acid does not inhibit microso-mal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabo-lized, and is excreted into the urine as the intact drug.7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides,since these agents may have an additive effect to lower serum calcium level for pro-longed periods. This effect has not been reported in Zometa clinical trials.7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loopdiuretics due to an increased risk of hypocalcemia.7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs.7.4 Thalidomide No dose adjustment for Zometa 4 mg is needed when co-administered with thalidomide.In a pharmacokinetic study of 24 patients with multiple myeloma, Zometa 4 mg givenas a 15 minute infusion was administered either alone or with thalidomide (100 mgonce daily on days 1-14 and 200 mg once daily on days 15-28). Co-administrationof thalidomide with Zometa did not significantly change the pharmacokinetics ofzoledronic acid or creatinine clearance.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category D [see Warnings and Precaution (5.9)]There are no adequate and well-controlled studies of Zometa in pregnant women.Zometa may cause fetal harm when administered to a pregnant woman. Bisphospho-nates, such as Zometa, are incorporated into the bone matrix and are gradually releasedover periods of weeks to years. The extent of bisphosphonate incorporation into adultbone, and hence, the amount available for release back into the systemic circulation,is directly related to the total dose and duration of bisphosphonate use. Althoughthere are no data on fetal risk in humans, bisphosphonates do cause fetal harm inanimals, and animal data suggest that uptake of bisphosphonates into fetal bone isgreater than into maternal bone. Therefore, there is a theoretical risk of fetal harm(e.g., skeletal and other abnormalities) if a woman becomes pregnant after completinga course of bisphosphonate therapy. The impact of variables such as time betweencessation of bisphosphonate therapy to conception, the particular bisphosphonateused, and the route of administration (intravenous versus oral) on this risk has notbeen established. If this drug is used during pregnancy or if the patient becomespregnant while taking or after taking this drug, the patient should be apprised of thepotential hazard to the fetus. In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation,the number of stillbirths was increased and survival of neonates was decreased inthe mid- and high-dose groups (≥0.2 times the human systemic exposure followingan intravenous dose of 4 mg, based on an AUC comparison). Adverse maternaleffects were observed in all dose groups (with a systemic exposure of ≥0.07 timesthe human systemic exposure following an intravenous dose of 4 mg, based on anAUC comparison) and included dystocia and periparturient mortality in pregnant ratsallowed to deliver. Maternal mortality may have been related to drug-induced inhibi-tion of skeletal calcium mobilization, resulting in periparturient hypocalcemia. Thisappears to be a bisphosphonate-class effect.In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- andhigh-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, thehuman systemic exposure following an intravenous dose of 4 mg, based on an AUCcomparison). These adverse effects included increases in pre- and postimplantationlosses, decreases in viable fetuses, and fetal skeletal, visceral, and external malfor-mations. Fetal skeletal effects observed in the high-dose group included unossifiedor incompletely ossified bones, thickened, curved or shortened bones, wavy ribs,and shortened jaw. Other adverse fetal effects observed in the high-dose groupincluded reduced lens, rudimentary cerebellum, reduction or absence of liver lobes,reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variationswere also observed in the low-dose group (with systemic exposure of 1.2 times thehuman systemic exposure following an intravenous dose of 4 mg, based on an AUCcomparison). Signs of maternal toxicity were observed in the high-dose group andincluded reduced body weights and food consumption, indicating that maximalexposure levels were achieved in this study.In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg,based on a comparison of relative body surface areas), no adverse fetal effects were

observed. Maternal mortality and abortion occurred in all treatment groups (atdoses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison ofrelative body surface areas). Adverse maternal effects were associated with, andmay have been caused by, drug-induced hypocalcemia.8.3 Nursing Mothers It is not known whether zoledronic acid is excreted in human milk. Because manydrugs are excreted in human milk, and because of the potential for serious adversereactions in nursing infants from Zometa, a decision should be made to discontinuenursing or to discontinue the drug, taking into account the importance of the drug tothe mother. Zoledronic acid binds to bone long term and may be released overweeks to years.8.4 Pediatric Use Zometa is not indicated for use in children.The safety and effectiveness of zoledronic acid was studied in a one-year active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolledpopulation was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55%male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7standard deviations below the mean for age-matched controls (BMD Z-score of -2.7).At one year, increases in BMD were observed in the zoledronic acid treatment group.However, changes in BMD in individual patients with severe osteogenesis imperfectadid not necessarily correlate with the risk for fracture or the incidence or severity ofchronic bone pain. The adverse events observed with Zometa use in children did notraise any new safety findings beyond those previously seen in adults treated forhypercalcemia of malignancy or bone metastases. However, adverse reactions seenmore commonly in pediatric patients included pyrexia (61%), arthralgia (26%),hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia,occurred most frequently within 3 days after the first infusion and became less com-mon with repeat dosing. Because of long-term retention in bone, Zometa shouldonly be used in children if the potential benefit outweighs the potential risk.Plasma zoledronic acid concentration data was obtained from 10 patients with severeosteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last)was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time pro-file of zoledronic acid in pediatric patients represent a multi-exponential decline, asobserved in adult cancer patients at an approximately equivalent mg/kg dose.8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients whowere 65 years of age or older. No significant differences in response rate or adversereactions were seen in geriatric patients receiving Zometa as compared to youngerpatients. Controlled clinical studies of Zometa in the treatment of multiple myelomaand bone metastases of solid tumors in patients over age 65 revealed similar efficacyand safety in older and younger patients. Because decreased renal function occursmore commonly in the elderly, special care should be taken to monitor renal function.

10 OVERDOSAGEClinical experience with acute overdosage of Zometa is limited. Two patients receivedZometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clini-cal or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia,hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serumlevels of calcium, phosphorus, and magnesium should be corrected by intravenousadministration of calcium gluconate, potassium or sodium phosphate, and magne-sium sulfate, respectively.In an open-label study of zoledronic acid 4 mg in breast cancer patients, a femalepatient received a single 48-mg dose of zoledronic acid in error. Two days after theoverdose, the patient experienced a single episode of hyperthermia (38°C), whichresolved after treatment. All other evaluations were normal, and the patient was dis-charged seven days after the overdose.A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on foursuccessive days for a total dose of 16 mg. The patient developed paresthesia andabnormal liver function tests with increased GGT (nearly 100U/L, each valueunknown). The outcome of this case is not known.In controlled clinical trials, administration of Zometa 4 mg as an intravenous infu-sion over 5 minutes has been shown to increase the risk of renal toxicity comparedto the same dose administered as a 15-minute intravenous infusion. In controlledclinical trials, Zometa 8 mg has been shown to be associated with an increased riskof renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intra-venous infusion, and was not associated with added benefit in patients with hyper-calcemia of malignancy [see Dosage And Administration (2.4) in the full prescribinginformation].

16 STORAGEStore at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Con-trolled Room Temperature].

Manufactured byNovartis Pharma Stein AGStein, Switzerland forNovartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936© NovartisT2012-66March 2012

MCCON486.indd 1 5/23/12 8:59 PM

computed tomography (CT), compared to an average 1.8% BMD reduction with placebo (P<0.0001; Lancet Oncol 2012;13:275-284, PMID: 22318095). This was despite the fact that most of the women were taking calcium and vitamin D supplements.

However, in neither the substudy nor the parent study—known as MAP.3 (Mammary Prevention 3) and funded by the National Cancer Institute of Cana-da—were there any significant differ-ences between the two groups’ rates of fragility fractures, total fractures, no less than 10% drop in areal BMD, or reduc-tion in height. Hence, the investigators are not recommending against exemes-tane in any eligible patient populations.

“I have been advising individuals to consider their own risks and benefits when thinking about taking this medica-tion,” lead investigator Angela Cheung, MD, PHD, told Clinical Oncology News. “For some women, their breast cancer risk is high and accepting the poten-tial risks to bone health is worthwhile because not all women experience BMD loss—in our study, 35% did not have any significant bone loss according to the usual BMD test [dual-energy x-ray

absorptiometry or DXA]. For others, this may not be the case.”

Dr. Cheung—the Lillian Love Chair in Women’s Health and director of the Osteoporosis Program at the University of Toronto in Canada—and her colleagues are conducting an extension study to determine whether their observations are due to an initial adjustment of bone to the lower circulating estrogen levels induced by exemestane or whether continued use results in a continual decline in BMD. The study also will examine whether stopping the medication reverses the BMD drop.

MAP.3 was a large trial of exemestane 25 mg per day in the primary prevention of breast cancer (NEJM 2011;364:2381-2391, PMID: 21639806). Exemestane significantly reduced the risk for inva-sive breast cancer but did not increase women’s fracture risk in the trial. (See “Exemestane Reduces Breast Cancer Risk in Postmenopausal Women” in the December 2011 issue of Clinical Oncolo-gy News, page 16.)

However, the study was underpowered to unequivocally determine bone health effects. Instead, Dr. Cheung performed a nested substudy of MAP.3 involving CT measurement of BMD at three cen-ters in Canada and two in the United States. The primary end point was the percent change in total volumetric BMD at the distal radius using high-resolution

peripheral quantitative CT from baseline to two years; 351 women were included in the study and 242 women complet-ed the full, two-year follow-up (exemes-tane, n=124; placebo, n=118).

The investigators found a significant reduction in the exemestane group com-pared with placebo with this end point. They also detected a significantly great-er reduction in mean percent change in cortical thickness at that site and a signif-icantly greater drop in total volumetric BMD at the distal tibia with exemestane versus placebo. They also document-ed significantly greater declines in are-al BMD using DXA at the lumbar spine,

hip and femoral neck.In an accompanying commentary

(Lancet Oncol 2012;13:221-222, PMID: 22318094), Jane A. Cauley, DrPH, a pro-fessor of epidemiology at the Universi-ty of Pittsburgh, noted that most of the BMD loss appears to occur in the corti-cal bone, which “is important because 80% of our bone mass is cortical and 80% of all fractures occur in non-verte-bral sites that are mainly cortical.”

–Rosemary Frei, MSc

Drs. Cheung and Cauley do not have any conflicts of interest to disclose.

Restricting their review to supplements that have been researched in sufficiently powered clinical trials or large observational studies, the authors focused on antioxidants, folate and folic acid, vitamin D and calcium.

Despite early evidence suggest-ing an anticancer benefit from antiox-idants, clinical studies have not borne out that promise, the authors argue. For example, b-carotene does not prevent

recurrence of non-melanoma skin can-cer (N Engl J Med 1990;323:789-795, PMID: 2202901); b-carotene and vita-min A do not protect against lung can-cer (N Engl J Med 1996;334:1150-1155, PMID: 8602180); vitamins C and E do not protect against total cancer inci-dence (JAMA 2009;301:52-62, PMID: 19066368); and a-tocopherol, vitamin C, and b-carotene do not protect against total cancer or cancer mortality (J Natl

Cancer Inst 2009;101:14-23, PMID: 19116389).

However, several trials have shown evidence of an increased cancer risk from antioxidants, the review authors, led by María Elena Martínez, PhD, at the University of California-San Diego, reported. One such study, conducted in a population at high risk for lung cancer, found a 39% increase in lung cancer inci-dence in the b-carotene arm compared with the placebo arm (N Engl J Med 1996;334:1150-1155, PMID: 8602180).

Similarly, the authors did not find evi-dence that folic acid and folate protect against cancer, whereas they did note evidence of increased risk for cancer

from long-term folic acid supplementa-tion. They found insufficient evidence to draw conclusions about vitamin D, and “diverse results” regarding calcium.

Many expert groups have reached a “general consensus” that “nutrition-al supplements have little to no bene-fit in preventing cancer,” the authors wrote. Even so, much of the public con-tinues to use dietary supplements, a fact that the authors attribute in large part to the marketing influence of supple-ment manufacturers. The authors call for “efforts by scientists and govern-ment officials to encourage the pub-lic to make prudent decisions based on sound evidence with respect to the use of dietary supplements for cancer prevention.”

—George Ochoa

Dietary Supplements May Raise Cancer Risk Dietary supplements have little to no effect in preventing cancer and may increase cancer risk, according to a review published in the Journal of the National Cancer Institute (2012;104:732-739, PMID: 22534785).

❖ Exemestane worsens age-related bone loss in postmenopausal women

❖ Although it is unclear whether exemestane-related bone loss translates into an increased risk for fractures, early results indicate that it does not

CHANGEScontinued from page 1

‘I have been advising individuals to consider their

own risks and benefits when thinking about taking

this medication.’ —Angela Cheung, MD, PHD

Article & Review ReprintsReprints of Clinical Oncology News

articles & reviews are available.

Call Julianna Dawson at (212) 957-5300 x271.

Reprints can be ordered in black & white or 4-color.

10 CliniCAl OnCOlOgy nEwS • JunE 2012SOLID TUMORS

Breast

care and standard oncologic care for patients with metastatic NSCLC.

In that study, patients with metastat-ic NSCLC who received both forms of care early on had both improved qual-ity of life and increased survival com-pared with patients who received stan-dard cancer care alone (N Engl J Med 2010;363:733-742, PMID: 20818875).

Although the available evidence is strongest for metastatic lung cancer, ASCO also called for palliative care to be considered early in the course of care for patients with other metastatic can-cers and for those with a high burden of cancer-related symptoms.

“For patients with advanced can-cer, the data are increasingly showing us that palliative care can be incredibly valuable for them and their caregivers from the time patients are diagnosed, not just at the end of life,” said Jamie Von Roenn, MD, co-author of the PCO and a professor of medicine in the Divi-sion of Hematology/Oncology at North-western University in Chicago.

A panel of oncology and palliative experts convened by ASCO developed the report, which was titled “Integra-tion of Palliative Care into Standard Oncology Care.”

The panel, led by Thomas Smith, MD, director of Palliative Care at Johns Hopkins University in Baltimore, ana-lyzed data from seven recently pub-lished randomized clinical trials (RCTs) involving patients with metastatic can-cer. All RCTs involved a standard can-cer care group and a concurrent care group, comprising patients receiving both standard and palliative care.

Overall, the authors found that “sub-stantial evidence demonstrates that pal-liative care—when combined with stan-dard cancer care or as the main focus of care—leads to better patient and care-giver outcomes.”

They identified benefits such as com-parable or improved survival, bet-ter symptom management, reduced depression and improved caregiver and patient quality of life. In some cas-es, patients can receive palliative care as an outpatient service and as an inpa-tient service when needed.

No trials to date have demonstrat-ed harm to patients or caregivers, or an

excessive increase in health care costs, from early involvement in palliative care.

Experts from both oncology and palli-ative care welcomed the statement, say-ing it marks a paradigm shift in pallia-tive care.

“It is wonderful that ASCO is encour-aging oncologists to provide support-ive care in addition to cancer-direct-ed therapy,” said Jennifer S. Temel, MD, an assistant professor of hematol-ogy/oncology at Massachusetts Gener-al Hospital in Boston and author of the original Phase III study.

“The main take-home message is that, as oncologists, we can do better than we are currently doing. Palliative care—and other supportive care servic-es—should be used in conjunction with cancer-directed therapy,” she said.

“This sends a strong message that palliative care is about providing high-quality care for patients living with can-cer and the palliative care team provides an extra layer of support to the patient’s oncologist right from diagnosis,” said R. Sean Morrison, MD, the director

of the Nation-al Palliative Care Research Center and a professor of

geriatrics and medi-cine at Mount Sinai School

of Medicine in New York City.The survival benefit of palliative care

shown in the RCT is similar to the sur-vival advantage associated with plati-num-based chemotherapy for lung can-cer, which has become the gold standard, he noted. “With platinum, you get hair loss, nausea, fatigue. With palliative care, you get a survival benefit and you feel better. So, it should be standard of care just the way platinum appropriate-ly became standard of care.”

Experts caution that the optimal delivery of palliative care to improve patient outcomes is still evolving. More research is needed to look at different

strategies of care delivery, as well as the effect on important patient and caregiv-er outcomes such as quality of life, sur-vival, health care services utilization and costs, they said (Table).

True palliative care is focused on the relief of suffering throughout the course of a patient’s illness, not just at the end, the report authors wrote.

Patients can reap benefits from the ongoing support of palliation services right from the beginning rather than, as often is the case, being enrolled in a hospice three weeks before their death.

“For a long time, patients’ options were seen as being therapy or palliative care but not both,” said F. Amos Bailey, MD, the director of palliative care and an associate professor at the Universi-ty of Alabama at Birmingham and Bir-mingham VA Medical Center. “That’s changing now. Oncologists and pallia-tive care consultants can work together as patients receive therapy. Doing this will allow the medical oncologist to focus more on the oncologic treatment and the palliative care consultant can

be available to assist with patient, fami-ly and symptom management.”

There are significant barriers that keep patients from palliative care ser-vices. One study, presented in 2011 at the ASCO annual meeting, showed that more than half of lung cancer patients do not access supportive care after cancer diagnosis and often cite lack of awareness and lack of physician refer-ral as barriers.

Workforce shortages often are cit-ed as a problem, also. There are not enough oncologists and palliative care physicians for the disease burden in the United States. Clinic- and community-based palliative services are extremely limited and there are not yet enough to meet the anticipated growing demand, said the study authors.

With limited funding available for patients before they formally enter hospice care, reimbursement is a major issue as well. Future priorities include developing aligned health policy and reimbursement mechanisms to facil-itate evidence-based palliative care models, said the report authors.

They noted that PCOs reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision-making and identify questions and settings for further research. PCOs are not contin-ually updated and cannot account for individual variation among patients. It is the responsibility of the treating physician or other health care provider to determine the best course of treat-ment for the patient.

—Christina Frangou

Key Phase III study on which the opinion was baseda

❖ Metastatic NSCLC patients who received early palliative care survived 2.7 months longer than those receiving standard oncology care alone

❖ They also had significantly higher quality-of-life scores and fewer depressive symptoms

a Temel JS, greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-742, PMiD: 20818875.

Table. Research Priorities Identified By ASCO

optimal timing and venue for provision of palliative care (i.e., inpatient vs. outpatient/community)

Evidence-based reimbursement models to support palliative care

Assess which components of palliative care have an impact

Interventions in other diseases besides lung cancer

Evaluate the effect of palliation across the continuum of care, especially during the delivery of antitumor therapy

NSCLCcontinued from page 1

‘For patients with advanced cancer, the data are

increasingly showing us that palliative care can be

incredibly valuable for them and their caregivers

from the time the patients are diagnosed, not just at

the end of life.’ —Jamie Von Roenn, MD

Visit ClinicalOncology.com for the

Cancer News Review With William Nelson, MDFrom the director of the Johns Hopkins Kimmel Cancer Center

Podcast Series

CliniCAl OnCOlOgy nEwS • JunE 2012 11SOLID TUMORS

Lung

QUESTIONS1. True or False. Adopting new ther-apies based on studies that use an end point that effectively lowers the bar for declaring activity in new drugs—for example, progression-free surviv-al (PFS)—may be of little value to can-cer patients.

2. True or False. The case-cohort study by Vincent Koppelmans, MD, and colleagues at Erasmus Medical Center in Rotterdam, The Netherlands, dem-onstrated that survivors of breast can-cer who received adjuvant chemothera-py with CMF (cyclophosphamide, meth-otrexate and fluorouracil), an average of 21 years ago, performed on neuropsy-chological tests comparably to random population controls.

3. True or False. The randomized, double-blind Phase III ZEPHYR tri-al [Zactima Efficacy Trial for NSCLC Patients with History of EGFR-TKI and Chemo-Resistance] of vandetanib (Cap-relsa, AstraZeneca) versus placebo dem-onstrated superiority in terms of overall survival (OS) in patients with advanced non–small cell lung cancer (NSCLC) fol-lowing failure of prior treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and one or two chemotherapy regimens.

4. True or False. Studies by the mul-ticenter European Early Lung Can-cer Detection Group (EUELC) project

indicate that high expres-sion of the three key ele-ments in the vascular endothelial growth factor (VEGF) pathway—VEGF, VEGFR1 and VEGFR2 pro-tein expression—is associat-ed with a good prognosis in patients with stage I squamous cell carcinoma (SCC) but not in patients with adenocarcinoma.

5. True or False. Research on psy-chosocial interventions indicates that when the caregiver and patient dyad is treated as the unit of care, important synergies are achieved that contribute to the well-being of both members.

6. True or False. Research-based psy-chosocial interventions have profound, positive effects on many aspects of life for cancer patients and their caregivers.

7. True or False. The risk for breast cancer death after any surgical approach to ductal carcinoma in situ is extreme-ly low, ranging from between 2.3% and 4.7% at 15 years in the National Surgi-cal Adjuvant Breast and Bowel Project (NSABP) B-17 and B-24 trials of breast-conserving surgery to less than 1% after mastectomy, and is further decreased by administration of adjuvant endocrine therapy with tamoxifen.

8. True or False. The RxPonder (SWOG S1007) trial is enrolling women with positive axillary nodal breast cancer that is estrogen receptor (ER)-positive

but for which the 21-gene Oncotype DX recurrence score is less than 25 to assess the role of adjuvant chemotherapy in this subtype of breast cancer.

9. True or False. Positron emission tomography (PET) scan is not sufficient-ly sensitive to detect positive axillary lymph nodes as demonstrated in a study from Ontario in 325 women with newly diagnosed, operable breast cancers.

10. True or False. The TET (ten-eleven-translocation) oncogene family member 2 (TET2) gene has been iden-tified as mutated in myeloid disorders. The TET2 protein is an enzyme believed to be involved in the conversion of 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine (5hmC) in DNA.

11. True or False. In acute myeloid leukemia (AML), azacitidine (Vida-za, Celgene) following reduced inten-sity conditioning (RIC) and allogene-ic stem cell transplantation (allo-SCT) has potential for augmenting the graft-versus-leukemia (GVL) effect without increasing the risk for graft-versus-host disease (GVHD).

12. True or False. Testing tumor DNA for the somatic BRAF mutation

V600E is recommended in those cas-es where immunohistochemistry (IHC) results indicate the absence of MLH1 protein expression, which correlates with sporadic colorectal cancer (CRC) and is rarely found in patients who have Lynch syndrome.

13. True or False. Thirty percent of patients with low-grade or follicular lymphoma (FL) who responded to ini-tial rituximab (Rituxan, Biogen Idec/Genentech) therapy failed to respond to repeat rituximab therapy, indicating that initially sensitive patients can acquire rituximab resistance.

14. True or False. Ofatumumab (Arzerra, GlaxoSmithKline) monother-apy may have greater clinical activity in patients with FL that is refractory to rituximab.

15. True or False. A large retro-spective analysis performed by the Cen-ter for International Blood and Marrow Transplant Research (CIBMTR) showed that transplantation from match-relat-ed (MRD) and match-unrelated (MUD) donors resulted in similar survival for patients with AML.

Clinical ConundrumsSpotlight on selected articles from the Journal of Clinical Oncology and Blood

“We found a gene that when mutated predisposes to breast cancer, and this adds to the small collection of breast cancer susceptibility genes previously identified,” senior author Melissa C. Southey, PhD, the head of the Genetic Epidemiology Laboratory at the University of Melbourne in Australia, told Clinical Oncology News.

By exome sequencing families with multiple individuals affected by breast cancer, the researchers identified two families with XRCC2 mutations. Subsequently, two further studies were conducted: one, a population-based case-control mutation screening study

of XRCC2 and the other an additional mutation screening of XRCC2 in index cases from multiple-case families and in male breast cancer cases. The researchers identified six distinct, rare variants in the gene that were predicted to severely affect protein function. Two of these variants were protein-truncating mutations and four resulted in missense changes.

Dr. Southey, also a group leader of Australia’s Victorian Breast Cancer Research Consortium, said the study would be relevant to “clinical oncologists who work with families with multiple cases of breast cancer.

This is another gene they can test for.” No commercially available tests have

yet been developed based on these findings; however, Dr. Southey said, “I imagine there will be [tests] soon, to help women determine their personal risk for breast cancer. Some treatment choices might be influenced by knowing if a woman has a mutation in XRCC2.”

In the paper, the researchers noted that specific targeted treatments such as poly-ADP ribose polymerase (PARP) inhibitors might benefit patients whose breast cancer is associated with homologous-recombination DNA repair dysfunction, as is the case with deleterious XRCC2 mutations.

The study is the first report of massively parallel sequencing being used in the discovery of a breast cancer susceptibility gene, said Dr. Southey,

who called this “one of the really exciting things about this paper.” She added, “We anticipate finding more genes related to susceptibility to breast cancer by applying this methodology.”

Massively parallel sequencing has been used previously to identify the genetic explanation for relatively simple autosomal-dominant diseases, Dr. Southey stated. “This is the first report applying it to a complex disease. Now the world’s our oyster.” Dr. Southey is currently using the technique to study genetic predisposition to prostate and colorectal cancers. “A large number of genetic research groups are applying this technology.”

—George Ochoa

Dr. Southey reported no relevant financial disclosures.

New Breast Cancer Susceptibility Gene IdentifiedAn international team of researchers has identified a new breast cancer susceptibility gene, XRCC2 (Am J Hum Genet 2012;90:734-739, PMID: 22464251).

Prepared by

Syed A. Abutalib, MD

Assistant Director Hematology & Stem Cell

Transplantation Program

Cancer Treatment Centers of America

Zion, illinois

for answers see CONUNDRUMS, page 24

12 CliniCAl OnCOlOgy nEwS • JunE 2012PRN

Community Oncology

San Antonio—New results from a Phase II trial reveal that patients with breast cancer who receive T-DM1 (Genentech) have an improved quali-ty of life (QoL) compared with patients who receive the traditional therapy of trastuzumab (Herceptin, Genentech) and docetaxel.

“This novel delivery system improves the tolerability and limits the toxicity experienced by patients,” said Sara Hur-vitz, MD, the director of the Breast Oncol-ogy Program at the University of Califor-nia in Los Angeles, who headed up the study. “I believe this is highly clinically meaningful to patients, especially patients with advanced breast cancer where palli-ation is a key objective of therapy.”

T-DM1 combines the biological HER2-targeted properties of trastuzumab with an anti-microtubule derivative of may-tansine called DM1, a highly potent che-motherapy. T-DM1 selectively deliv-ers DM1 to HER2-positive tumor cells; DM1 is released within the tumor cells and thus spares healthy tissue.

In the study, 137 patients with HER2-positive locally advanced breast cancer or metastatic breast cancer who had not received prior chemotherapy for metastatic disease were randomized to T-DM1 or docetaxel plus trastuzumab. At the 2011 European Multidisciplinary Cancer Congress, researchers report-ed that patients in the T-DM1 arm had a longer median progression-free sur-vival (PFS) than patients in the place-bo arm (14.2 vs. 9.2 months; P=0.0353). At the most recent San Antonio Breast Cancer Symposium, researchers pre-sented data on QoL (poster p1-12-02).

Approximately 30% of patients in the traditional therapy arm stopped one or both drugs because of adverse events compared with 7% of patients in the T-DM1 arm. A total of 132 patients filled out the Functional Assessment of Can-cer Therapy-Breast Trial Outcome Index (FACT-B TOI) at baseline and at least once after baseline. Patients receiving trastuzumab and docetaxel had wors-ening FACT-B TOI scores much earlier than patients receiving T-DM1 (3.5 vs. 7.5 months; hazard ratio, 0.58; P=0.022).

An exploratory analysis showed an average difference of 3.65 in FACT-B TOI scores (P=0.023). This was chiefly driven by improved physical well-being scores (mean difference, 2.28; P=0.002) in the T-DM1 arm, but this was below the five-point change considered clini-cally meaningful.

Five of the seven physical well-being items showed significantly bet-ter scores in the T-DM1 arm. These included lack of energy (P=0.011), trou-ble meeting needs of family (P=0.025), bothered by side effects (P<0.001), feeling ill (P=0.016) and forced to

spend time in bed (P=0.015).According to Robert Carlson, MD, an

oncologist at Stanford Comprehensive Cancer Center in Stanford, Calif., the QoL patient-reported outcomes come as “no surprise” because the drug has not been associated with any nausea, vomiting, alopecia or neutropenia in Phase I/II trials.

“Compared with standard FDA-approved chemo plus trastuzumab in terms of safety, T-DM1 would appear to

be the winner by any measure,” said Dr. Carlson. “The only thing that you may have to be mindful of with T-DM1 is transient and reversible thrombocyto-penia, usually not associated with any clinical bleeding features, and revers-ible transaminase elevation. But apart from those two adverse events, the safety profile appears to be particular-ly clean and superior to standard che-mo and Herceptin.”

Researchers are anxiously awaiting

results from three Phase III trials of T-DM1 currently under way, includ-ing EMILIA (Trastuzumab-MCC-DM1 vs Capecitabine + Lapatinib) that is expected to report data during 2012.

—Kate O’Rourke

Dr. Hurvitz has received research grants from Genentech and Sanofi. Dr. Carlson disclosed serving as an unpaid advisor/

consultant to Genentech/Roche.

T-DM1: Significantly Better Safety Profile for Breast Cancer

HIGHLIGHTS OF ASH & ASCO

September 7–8, 2012Trump International Hotel & TowerChicago, Illinois

Partially supported by Cancer Treatment Centers of America®.

Jointly sponsored by Dannemiller and Athena Education Group.

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Breast

CD26 Expression Is Mesothelioma Therapy Biomarker

Dr. Keisuke Aoe and his co-work-ers reported in Clinical Cancer

Research their expression analysis of dipeptidyl peptidase IV cell sur-face glycoprotein CD26 in MPM. The authors retrospectively stud-ied the biopsies or surgical formalin-fixed, paraffin-embedded specimens of 79 MPM patients using standard

immunohistochemistry techniques. They found that 73.4% of MPM expressed CD26 on the surface, the majority of which were epitheli-oid and biphasic types, whereas the sarcomatoid type was found to lack CD26 surface expression. A higher level of CD26 expression was found to be predictive of better response to

chemotherapy treatment. However, it was not found to be prognostic of sur-vival, despite its low expression in the sarcomatoid type, which is known to be poorly prognostic.

The authors conducted various survival prognostic analyses among patients treated with different che-motherapeutic regimens (peme-trexed vs. non–pemetrexed-based) and had mixed results. Overall, this study highlights the difficulties in con-ducting biomarker analysis, especial-ly in a rare malignancy type such as MPM. Ultimately, validation of poten-tial biomarkers needs to be carried out in prospective studies in properly designed randomized treatment arms. Clear differentiation between wheth-er a biomarker is predictive (of treat-ment response) versus prognostic (of

survival outcome irrespective of treat-ment), or both, needs to be made.

In this study, CD26 is thought to have an important role in T-cell biology and overall immune function, and has mul-tifunctional characteristics, with com-plex biological functions that likely are dependent on tumor type and the stro-mal microenvironment. These intrin-sic complex properties of the molecule might confer more variables and diffi-culties in biomarker analysis. Although it may be of potential as a biomarker of treatment response in MPM, fur-ther studies with larger cohorts, and ideally in prospective trials, would be warranted for establishing its eventual clinical utility.

Dr. Ma reported no financial disclosures relevant to this study.

Cleveland Clinic Taussig Cancer Institute:

Multidisciplinary Care and Breakthrough Research

For the next three months, Clinical Oncology News is pleased to provide commentaries on

important research affecting oncology from experts at Cleveland Clinic’s Taussig Cancer institute.

At Cleveland Clinic Taussig Cancer institute, more than 250 cancer specialists, researchers, nurses and technicians are dedicated to developing and applying the latest and most effective medical techniques to achieve long-term survival and improve the quality of life of more than 10,000 new cancer patients every year. Because of Taussig Cancer institute’s patient-centered approach to care, leading-edge treatments, innovative research, access to clinical trials and state-of-the-art medical technologies, U.S. News & World Report has ranked Cleveland Clinic among the top 10 cancer centers in the nation for two consecutive years.

Taussig Cancer institute’s oncologists work closely with multidisciplinary teams of specialists in digestive disease, urology, neurology and women’s health, among others, to provide patients with innovative diagnostic techniques, the latest chemotherapy or anticancer agents, surgical options, access to clinical trials and novel therapies and genetic counseling.

Taussig Cancer institute’s physicians are nationally and internationally known for their contributions to cancer research and their ability to deliver superior outcomes for their patients. in 2011, 16 Taussig physicians were included in the seventh edition of Castle Connolly’s America’s Top Doctors for Cancer. Taussig staff also authored more than 650 publications in high-impact journals, including results from the pivotal Phase iii AXiS 1032 trial published in The Lancet (2011;378:1931-1939, PMiD: 22056247), whose lead author was Brian Rini, MD, staff physician in the Department of Solid Tumor Oncology. in January, the FDA approved axitinib, the drug under investigation in the AXiS 1032 trial, for the treatment of advanced renal cell carcinoma.

Cleveland Clinic has a rich history in oncology research. Since the Clinic’s inception in 1921, Taussig researchers have been at the forefront of cancer break-throughs. Cleveland Clinic physicians and scientists have developed new surgical techniques, discovered new treatments and uncovered key information about cancer cells that have resulted in significant changes in the way patients are screened, diagnosed and treated.

Providing cancer care close to home is integral to

Taussig Cancer institute’s mission. in addition to providing care to more than 28,000 patients annually on the main campus, treatment is offered at 12 other locations in northeast Ohio and at Cleveland Clinic Florida. Recently, Taussig Cancer institute entered into its first adult medical oncology affiliation with Cadence Health in winfield, ill. Once the oncology program is fully implemented, Cadence Health patients will have access to treatment protocols, clinical trials and additional research opportunities.

The physicians at Cleveland Clinic Taussig Cancer institute are inspired by their patients to challenge today’s status quo and develop new ways to treat cancer—with the ultimate goal of eradicating it in the future.

From Clinical Cancer Research

A recent study has found that the CD26 glycoprotein is a significant

biomarker for predicting chemothera-peutic response for malignant pleural mesothelioma (MPM), a therapy-resis-tant neoplasm that currently lacks any established indicator of therapeutic responsiveness.

MPM is notoriously aggressive, with most patients succumbing with-in 10 to 17 months after noticing their first symptoms. CD26 plays a com-plex role in tumor behavior, which var-ies depending on tumor type and the microenvironment. For some subsets

of T-cell non-Hodgkin’s lymphomas and leukemias, for example, CD26 is an indicator of aggressive disease. CD26 also is a prognostic marker in B-cell chronic lymphocytic leukemia, as well as a therapeutic target, as reported in recent studies with anti-CD26 mono-clonal antibody treatment for lympho-ma and renal cell carcinoma.

Keisuke Aoe and colleagues, based largely in Japan, have studied CD26 extensively and felt earlier findings sug-gested that it may be a clinically signifi-cant biomarker for MPM. In this study, published in Clinical Cancer Research (2012;18:1447-1456, PMID: 22261805), the investigators examined tissue

samples from 79 patients with MPM who had undergone surgery or biopsy.

Analysis found that 73.4% of the patients expressed CD26 on the cell membrane. More specifically, although most epithelioid and biphasic types of MPM expressed CD26 on the cell membrane, the sarcomatoid type of MPM did not show surface expression. A trend was noted of an association between response to chemotherapy and CD26 expression (P=0.053), with great-er degree of overexpression indicating better response to chemotherapy.

CD26 expression was associated with improved survival in patients receiving chemotherapy, and CD26

expression also was associated with a better prognosis in those patients whose chemotherapy did not con-tain pemetrexed (Alimta, Lilly; mean survival time, 14.2 vs. 7.4 months; P=0.0042). The researchers also not-ed through in vitro and microarray studies that those mesothelioma cells that highly expressed CD26 also were highly proliferative.

The researchers found that CD26 expression is “closely linked to cell cycle regulation, apoptosis and chemo-therapy resistance.” They concluded that CD26 overexpression is a biomark-er that can help predict response to chemotherapy in patients with MPM.

EXPERT INSIGHT

Patrick Ma, MD, MSDirector, Aerodigestive Oncology Translational ResearchCleveland Clinic Taussig Cancer InstituteAssistant Professor of Molecular MedicineCleveland Clinic Lerner College of Medicine of Case Western Reserve University

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Lung

Intraoperative Radiotherapy, Yes; External Beam, NoFrom the International Journal of

Radiation Oncology, Biology, Physics

A Japanese institution’s three-decade-long experience with intra-

operative radiation therapy (IORT), administered with or without external beam radiotherapy (EBRT), for pancre-atic cancer has demonstrated excellent local control and few cases of severe late toxicity. Additionally, the overall sur-vival (OS) of patients treated with IORT

with or without EBRT significantly improved over time.

The records of 322 patients treated with IORT with or without EBRT from 1980 to 2009 were reviewed. 192 patients who had neither distant organ metasta-ses nor dissemination at the time of sur-gery were included in the study, led by Keiichi Jingu, MD, of the Tohoku Univer-sity School of Medicine in Sendai, Japan (Int J Radiat Oncol Biol Phys 2012 Mar 21. [Epub ahead of print], PMID: 22445002).

Gross total resection was performed on 83 patients (48 patients, R0; 35 patients, R1), biopsy or palliative resection was undertaken on 109 patients, adjuvant EBRT was performed on 53 patients, and adjuvant chemotherapy was adminis-tered to 124 patients. Disease recurrence occurred in 163 patients, as did local fail-ure in 35 patients. The two-year local con-trol (LC) and OS rates were 71.0% and 16.9%, respectively. OS improved signif-icantly through the decades (two-year

OS: 25.0% for 2000-2009; 18.8% for 1990-1999; and 4.2% for 1980-1989; P<0.001). Analysis showed that the degree of resec-tion and use of adjuvant chemotherapy exerted a significant effect on OS.

There were three cases of severe gas-trointestinal (GI) bleeding and one ileus. The authors noted that the second and third duodenal portions may be given high doses of irradiation in patients with unresectable pancreas head cancer.

EBRT did not correlate with any improvements in LC or OS; IORT, on the other hand, has allowed for excel-lent LC and improvements in OS.

Kevin Stephans, MDAssociate Staff Physician, Department of Radiation OncologyCleveland Clinic Taussig Cancer InstituteAssociate Professor of Medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

EBRT for pancreatic cancer has been challenging due to the prox-

imity of sensitive dose-limiting nor-mal tissue, such as the stomach and small bowel. This has limited the deliverable radiation dose and led to both acute and late treatment-related toxicity. IORT is a logical alterna-tive due to the ability to displace the sensitive tissue prior to radiation. IORT at present, however, remains unproven, with inconsistent and lim-ited supporting level 1 evidence.

Jingu et al’s series is a valuable addi-tion. The 71% rate of two-year LC with IORT is an improvement on historical standards where approximately half of unirradiated patients typically expe-rience local failure as part of recur-rence. Interestingly, adding EBRT did not appear to confer additional LC or affect OS. This raises an interesting question of whether IORT might effec-tively substitute for EBRT, thus simpli-fying the overall treatment course.

There was a 2.1% rate of grade 4 or 5 late GI toxicity, notably occuring in patients treated without supplemen-tal external beam. Further investiga-tion would be insightful, as toxicity occurred in four patients at doses of 20 to 25 Gy, typically considered safe for intraoperative treatment. The potential effect of recurrent tumor, other cancer-directed therapies and volume of sensitive tissue radiated should be considered.

Dr. Stephans reported no financial disclosures relevant to this study.

EXPERT INSIGHT

Clinical Oncology Newswants to publish you!

As part of the Clinical Oncology Newsinaugural writer’s contest, from now

until July 30 the magazine will be

accepting essays on the topic

‘Change in Medical Oncology or Hematology/Oncology’.

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Nationalliteraryexposure!

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Essays can relate to the topic in any way the author sees fit — how medicine has changed for the worse, how it should be changed for the better, or simply a

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maximum of 3,500 words.

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second place $500 and third place $250. All will receive recognition and prominent

placement in Clinical Oncology News.

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managing editor Gabriel Miller at [email protected].


Pancreatic

Bortezomib Regimen Improves Primary Amyloidosis Survival

AL amyloidosis treatment regi-mens that include bortezomib

are able to produce rapid and poten-tially deep hematologic responses.1 Hematologic VGPR or better is a reli-able surrogate end point for predicting improved OS in patients with AL amy-loidosis.2 The present study by Venner provides more evidence that three-drug combinations, including an alkyl-ating agent, a proteasome inhibitor and a corticosteroid, yield high rates of hematologic response. Complete hematologic response in untreated patients was 65%, which was similar to the 60% reported in another CVD

study by Mikhael.3 Among all patients treated in the Venner study, 51% expe-rienced a hematologic VGPR. The time to maximal response was 4.1 months. Neurologic toxicity occurred in 30% of the patients, although the grade of neuropathy was not reported. It was reported that 14% of patients discon-tinued therapy due to the development of neuropathy.

There are several challenges in inter-preting results from AL amyloidosis tri-als. Sample sizes often are small in pro-spective trials, including novel agents such as bortezomib. Phase II trials have used a variety of bortezomib dosing schedules, complicating toxicity assess-ment. Furthermore, there is a lack of prospective randomized trials compar-ing bortezomib-based therapy to alkylat-ing agent–based therapy and comparing three-drug regimens to two-drug regi-mens. Additionally, the use of high-dose chemotherapy and autologous peripher-al blood progenitor cell rescue is beyond the scope of this discussion.

As stated in the Venner article, further study with novel agent combination

therapy in AL amyloidosis is needed. It would be ideal to identify the optimal dosing schedule and route of adminis-tration of bortezomib in patients with AL amyloidosis. Weekly and subcu-taneous administration of bortezo-mib minimizes neurologic side effects but subcutaneous administration may be complicated by profound periph-eral edema in amyloid patients. Larg-er trials investigating the role of nov-el agents before and/or after high-dose chemotherapy and autologous periph-eral blood progenitor cell rescue also are warranted in eligible patients with AL amyloidosis.4

The obvious question is whether or not the results and limited toxicity of bortezomib-containing three-drug reg-imens establish a new “standard” treat-ment for AL amyloidosis. An ongoing Eastern Cooperative Oncology Group trial comparing melphalan and dexa-methasone with or without bortezo-mib will help answer this question in untreated patients with AL amyloido-sis. In the absence of trial participation, the three-drug regimen of bortezomib,

cyclophosphamide and dexamethasone is acceptable treatment for AL amy-loidosis, with rapid and high rates of hematologic response documented in the Venner study.

References1. Reece D, Sanchorawala V, Hegenbart U,

et al. Weekly and twice-weekly bortezo-mib in patients with systemic AL amyloi-dosis: results of a phase 1/2 study. Blood. 2009;114:1489-1497, PMID: 19498019.

2. Palladini G, Dispenzieri A, Gertz M, et al. Validation of the criteria of response to treatment in AL amyloidosis. Blood. 2010;116:1364a.

3. Mikhael J, Schuster S, Jimenez-Zepeda V, et al. Cyclophosphamide-bortezomib-dexamethasone (CYBORD) produces rap-id and complete hematological response in patients with AL amyloidosis. Blood. doi: 10.1182/blood-2011-11-390930. Feb 13, 2012 [Epub ahead of print].

4. Landau H, Hassoun H, Bello C, et al. Consolidation with bortezomib and dexa-methasone following risk-adapted melphalan and stem cell transplant in systemic AL amyloidosis. Amyloid. 2011;18(suppl 1):130-131, PMID: 21838462.

Dr. Valent reported no financial disclosures relevant to this study.

From Blood

A three-drug regimen of cyclophos-phamide, bortezomib (Velcade,

Millennium) and dexamethasone (CVD) as initial therapy or upon relapse for amyloid light-chain (AL; primary) amyloidosis has proved effective in improving both two-year progression-free survival (PFS) and overall survival (OS).

Bortezomib previously was found to be effective in treating AL amyloi-dosis, with and without dexametha-sone, as well as myeloma. The Lon-don-based researchers, headed by Christopher P. Venner, noted excel-lent results in myeloma trials in which

a steroid/alkylator was used in combi-nation with bortezomib. They decided to attempt a similar strategy against AL amyloidosis, using CVD for initial ther-apy and upon relapse. The study was published in Blood (2012;119:4387-4390, PMID: 22331187).

This retrospective series included 43 patients from the National Amyloido-sis Centre of London. Median age was 54 years; 58% were male. The organs involved were cardiac, 74%; renal, 79%; liver, 23%; and other, 35%; 18% reported peripheral neuropathy and 21% report-ed autonomic neuropathy. Mayo Clinic staging was available for most patients, of whom 43% were stage III.

The CVD regimen was bortezomib, 1 mg/m2 IV, days 1, 4, 8 and 11 (increasing

to 1.3 mg/m2 if tolerated); oral cyclo-phosphamide, 350 mg/m2, days 1, 8 and 15; and oral dexamethasone, 20 mg, days 1, 4, 8 and 11 (increasing to 20 mg every two days if tolerated). The researchers aimed for a maximum of eight cycles. The maximal hematolog-ic response was defined as the low-est attained involved light-chain val-ue. A reduction in the difference in free light-chain (dFLC) value of 50% to 90% was considered a partial response and a reduction of more than 90% defined a very good partial response (VGPR).

The overall hematologic response rate was 81.4%, of which 41.9% achieved a complete response (CR) and 51.4% achieved a VGPR. Patients who received CVD therapy initially

had a CR rate of 65% and VGPR rate of 66.7%. Two-year PFS was 66.5% in initial patients and 41.4% in relapsed patients. Two-year OS was 97.7%, and was 94.4% for those with Mayo stage III disease.

The authors concluded that CVD was highly effective for AL amyloidosis, and the hematologic responses appeared “durable,” especially in those patients achieving CR or VGPR. Because CVD spares stem cells, the improvement in organ function may possibly allow later stem cell transplant in patients previously deemed ineligible. “The regime is tolerated by stage III patients with possible improvement in out-comes in this poor-risk group,” the investigators wrote.

Jason N. Valent, MDAssociate Staff Physician, Department of Regional OncologyCleveland Clinic Taussig Cancer Institute

EXPERT INSIGHT

Having trouble keeping up with all of the oncology and medical journals that cross your desk?

on a monthly basis, Clinical Oncology News highlights key studies

from the journals and provides guest clinician perspectives to help

you stay up to date.

We hope you find this a useful tool.

16 CliniCAl OnCOlOgy nEwS • JunE 2012HEMATOLOGIC DISEASE

Myeloma

problem is and how many cancer drugs may be of concern.”

Dr. Witteles and other U.S. physi-cians are calling for significant changes in how cardiac adverse events (AEs) are reported in clinical trials involving new-er chemotherapeutic agents. They have found significant evidence of underre-porting of the possible cardiac damage from cancer drugs. They claim the prob-lem is now placing a significant number of oncology patients at an increased risk for heart failure.

In a commentary published online on March 26 in the Journal of Clinical Oncology (doi: 10.1200/JCO.2011.40.4012), Dr. Witteles wrote that urgent reforms are needed to standardize measurements of the potential toxicity of cancer drugs dur-ing clinical trials in order to prevent the publication of misleading results, which have already appeared in such prestigious scientific journals as The Lancet and The New England Journal of Medicine. “It’s a major issue when adverse events aren’t being counted in clinical trials, and this has led to a profound underapprecia-tion of the risk for heart failure and other adverse cardiac events,” said Dr. Witteles.

Dr. Witteles, who is a cardiologist at Stanford Hospital & Clinics, and co-author Melinda Telli, MD, assistant

professor of oncology at Stanford, became concerned when they started seeing a surprising number of patients with heart failure who were being treated with sunitinib (Sutent, Pfiz-er). “That’s what first raised our eye-brows,” said Dr. Witteles.

Over the past five years, the FDA approved sunitinib for the treatment of renal cell carcinoma (RCC) and certain types of pancreatic and gastrointestinal

cancers. What the two authors found was a complete disconnect between reported incidences of cardiac toxicities in journal articles on one hand and the FDA’s drug labeling on the other. The labeling raised red flags, indicating that clinicians should be aware of the pos-sible side effects of cardiac damage in patients using the drug. This was a very different picture from what had been presented in the journal articles. “It didn’t make any sense,” said Dr. Wittel-es. “The labeling warned of a high inci-dence of heart failure during the clini-cal trials that was not even mentioned

in the journal articles.”The authors said sunitinib is a good

example of how the current method of measuring cardiac side effects dur-ing cancer drug trials is inadequate. Although the commentary focuses sole-ly on sunitinib, the authors believe that studies of other cancer drugs have sim-ilar methodologic problems and are prone to the same underreporting of side effects.

“Sunitinib is just the clearest exam-ple, but the same problems can be and undoubtedly are present in other

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Clinical Trials

trials. Some may not be as obvious,” said Dr. Witteles in an interview with Clinical Oncology News. “We saw way too many patients developing heart fail-ure and we started questioning what was going on. The irony is that the data were there from the beginning, but it was just misrepresented.”

For example, in October 2006, the results of the first Phase III study of suni-tinib published in The Lancet stated that there was no evidence of a decrease in left ventricular ejection fraction (LVEF) measurements (Lancet 2006;368:1329-1338, PMID: 17046465). Yet, the FDA’s 2007 labeling of sunitinib for use in RCC treatment, which was based on the same data set from the same trial, stated that 11% of trial subjects on sunitinib and 3% on placebo developed EF measurements below the lower limit of normal.

The underreporting is very worri-some because many clinicians read jour-nal articles on new drugs but few read a drug’s labeling, according to Dr. Wittel-es. The three sunitinib studies referred to in the article—two in The New England Journal of Medicine (2007;356:115-124, 2011;364:501-513) and one in The Lan-cet—were all funded by Pfizer, which rais-es the potential of conflict of interest.

It is clear that these inconsistencies in reporting are partly due to an inadequate method of measuring AEs in clinical tri-als. The current system allows for too much variability in how individual inves-tigators at different sites can grade pos-sible AEs. For instance, there are incon-sistencies in defining what an AE is and whether an AE may be ignored if there are questions as to whether the event was caused by the drug treatment. Addi-tionally, there currently is no requirement that the results from primary data sets—such as an imaging finding or a laboratory test—be reported at all. The system places more reliance on the judgments made by the individual site investigator.

“Some subjective findings, such as the description of a rash or the qualitative assessment of a symptom such as short-ness of breath, are necessarily reliant on the site investigator’s judgment. Howev-er, in the case of objective findings, such as laboratory findings like decreased platelets or imaging findings like drops in LVEF, it is far more relevant to focus on the actual validated data, which is not dependent on the idiosyncrasies of a site investigator remembering to list and properly categorize the event as an AE,” said Dr. Witteles.

The figures reported by the FDA on sunitinib’s drug label were based on the real decreases in cardiac function as reflected by the primary data, which enabled the agency to come closer to determining the actual number of cardiac

AEs, according to Dr. Witteles. He and Dr. Telli suggest that whenever there has been a signal of heart toxicity in a drug trial, routine cardiac monitoring should be built into the trial. This is one of sever-al recommendations they make to assure reliable, accurate and consistent report-ing of cardiac safety in cancer trials (see recommendations sidebar).

“It is a problem with the way toxicity is reported. The way it is graded and list-ed can vary significantly depending on what the investigator wants to do. The problem is with the reporting system and it has to be much more rigorous, and the objective information should always trump the subjective information,” said Dr. Telli in an interview with Clinical Oncology News. “One doctor may call something one thing and another doctor may call it something else.”

Problems Go Beyond One DrugCurrent anticancer therapies com-

monly have unintended cardiotoxic con-sequences. Newer chemotherapeutic agents are being developed and some may have significant potential for cardio-toxicity, according to Ronald Krone, MD, a cardiologist at Washington University School of Medicine in St. Louis. He claims that current cancer therapies may cause overt damage to the heart and circulation. Additionally, they may alternately exacer-bate or mask existing heart disease.

“We have known for a long time that the breast cancer drugs can cause serious heart problems,” Dr. Krone told Clinical Oncology News. “Tyrosine kinase inhib-itors could be involved in the heart. We may need to start monitoring patients on these medications for cardiac effects or start a registry. There may be a very seri-ous problem. We need to know the actu-al incidence.”

Greg Hundley, MD, a professor of car-diology at Wake Forest Baptist Medical Center in Winston-Salem, N.C., agrees with Dr. Krone. He is currently conduct-ing magnetic resonance imaging (MRI) studies to see if it is possible to predict which patients will suffer heart damage as a result of chemotherapeutic agents.

“Now, the game has changed. The oncologists have become very effective at treating cancer and so we need to start thinking about cardiac issues. We need to make sure that we don’t trade the adverse impact of cancer for another disease, the largest killer in the world, heart disease,” said Dr. Hundley.

He said in breast cancer there is now improved survival and a growing number of clinicians are seeing patients who are eight to 10 years out from treatment and they are having cardiac events. “They are turning up through billing databases and

Table. Potential Cardiovascular Events Associated With Common Chemotherapies

Chemotherapy Potential Cardiovascular Adverse Events

Anthracyclines and anthraquinolones

Acute myocarditis, arrhythmia, CHF, LVD

Bevacizumab GI tract bleeding, hypertension, thromboembolism

Capecitabine, 5-fluorouracil, cytarabine

CHF, cardiogenic shock, ischemia, pericarditis

Cyclophosphamide Mitral regurgitation, neurohumoral activation

CoX-2–specific inhibitors Thromboembolism

Imatinib Arrhythmias, angioedema, CHF, LVD

Paclitaxel, vinca alkaloids Atrioventricular block, CHF, sinus bradycardia, hypotension, ischemia, ventricular tachycardia

SERMs LDL/HDL modulation, thromboembolism

Sorafenib Arrhythmias, hypertension

Sunitinib Arrhythmias, hypertension

Thorax irradiation LVD, myocardial fibrosis, valvular heart disease

Trastuzumab Arrhythmias, angioedema, CHF, LVD

CHF, congestive heart failure; COX, cyclooxygenase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVD, left ventricular dysfunction; SERMs, selective estrogen receptor modulators


‘We need to make sure that we don’t trade the

adverse impact of cancer for another disease, the

largest killer in the world, heart disease.’

—Greg Hundley, MD

‘The labeling warned of a high incidence of heart

failure during the clinical trials that was not even

mentioned in the journal articles.’

—Ronald Witteles, MD


Clinical Trials

Monitor Thyroid During Sunitinib, Sorafenib Therapy

It is well described that patients receiving inhibitors of the vascular

endothelial growth factor receptor, prominently including sunitinib and

sorafenib, can experience abnormali-ties of thyroid function.1,2 This appears most commonly to be hypothyroid-ism, and has been reported to be more common with sunitinib. The mech-anism of this particular toxicity is as yet undefined. Furthermore, whether this toxicity may serve as a predictive biomarker of response to these agents is debated.3

The current report by Feldt et al adds to existing data by reporting from a large German claims database on the receipt of thyroid replacement thera-py in patients treated with one of these agents. The true incidence of thyroid

abnormalities from these medications is likely higher, accounting for abnor-malities that did not require hormone replacement. Nonetheless, baseline and routine monitoring of thyroid function is indicated (e.g., every two cycles), with clinical judgment prevailing as to when hormone replacement is indicated. Such vigilance to this potential toxicity may help alleviate the fatigue associat-ed with these agents, and occurrence of thyroid abnormalities do not appear to adversely affect clinical outcome.

References1. Rini BI, Tamaskar I, Shaheen P, et al.

Hypothyroidism in patients with meta-static renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2007;99:81-83, PMID: 17202116.

2. Tamaskar I, Bukowski R, Elson P, et al. Thyroid function test abnormalities in patients with metastatic renal cell carci-noma treated with sorafenib. Ann Oncol. 2008;19:265-268, PMID: 17962201.

3. Rini B. Kidney cancer: Does hypothyroid-ism predict clinical outcome? Nat Rev Urol. 2011;8:10-11, PMID: 21116300.

Dr. Rini disclosed that he receives consulting and research funding from

Pfizer, which makes sunitinib.

it is making us ask questions now about whether we should start doing surveil-lance for cardiac markers,” said Dr. Hund-ley in an interview. “Should we start try-ing to detect subclinical cardiac disease? The answer appears to be yes.”

He noted that some medical cen-ters are now starting to monitor oncol-ogy patients for subclinical cardiac dis-ease. Inexpensive generic therapies can cut cardiovascular risk in high-risk pop-ulations and Dr. Hundley’s team is now investigating how MRI imaging may be used to identify those who have damaged heart function and blood vessels follow-ing cancer therapy.

“We don’t know yet if this needs to be done in patients with renal cell car-cinoma on sunitinib. If you are going to make a clinical recommendation, we need a lot more information,” said Dr. Hundley. “We are starting to real-ize that there is another frontier and it is called cardio-oncology. We need to merge the expertise of oncologists with the expertise of cardiologists. They need to be working together to

see which agents cause problems.”He said that oncologists have tradi-

tionally collaborated closely with sur-geons. However, that has not been the case with cardiologists. Histori-cally, they don’t interact and collabo-rate a great deal during chemotherapy and radiation and surgical treatments. “Maybe a little bit, but they are not two groups that have gotten together like oncologists and surgeons,” said Dr. Hundley. “We need to blend the two.”

The Clinical Effect

Dr. Witteles said that clinicians and cancer patients are being harmed under the current system and there is a need for significant change.

“I would emphasize here that this underreporting in journal articles has

very real consequences,” said Dr. Wit-teles. “These are exceptionally useful drugs, but clinicians need to know the full array of possible cardiac side effects so that they can monitor cardiac function appropriately and consider starting car-diac medications or holding the antican-cer therapy altogether when necessary.”

He said that frequently the appropri-ate cardiac treatments may not get start-ed because patients are not being moni-tored for cardiac function. “There is no standard for monitoring for cardiac func-tion for sunitinib and that’s because it was never known that it was needed. No one knew it was a concern,” said Dr. Witteles.

However, Paul Pretruska, MD, a profes-sor of medicine in the Division of Hema-tology/Oncology at Saint Louis Univer-sity School of Medicine, in Missouri,

disagrees. He contends that this issue is being far overblown. “Yes, there is some heart failure and yes, it has been known for some time,” said Dr. Pretruska.

He believes there is not enough data to warrant registry development or rou-tine cardiac monitoring during clini-cal trials with newer chemotherapeu-tic agents. “I think this is blowing this up quite a bit,” said Dr. Pretruska in an interview. “If the problem is that

From European Journal of Cancer

A large German cohort study has better defined the incidence of

hypothyroidism as a serious adverse drug reaction in patients with advanced or metastatic renal cell car-cinoma taking either sunitinib (Sutent, Pfizer) or sorafenib (Nexavar, Bayer and Onyx). For both of these drugs, the potential for hypothyroidism appears higher than current labeling suggests, and routine monitoring of thyroid functioning is suggested.

The study, whose lead author was San-dra Feldt, PhD, appeared in the Europe-an Journal of Cancer (2012;doi:10.1016/j.ejca.2012.01.036). The authors note that both sunitinib and sorafenib are

multikinase inhibitors (MKIs) and rep-resent significant advances in the treat-ment of renal cell carcinoma. Sunitinib has become the standard therapy for patients receiving first-line treatment of metastatic renal cell carcinoma; like-wise, sorafenib is the standard thera-py for second-line treatment in these patients. These agents also have been approved for gastrointestinal stromal tumors and hepatocellular carcinoma.

Hypothyroidism can occur early or late during treatment with MKIs. The rates of hypothyroidism requir-ing therapeutic intervention with a thyroid hormone (TH), usually levo-thyroxine, have ranged from 14% to 46% in sunitinib studies and 3% to 6% in sorafenib studies, but the num-ber of patients in these trials has been

limited and the methodologic dif-ferences have been substantial. The researchers aimed to obtain a more reliable understanding of hypothy-roidism in these patients by accessing a larger representative database.

The authors reviewed claims data filed at pharmacies that covered more than 80% of all German prescriptions. Patients who were identified by fill-ing a new prescription for either suni-tinib or sorafenib between June 2006 and December 2007 were followed. If these patients went on to fill a prescrip-tion for TH therapy, then that was con-sidered an event of interest. The study found that 178 of 1,295 patients admin-istered sunitinib (13.7%) and 77 of 1,214 patients taking sorafenib (6.3%) received TH therapy. The incidence

rates were 24.2 and 12.1 per 100 person-years, respectively, and the unadjusted hazard ratio for TH therapy for suni-tinib compared with sorafenib was 2.0 (95% confidence interval, 1.5-2.6).

The authors concluded that clini-cians should obtain baseline and treat-ment measurements of thyroid func-tion for those taking both sunitinib and sorafenib. They cautioned, howev-er, that TH therapy should not be pre-scribed for cancer patients with only slightly increased serum thyroid-stim-ulating hormone (TSH) levels who are asymptomatic to hypothyroidism because TH therapy “leads to fast and complete correction of increased TSH values and should not restrict the use of sunitinib and sorafenib in malignant diseases.”

❖ Cardiac adverse events are underreported in anticancer drug trials

❖ Longer cancer survival may be leading to an increased incidence of late cardiac events

❖ Newer chemotherapeutic agents may have potentially significant cardiotoxic effects

Brian I. Rini, MDStaff Physician, Department of Solid Tumor OncologyCleveland Clinic Taussig Cancer Institute

EXPERT INSIGHT


‘I would emphasize … that this underreporting in

journal articles has very real consequences.’

—Ronald Witteles, MD


Renal

Extended Imatinib Rx Improves Survival in GIST

In 2001, Joensuu and colleagues reported a dramatic response to ima-

tinib mesylate in a 50-year-old woman with advanced GIST.1 The efficacy of this agent was substantiated in Phase III trials,2 leading to an adjuvant study.3 This study, performed in patients with GISTs 3 cm or more in size, showed that imatinib produced a superior disease-free survival (DFS) at one year com-pared with placebo. Although follow-up

is ongoing, examination of the DFS curves from this study suggested that relapses occurred after imatinib was discontinued, leading many physicians to hypothesize that a longer duration of treatment would be superior.

The current report by Joensuu et al tests this hypothesis in a group of patients felt to be at high risk for recur-rence, defined as patients with tumors larger than 10 cm in size; a mitotic count

greater than 10 mitoses per high-pow-er field; a tumor diameter greater than 5 cm and a mitotic count greater than 5; or having tumor rupture before or dur-ing surgery. Four hundred patients were randomized to receive imatinib mesylate 400 mg per day for one or three years. Three years of therapy proved to be sig-nificantly better than one year of treat-ment (five-year relapse-free survival of 65.6% vs. 47.9%). Moreover, a significant survival advantage for patients treat-ed for three years was noted (92% at five years vs. 81.7%). The current study clearly indicates that at least three years of adjuvant imatinib should be recom-mended for patients with resected high-risk GISTs.

Like all good studies, however, this report raises more questions than it answers. Can these results be applied to lower-risk tumors? Should adjuvant ther-apy be continued for longer than three

years? While we await data that address these issues, physicians must make choic-es with their patients based on improved prognostic tools and extrapolation from currently available information.

References1. Joensuu H, Roberts PJ, Sarlomo-Rikala M,

et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gas-trointestinal stromal tumor. N Engl J Med. 2001;344:1052-1056, PMID: 11287975.

2. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesyl-ate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472-480, PMID: 12181401.

3. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointes-tinal stromal tumour: a randomised, dou-ble-blind, placebo-controlled trial. Lancet. 2009;373:1097-1104, PMID: 19303137.

Dr. Budd reported no financial disclosures relevant to this study.

serious, then I would stop the drug.”Dr. Pretruska contends the informa-

tion is available and the company sends it all to the FDA. Furthermore, he said it is important to note how the FDA addressed this issue. “It did not give it the black box warning. I am not real-ly sure there is a disconnect. People are aware of it, and the doctors know. I have known about this from day 1,” added Dr. Pretruska.

Right now, the potential collateral dam-age to the heart by many of the newer che-motherapeutic agents is still unknown. However, the acquisition of cardi-ac outcomes data from trials involving

newer chemotherapeutic agents is vital for developing specific evidence-based practice guidelines, according to Dr. Kro-ne. He said more thorough research may be optimal for keeping the heart from interfering with the war on cancer. Addi-tionally, more open reporting also may be beneficial.

“It is a blossoming area of interest. The oncologists have created a whole new realm of hope for patients. Cancer is becoming a chronic disease like diabe-tes. Today, patients are living a lot longer and so the landscape has changed,” said Dr. Hundley.

—John Schieszer

From JAMA

In patients at high risk for recur-rence of gastrointestinal stromal

tumor (GIST), the administration of 36 months of adjuvant imatinib ther-apy improved recurrence-free sur-vival (RFS) and overall survival (OS) compared with 12 months of adminis-tration, the current standard, accord-ing to a new study published in JAMA (2012;307:1265-1272, PMID: 22453568).

Most GISTs have been found to include an activating mutation in the KIT oncogene, which is essential for tumor pathogenesis, as is a muta-tion in platelet-derived growth fac-tor receptor-a (PDGFRA), found in

5% to 10% of GISTs. The risk for GIST recurrence is stratified based on these and other factors. Imatinib mesylate often is successful initially in patients with advanced GIST because it inhib-its both KIT and PDGFRA, although typically the disease eventually pro-gresses. The administration of adju-vant imatinib for 12 months following surgical resection of a KIT-immu-nopositive GIST lengthens RFS; how-ever, recurrence of GIST after imatinib discontinuation is common. Thus, the question has been raised whether the administration period of 12 months might be extended.

This randomized, open-label, Phase III study sought to increase the treat-ment period to 36 months in patients whose risk for GIST recurrence was

estimated to be high. Twenty-four hos-pitals in Finland, Germany, Norway and Sweden participated in this rela-tively large study, which was headed by Heikki Joensuu, MD. Patients with KIT-positive GISTs were given oral imatinib, 400 mg per day, for either 12 or 36 months. The primary end point was RFS, and secondary end points were OS and treatment safety.

Each treatment group consisted of 200 patients. Median follow-up was 54 months. The 36-month cohort had a longer period of RFS than those in the 12-month cohort, with a five-year RFS of 65.6% versus 47.9%, respec-tively. The authors noted that the five-year RFS in the 36-month group is favorable to the reported five-year RFS of 45% in high-risk GIST patients

treated with surgery alone. The haz-ard ratio (HR) was 0.46 (95% con-fidence interval [CI], 0.32-0.65; P<0.001). The 36-month group also experienced longer OS (HR, 0.45; 95% CI, 0.22-0.89; P=0.02; five-year sur-vival, 92% vs. 81.7%). However, dis-continuation rates for reasons other than GIST recurrence were higher in the 36-month group (25.8%) than the 12-month group (12.6%). The research-ers reported relatively mild adverse events (AEs), however, and noted that although imatinib may have cardiac toxicity, few such AEs were recorded.

The authors added, “Because GIST recurrence is frequent after discon-tinuation of adjuvant imatinib, studies that evaluate still longer treatments are warranted.”

G. Thomas Budd, MDStaff Physician, Department of Solid Tumor OncologyCleveland Clinic Taussig Cancer InstituteProfessor of Medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

EXPERT INSIGHT


Recommendations for Accurately Reporting Cardiac Adverse Events• Urgent reform of Common Terminology Criteria for Adverse Events is

needed to ensure consistent grading of cardiac adverse events (AEs). At a minimum, this necessitates consolidation of the three terms that can currently be used to grade a left ventricular ejection fraction (LVEF) drop into a single consistent term.

• objective measures (e.g., laboratory and imaging findings) should be reported when data is available.

• In controlled trials, differences in AE rates should be considered more relevant than differences in treatment-related AE rates.

• Routine LVEF monitoring should be mandatory in clinical trials of any new therapeutics considered to carry risk for cardiac toxicity based on mecha-nism of action or when a previous cardiac toxicity signal has been present.

• Cardiac events should be adjudicated by a safety committee with access to all primary data (e.g., LVEF measurements) when a potential safety sig-nal is present.

Adapted from witteles RM, Telli M. underestimating cardiac toxicity in cancer trials: lessons learned? J Clin Oncol. 2012 Mar 26. [Epub ahead of print], PMiD: 22454419.


GIST

Higher Cumulative Dosing of Gemtuzumab Ozogamicin Key in AML

The prognosis for adult AML remains poor, and novel treatment

strategies are needed. CD33 is highly expressed on the surface of the major-ity of AMLs. Gemtuzumab ozogamicin is a humanized anti-CD33 monoclo-nal antibody linked to calicheamicin. After internalization and intracellular release, this chemotherapeutic agent is targeted to CD33-expressing cells. In this paper, Castaigne et al examine the addition of fractionated gemtuzumab ozogamicin during induction and post-remission therapy to adult patients aged 50 to 70 years with de novo AML.

This is a large randomized study with well-matched patient charac-teristics between the two arms. Addi-tional molecular studies (FLT3, NPM and CEBP) are well described. There is a statistically significant improve-ment in EFS, OS and RFS, by the addi-tion of gemtuzumab ozogamicin; and the percentages are striking (40.8% vs. 17.1% EFS at two years), despite the inclusion of 20% of patients with

unfavorable cytogenetics. One con-cern with this trial is the dose of dau-norubicin (60 mg/m2), particularly in the control arm. Although no trial has examined the superiority of 90 versus 60 mg/m2 of daunorubicin, two trials have demonstrated a survival benefit

to 90 mg/m2 over 45 mg/m2 in AML patients up to 65 years of age.1,2 Howev-er, the overall survival of patients aged 60 to 65 years in the “high-dose” dau-norubicin group of Löwenberg’s tri-al is 38%, similar to the control arm in this trial, making this less of a concern. Castaigne’s trial may also have some-what limited applicability to the larg-er group of AML patients in this age range because it excluded secondary AML (which is more common in this age range), and because 80% to 90% of patients had an Eastern Coopera-tive Oncology Group performance sta-tus of 0-1. This latter point is relevant because the addition of gemtuzum-ab ozogamicin did lead to increased toxicity: persistent thrombocytope-nia, prolonged neutropenia and a few cases of veno-occlusive disease, and

may have led to a higher mortality in a “sicker” group of patients.

Overall, however, Castaigne’s paper is encouraging in that it demon-strates statistically significant EFS and OS advantages to adding gemtu-zumab ozogamicin in adult patients

aged 50 to 70 years of age, where the overall prognosis is poor. Two previ-ous trials have examined the addition of gemtuzumab ozogamicin to stan-dard chemotherapy. The U.K. Medical Research Council trial only demon-strated a survival advantage in patients with favorable cytogenetics, predomi-nantly younger than age 60 years.3 The Southwest Oncology Group trial S0106 demonstrated no improvement in out-comes.4 The major difference between these trials and Castaigne’s is the frac-tionated use of gemtuzumab ozogami-cin, with more frequent dosing dur-ing both induction and post-remission treatment, suggesting that such a strat-egy may be critical to the improved outcome. Additionally, Castaigne’s cohort of patients was older (aged 50-70 years), whereas the other two

trials included patients predominant-ly younger than 60 years.

Gemtuzumab ozogamicin current-ly is not available and the above study suggests that further study of the frac-tionated schedule in adults with AML is warranted. If the above results are confirmed, this could justify bringing the drug back on the market.

References

1. Löwenberg B, Ossenkoppele GJ, van Put-ten W, et al. High-dose daunorubicin in older patients with acute myeloid leuke-mia. N Engl J Med. 2009;361:1235-1248, PMID: 19776405.

2. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361:1249-1259, PMID: 19776406.

3. Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29:369-377, PMID: 21172891.

4. Petersdorf S, Kopecky K, Stuart RK, et al. Preliminary results of Southwest Oncol-ogy Group Study S0106: An internation-al intergroup Phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction thera-py versus standard induction therapy fol-lowed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previ-ously untreated acute myeloid leukemia. 51st ASH Annual Meeting; December 7, 2009; New Orleans, LA. Abstract 790.

Dr. Advani disclosed that she receives consulting and research funding from Pfizer.

From The Lancet

The addition of fractionated-dose gemtuzumab ozogamicin (Mylo-

targ, Pfizer and Ben Venue Labo-ratories) to the standard front-line chemotherapy regimen for de novo acute myeloid leukemia (AML) allowed for the safe administration of high cumulative doses that improved out-comes in these patients.

The current standard induction reg-imen for AML is daunorubicin (50-60 mg/m2 per day for three days) plus continuous cytarabine (100-200 mg/m2 per day for seven days), the so-called 3+7 regimen. Better-ing the results from this regimen has failed, however, as no drug added to the 3+7 regimen has demonstrat-ed a significant improvement. In an

earlier Phase II study, gemtuzumab ozogamicin, a humanized anti-CD33 monoclonal antibody, was adminis-tered to patients with AML at a dose of 9 mg/m2 on days 1 and 14, resulting in a 26% complete remission rate but also resulting in hematologic and liv-er toxicity.

A different study used a reduced dose of gemtuzumab ozogamicin, at 3 mg/m2 (maximum, 5 mg) on days 1, 4 and 7 (the so-called 3-3-3 regimen). Two such Phase II studies using this reduced-dose regimen proved “effec-tive,” after which the authors, in the current study, decided to assess the use of the 3-3-3 regimen in combina-tion with 3+7 induction chemother-apy in patients with de novo AML. This French study, headed by Sylvie Castaigne, MD, was reported in The Lancet (2012;379:1508-1516, PMID:

22482940) and was funded by Wyeth (Pfizer).

In the current Phase III, open-label trial, 280 patients aged 50 to 70 years were assigned to receive either the standard 3+7 regimen (i.e., the control group) or the standard treatment plus the 3-3-3 regimen (i.e., the gemtuzum-ab group). The primary end point was event-free survival (EFS); secondary end points were relapse-free survival (RFS), overall survival (OS), and safe-ty. Each group consisted of 139, all of whom were included in the analysis.

Complete response was seen in 104 (75%) patients in the control group and 113 (81%) in the gemtuzumab group, with or without incomplete platelet recovery to induction (odds ratio, 1.46; 95% confidence interval [CI], 0.82-2.59; P=0.25). EFS at two years was 17.1% (control) versus 40.8%

(gemtuzumab; hazard ratio [HR], 0.58; 95% CI, 0.43-0.78; P=0.0003); OS was 41.9% (95% CI, 33.1%-53.1%) versus 53.2% (95% CI, 44.6%-63.5%), respectively (HR, 0.69; 95% CI, 0.49-0.98; P=0.0368); and RFS was 22.7% (95% CI, 14.5%-35.7%) versus 50.3% (41.0%-61.6%), respectively (HR, 0.52; 95% CI, 0.36-0.75; P=0.0003).

Thrombocytopenia and other hema-tologic toxicity were more common in the gemtuzumab group (16%) than the control group (3%; P<0.0001), although there was no increase in risk for death from this toxicity.

The researchers concluded that lower doses of fractionated gemtu-zumab ozogamicin improved out-comes in patients with AML, and the use of gemtuzumab ozogamicin as part of front-line regimen for the dis-ease should be reassessed.

Anjali Advani, MDStaff PhysicianDepartment of Hematologic Oncology & Blood DisordersCleveland Clinic Taussig Cancer Institute

EXPERT INSIGHT

‘Gemtuzumab ozogamicin currently is not available

and the above study suggests that further study of

the fractionated schedule in adults with AML is

warranted.’—Anjali Advani, MD

CliniCAl OnCOlOgy nEwS • JunE 2012 21HEMATOLOGIC DISEASE

Leukemia

Yearlong Oral Adjuvant Chemotherapy for NSCLC Feasible

Although patients with early-stage (stages I-IIIA) NSCLC are poten-

tially curable with surgery, many will relapse and eventually die of recurrent lung cancer. Since 2004, with the publi-cation of IALT (International Adjuvant Lung Trial),1 we have had evidence that four cycles of cisplatin-based doublet chemotherapy can improve cure rates in patients with stage II or III NSCLC. This was confirmed by the LACE (Lung Adju-vant Cisplatin Evaluation) meta-anal-ysis,2 which indicated approximately a 5% improvement in long-term survival with adjuvant chemotherapy in patients with stage II and III disease. In 2012,

adjuvant chemotherapy with a cisplatin doublet is the accepted standard of care in this population. Adjuvant chemother-apy is generally well tolerated and is fin-ished in only nine weeks, although there is significant toxicity and only about half of patients in Phase III trials completed the prescribed four cycles.

In the present study, Tsuchiya and col-leagues report a nonrandomized Phase II study of one year of twice daily S-1, an oral fluoropyrimidine that is not com-mercially available in the United States, in 50 patients with resected stage IB-IIIA NSCLC. This is essentially a feasi-bility study because it is not randomized

and the numbers are much too small to make judgments about improvement in long-term survival. They report that an impressive 72% of the enrolled patients completed eight cycles of therapy over the course of one year, and that overall the regimen was tolerable. The average age of the patients was 71 years, simi-lar to the general population and much older than the average age of patients on prior Phase III adjuvant trials (59 years2), suggesting this may be a more tolerable choice for older patients than standard chemotherapy. The authors suggest that this regimen deserves to be tested in a Phase III trial.

There are several issues with this study, however, that raise concerns. For one, the drug being tested is only avail-able in Japan and is metabolized differ-ently in patients of European descent, making results difficult to generalize outside of Japan. Second, trial data sug-gests that S-1 is not particularly effec-tive in NSCLC,3 raising the question of why this drug should be used instead of other, proven chemotherapy agents. Its only real advantage seems to be its

oral formulation. Finally, it is question-able whether patients would prefer one year of therapy, however tolerable, to nine weeks of usual IV chemotherapy. Despite these concerns, it is likely that this drug will proceed to a Phase III, randomized, head-to-head trial against standard chemotherapy, so that will answer at least some of these questions.

References1. Arriagada R, Bergman B, Dunant A, et al.

Cisplatin-based adjuvant chemothera-py in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350:351-360, PMID: 14736927.

2. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552-3559, PMID: 18506026.

3. Sandler A, Graham C, Baggstrom M, et al. An open-label, multicenter, three-stage, phase II study of s-1 in combination with cisplatin as first-line therapy for patients with advanced non-small cell lung cancer. J Thorac Oncol. 2011;6:1400-1406, PMID: 21673602.

Dr. Pennell reported no financial disclosures relevant to this study.

From JAMA

A large, retrospective study compar-ing brachytherapy with whole-

breast irradiation (WBI) in older women with invasive breast cancer has found no difference in overall sur-vival (OS) at five years, but found worse long-term breast preservation and increased complications among recip-ients of brachytherapy.

The emergence of brachytherapy as an alternative to WBI has resulted in a substantial increase in women adopting this therapeutic option, despite a lack of randomized trial data to support it.

Long-term randomized prospective trials are ongoing, but these results are years away. The authors of this study, which was reported in the May 2 edition of JAMA (2012;307:1827-1837, PMID: 22550197) and headed by Grace Smith, MD, PhD, MPH, of the Universi-ty of Texas MD Anderson Cancer Cen-ter, in Houston, decided that a nonran-domized comparison, using a cohort of older Medicare patients, would provide useful guidance in the interim.

The study compared breast preserva-tion, infectious and noninfectious com-plications and OS among 92,735 wom-en, aged 67 years or older, who were

diagnosed and treated between 2003 and 2008. Following lumpectomy, 6,952 of the patients received brachytherapy and the rest received WBI.

Results favored WBI in these older patients. Five-year incidence of mas-tectomy was higher in the brachyther-apy group (3.95%) than the WBI group (2.18%; P<0.001). Postoperative compli-cations of all types also were more fre-quent among those receiving brachy-therapy (infectious: 16.20% vs. 10.33%, P<0.001; and noninfectious: 16.25% vs. 9.00%, P<0.001). Additionally, the five-year incidence of breast pain was higher in the brachytherapy cohort

(14.55% vs. 11.92%; P≤0.01), as were the five-year incidences of fat necrosis (8.26% vs 4.05%; P≤0.01) and rib frac-ture (4.53% vs 3.62%; P≤0.01). Howev-er, five-year OS was 87.66% in patients treated with brachytherapy and 87.04% in those receiving WBI (P=0.26).

The authors believe that the “public health implications of these findings are substantial,” particularly given the continued adoption of brachytherapy, which the researchers note is as many as 10% of patients with breast cancer. The authors concluded, “Although these results await validation in the prospective setting, they also prompt caution over widespread application of breast brachytherapy outside the study setting.”

Brachytherapy on Trial in Retrospective Analysis

From Clinical Lung Cancer

S-1, an oral fluoropyrimidine, proved effective as adjuvant chemotherapy

in patients with non-small cell lung can-cer (NSCLC) in a Phase II trial. Because the oral therapy is administrable on an outpatient basis, it may effectively reduce both psychological and physio-logic burdens on oncology patients and improve their quality of life.

This Japanese study was headed by Tomoshi Tsuchiya, MD, PhD, and pub-lished in Clinical Lung Cancer (2012 Mar 14. [Epub ahead of print], PMID:

22424872). The researchers felt that avoiding hospitalization by taking an orally administered adjuvant chemo-therapeutic agent might be an impor-tant advance if effectiveness proved similar to other methods. S-1 is a nov-el oral derivative of 5-fluorouracil con-sisting of tegafur and two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate, and has been the subject of several studies in Japan.

S-1 was administered postoperative-ly in patients with pathologic stage IB-IIIA NSCLC who had undergone curative resection. The adjuvant che-motherapy entailed eight courses, each

of which required a four-week adminis-tration period followed by a two-week withdrawal period, thus totaling 12 months. The S-1 dosing ranged from 80 to 120 mg per day and was delivered in two daily doses.

The study, which was undertaken from 2005 to 2007, was multi-insti-tutional, with 50 patients ultimately being eligible. The primary end point was simply the completion of the adju-vant chemotherapy; secondary end points included the incidence and grade of adverse reactions.

The eight full courses of S-1 adminis-tration were completed by 72% (n=36)

of patients. Although no grade 4 adverse effects were recorded, some grade 3 reac-tions were noted, and included neutro-penia (4%), anorexia (4%), and throm-bopenia, anemia, elevated total bilirubin, hypokalemia, nausea and diarrhea (all 2%). The overall survival rate at three years was 87.7%; the relapse-free survival rate for the same time period was 69.4%.

Citing acceptable survival rates as well as the low incidence of adverse reactions, the researchers conclud-ed that nonhospitalized, oral adjuvant chemotherapy with S-1 for NSCLC was feasible and deserving of a larger Phase III trial.

Nathan Pennell, MD, PhDAssociate Staff Physician, Department of Solid Tumor OncologyCleveland Clinic Taussig Cancer InstituteAssistant Professor Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

EXPERT INSIGHT


Lung

In the May 2, 2012 issue of JAMA, Smith and colleagues reported

their findings of a Medicare analysis of women undergoing breast conser-vation therapy comparing the rates of subsequent mastectomy following adju-vant WBI versus brachytherapy. Breast

brachytherapy is a method of deliver-ing accelerated partial breast irradia-tion (APBI), which has been advocated as being more convenient for patients by completing radiation treatment in just one week. In recent years, brachyther-apy utilization has increased despite the

lack of long-term data or direct compar-ative analysis with WBI, which remains the current standard of care for early stage breast cancer. The National Surgi-cal Adjuvant Breast and Bowel Project (NSABP) and Radiation Therapy Oncol-ogy Group (RTOG) are presently con-ducting a large Phase III trial in which early-stage breast cancer patients are randomized to either WBI or APBI, and accrual to this important trial is ongoing.

Smith et al found that women receiv-ing APBI with brachytherapy were about twice as likely to undergo a mas-tectomy as women receiving WBI, and were also at increased risk for postop-erative complications. The reasons for these patients to have a greater likeli-hood of mastectomy are not discernible

in such a Medicare claims data analy-sis, but presumably may be related to either an increased risk for in-breast recurrence or treatment-related tox-icity. Unfortunately, only the ongoing NSABP/RTOG randomized trial will adequately address the issue of the rel-ative benefit of APBI versus WBI with regard to these end points, and the long-term results will not be available for at least a decade from now. In the meantime, we may be encouraged that the rates of subsequent mastectomy in the current report were quite low, less than 4% in both groups, with no differ-ences in overall survival at five years.

Dr. Tendulkar reported no financial disclosures related to this study.

A study has found that leptin expression is associat-ed with chemoresistance and may be a biomarker that can be combined with fluorodeoxyglu-cose–positron emis-sion tomography (FDG-PET) to deter-mine patient response to chemotherapy.

“Leptin has the potential to be a clinically useful biomarker,” said Russell Petty, MB, PhD, a consultant medical oncologist at the University of Aberdeen in Scotland. He presented the study at the 2012 Gastrointestinal Can-cers Symposium (ASCO-GI; abstract 1).

In the past decade, the incidence of EGJAc has risen alarmingly, driv-en in part by the obesity epidemic. The disease has a poor prognosis and for patients with resectable disease, it has been recognized that neoadjuvant treatment is beneficial for some but not all patients.

Studies have shown that a 35% or greater decrease in FDG standard uptake value (SUV) after just 14 days of treat-ment indicates a metabolic respond-er to chemotherapy, whereas less than 35% indicates a metabolic non-respond-er. Only 50% of patients who are clas-sified as metabolic responders, howev-er, will go on to have a histopathologic response. Of patients who are metabolic

non-responders, less than 5% will have a histopathologic response.

“There is a need to improve the posi-tive predictive value,” said Dr. Petty. The

researchers hypoth-esized they could com-

bine molecular biomarkers with FDG-PET to subclassify

FDG-PET metabolic responders. They launched a study that included 28 patients with locally advanced or met-astatic EGJAc who received platinum-based chemotherapy. Patients under-went FDG-PET computed tomography (PET-CT) scans at baseline and day 14. Chemotherapy continued regardless of radiologic response at day 14. Gene expression profiling with an Affymetrix 1.0 ST Exon Genechip was performed

on tumor biopsies. A tissue microarray comprising an independent set of 154 patients with EGJAc who underwent surgery, with or without neoadjuvant chemotherapy, was used with immuno-histochemistry (IHC) for qualification of the gene expression profile results.

The researchers identified an 86-gene

signature that could distinguish patients who had a radiologic response on CT after completing their full round of che-motherapy, compared with those who

did not respond. Leptin expression was the biggest predictor.

“In those FDG-PET metabolic respon-dent patients who did not have a subse-quent radiologic response, leptin was significantly overexpressed compared to those patients who had a metabol-ic response and then went on to have a radiologic response as well,” said Dr. Petty. “This data suggests that leptin expression in tumor is a marker of chemoresistance.”

Somewhat surprisingly, in an IHC analysis of an independent group of 154 patients, high leptin expression was associated with better survival (hazard

ratio, 0.85; P=0.04). But when the inves-tigators conducted a stratified analysis, they found that patients with leptin-pos-itive tumors derived little survival bene-fit from neoadjuvant chemotherapy, and those with leptin-negative tumors fared better if they received chemotherapy.

A variety of data supports leptin’s

pathogenic role in EGJAc. It is produced by adipocytes and a strong epidemio-logic link between obesity and EGJAc exists. High serum and gastric fun-dus leptin levels have been associated with an increase in Barrett’s esophagus. Leptin receptors are expressed in more than 90% of esophageal adenocarcino-mas, and in vitro studies show that leptin stimulates esophagogastric cancer cell proliferation and can inhibit apoptosis.

According to Dr. Petty, his study sug-gests that leptin expression has value as a predictive biomarker and also as a therapy-independent prognostic mark-er as well. “I would suggest that the paradigm of combining molecular bio-markers and FDG-PET appears to be valuable to predict therapy response, and perhaps should be further investi-gated,” Dr. Petty said.

Karyn Goodman, MD, a radiation oncologist at Memorial Sloan-Ketter-ing Cancer Center, in New York City, said the study was hypothesis-generat-ing, but not ready for prime time. “This is not something that will be incorporat-ed into clinical practice, until the results have been validated with further stud-ies,” she said.

—Kate O’Rourke

Drs. Petty and Goodman have no relevant disclosures.

Marker for Esophagogastric Cancer Treatment FoundWith FDG-PET, leptin expression may help determine response to therapy

San Francisco—A new tool to guide treatment decisions in patients with esophagogastric junction adenocarcinoma (EGJAc) is on the horizon.

• Leptin expression is associated with che-moresistance in esophagogastric junction adenocarcinoma

• A variety of data suggest multiple associ-ations between leptin and esophagogas-tric cancer

• In the future, leptin expression may be combined with FDG-PET to estimate response to chemotherapy

Rahul Tendulkar, MDAssociate Staff Physician, Department of Radiation OncologyCleveland Clinic Taussig Cancer InstituteAssistant Professor, Department of MedicineCleveland Clinic Lerner College of Medicine ofCase Western Reserve University

EXPERT INSIGHT

‘This is not something that will be

incorporated into clinical practice, until

the results have been validated with

further studies.’

—Karyn Goodman, MD

‘This data suggests that leptin expression in tumor

is a marker of chemoresistance.’—Russell Petty, MB, PhD


Esophageal

ANSWERS

1. True. It is not prudent to assign clinical meaning to an outcome that is merely measurable, while failing to measure, or failing to make decisions based on, those things that are truly important to the patient, such as quality of life (QOL) and overall survival (OS).

Booth CM, Eisenhauer EA. Progression-free survival: meaningful or simply measurable? J Clin Oncol. 2012;30:1030-1033, PMID: 22370321.

2. False. The women exposed to chemotherapy performed significant-ly worse than the reference group on cognitive tests of immediate (P=0.015) and delayed verbal memory (P=0.002), processing speed (P<0.001), executive functioning (P=0013) and psychomotor speed (P=0.001).

Koppelmans V, Breteler MM, Boogerd W, Sey-naeve C, Gundy C, Schagen SB. Neuropsycholog-ical performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. J Clin Oncol. 2012;30:1080-1086, PMID: 22370315.

3. False. Vandetanib is a once-dai-ly oral inhibitor of VEGFR, EGFR and RET signaling. This agent is FDA-approved for symptomatic or metastat-ic medullary thyroid cancer (MTC). It did not improve OS in patients with advanced NSCLC who had progressed on prior therapies including an EGFR-TKI. There is currently no approved treatment option for this high-risk patient population.

Lee JS, Hirsh V, Park K, et al. Vandetanib ver-sus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epi-dermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol. 2012;30:1114-1121, PMID: 22370318.

4. True. The combination of high VEGF levels and its receptors VEGFR1 and VEGFR2 protein expres-sion—cumulatively known as the “VEGF signaling score”—was associat-ed with a lower risk for disease progres-sion in stage I SCC. Tumors were clas-sified according to the World Health Organization 2004 classification.

Pajares MJ, Agorreta J, Larrayoz M, et al. Expression of tumor-derived vascular endothe-lial growth factor and its receptors is associat-ed with outcome in early squamous cell carcino-ma of the lung. J Clin Oncol. 2012;30:1129-1136, PMID: 22355056.

5. True. Laurel Northouse, PhD, RN, and colleagues at the University of Michigan reviewed published evidence, health policy legislation including the Affordable Care Act and the Family Leave Act, and current practice trends,

and found that family caregivers’ needs are seldom addressed in clinical prac-tice. Evidence suggests that appropriate interventions geared toward the care-givers of patients with cancer or other chronic illnesses can improve their cop-ing skills, knowledge and quality of life.

Northouse L, Williams AL, Given B, McCorkle R. J Clin Oncol. Psychosocial care for family caregivers of patients with cancer. J Clin Oncol. 2012;30:1227-1234, PMID: 22412124.

Jacobsen PB, Holland JC, Steensma DP. Car-ing for the whole patient: the science of psycho-social care. J Clin Oncol. 2012;30:1151-1153, PMID: 22412125.

6. True. Given the centrality of psy-chosocial issues in cancer care, it is sur-prising that the formal history of the field in the United States dates only to the 1970s. The emergence of psycho-social care reflects growing public and professional awareness of the poten-tial for cancer and its treatment to have profound effects on many aspects of life in a positive manner.

Jacobsen PB, Holland JC, Steensma DP. Car-ing for the whole patient: the science of psycho-social care. J Clin Oncol. 2012;30:1151-1153, PMID: 22412125.

7. False. Tamoxifen reduces the inci-dence of both local recurrence and con-tralateral breast cancer, but not OS in this particular setting.

Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103:478-488, PMID: 21398619.

Lee LA, Silverstein MJ, Chung CT, et al. Breast cancer-specific mortality after invasive local recurrence in patients with ductal carcinoma-in-situ of the breast. Am J Surg. 2006;192:416-419, PMID: 16978940.

Morrow M. Refining the use of endocrine ther-apy for ductal carcinoma in situ. J Clin Oncol. 2012;30:1249-1251, PMID: 22393104.

8. True. The outcome of this tri-al will definitively demonstrate if the 21-gene Oncotype DX assay can iden-tify a group of ER- and node-positive breast cancer patients who do not ben-efit from adjuvant chemotherapy, for example, the luminal A subtype. If so, over-treatment with chemotherapy may be avoided in this group, and research

efforts can focus on other molecular pathways that permit these cancers to escape endocrine therapy.

Hayes DF. Targeting adjuvant chemotherapy: a good idea that needs to be proven! J Clin Oncol. 2012;30:1264-1267, PMID: 22355050.

9. True. Using axillary lymph node analysis (ALNA) as the gold standard, sensitivity for PET was 23.7% (95% confidence interval [CI], 15.9%-33.6%), specificity was 99.6% (95% CI, 97.2%-99.9%), positive predictive value was 95.8% (95% CI, 76.9%-99.8%), nega-tive predictive value was 75.4% (95% CI, 70.1%-80.1%) and prevalence was 29.8% (95% CI, 25.0%-35.2%). Patients were excluded if they had clinically pal-pable nodes or metastatic disease.

Pritchard KI, Julian JA, Holloway CM, et al. Prospective study of 2-[18F] fluorodeoxyglucose positron emission tomography in the assessment of regional nodal spread of disease in patients with breast cancer: an Ontario Clinical Oncolo-gy Group study. J Clin Oncol. 2012;30:1274-1279, PMID: 22393089.

10. True. Sequencing analysis has revealed that TET2 mutations (TET-2mut) are present in 7% to 23% of de novo AML and in 14% to 55% of oth-er myeloid malignancies. It has been shown that TET2mut samples display uniformly low levels of 5hmC com-pared with normal controls, support-ing functional relevance for TET2mut in leukemogenesis.

Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468:839-843, PMID: 21057493.

Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289-2301, PMID: 19474426.

Gaidzik VI, Paschka P, Späth D, et al. TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clini-cal analysis of the AML study group. J Clin Oncol. 2012;30:1350-1357, PMID: 22430270.

11. True. Oliver Goodyear, PhD, and colleagues in the United Kingdom demonstrated that in AML, azacitidine after RIC allo-SCT can increase the number of regulatory T-cells (T-regs) while inducing a cytotoxic CD8+ T-cell response, suggesting a potential mech-anism for augmenting the GVL effect without an increase in GVHD. The opti-mal dosing, schedule timing and dura-tion of azacitidine administration after RIC allo-SCT are yet to be established. The use of azacitidine in combination with donor lymphocyte infusion (DLI) may further augment the safety and antitumor effect of DLI (ClinicalTrials.gov Identifier: NCT01541280).

Goodyear OC, Dennis M, Jilani NY, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood. 2012;119:3361-3369, PMID: 22234690.

Mohty M, Chevallier P. Azacitidine after allo-SCT: the good without the bad? Blood. 2012;119:3199-3200, PMID: 22493216.

12. True. Microsatellite instabili-ty (MSI) is a hallmark feature associat-ed with Lynch syndrome, with approx-imately 15% of sporadic CRCs exhibit-ing the MSI-high phenotype as a result of somatic MLH1 promoter hypermeth-ylation. BRAF testing in the absence of MLH1 protein expression by IHC should reduce the number of patients that need germline mutation analysis and the associated costs.

Kastrinos F, Syngal S. Screening patients with colorectal cancer for Lynch syndrome: what are we waiting for? J Clin Oncol. 2012;30:1024-1027, PMID: 22355054.

13. False. Sixty percent of patients with low-grade or FL who respond-ed to initial rituximab therapy failed to respond to repeat rituximab ther-apy, indicating that initially sensitive patients can acquire rituximab resis-tance. Several mechanisms have been proposed for rituximab resistance. With the increasing use of repeated rituximab exposure in clinical practice, acquired resistance has become a grow-ing challenge, highlighting the need for alternative treatment options.

Davis TA, Grillo-Lopez AJ, White CA, et al. Rituximab anti-CD20 monoclonal antibody ther-apy in non-Hodgkin’s lymphoma: safety and effi-cacy of retreatment. J Clin Oncol. 2000;18:3135-3143, PMID: 10963642.

14. False. Ofatumumab monother-apy might have greater clinical activ-ity in patients with FL in a frontline setting or with those not refractory to chemotherapy. Several trials (Clinical-Trials.gov Identifiers: NCT01190449, NCT01200589, NCT01077518) with this agent, alone or in combination, are under way to define the exact role of ofatumumab in front-line and the relapsed/refractory FL setting.

Czuczman MS, Fayad L, Delwail V, et al. Ofa-tumumab monotherapy in rituximab-refracto-ry follicular lymphoma: results from a multi-center study. Blood. 2012;119:3698-3704, PMID: 22389254.

15. True. The results of this study demonstrate that an important clini-cal question—the suitability of unrelat-ed donors for an accepted hematopoi-etic stem cell transplantation indica-tion—related to an expensive treatment can be addressed by a federally funded outcomes registry that is charged with systematic data collection and analy-sis to inform policy makers. The use of resources such as the CIBMTR data-base allows policy decisions to be for-mulated in a way that ensures efficient use of resources while maintaining optimal clinical outcomes.

Saber W, Opie S, Rizzo JD, Zhang MJ, Horow-itz MM, Schriber J. Outcomes after matched unrelated donor versus identical sibling hemato-poietic cell transplantation in adults with acute myelogenous leukemia. Blood. 2012;119:3908-3916, PMID: 22327226.

CONUNDRUMScontinued from page 12


Community Oncology

AYA oncology now has its own society and its own journal, and in March, the National Comprehensive Cancer Net-work (NCCN) issued its first set of AYA guidelines.

The attention to this group of cancer patients is needed. In the past 40 years of the battle against cancer, survival rates of children and older adults have improved significantly, whereas surviv-al rates among AYAs with cancer have barely budged.

“Improvements in cancer surviv-al among AYA patients definitely have lagged behind other sectors of the pop-ulation,” said Kerry Parsons, PharmD, pediatric oncology pharmacist at Chil-dren’s of Alabama, in Birmingham, who discussed AYA oncology at the annual meeting of the Hematology/Oncology Pharmacy Association.

According to the American Can-cer Society, 70,000 AYAs, defined as

patients aged 15 to 39 years, are diag-nosed with invasive cancer each year in the United States. (For a breakdown of cancer types, see Table 1.) Some of those malignancies are associated with a poorer prognosis due to either more aggressive or unique biology features, including breast cancer, colorectal can-cer, soft tissue sarcoma, non-Hodgkin’s lymphoma and acute leukemia, accord-ing to Leonard Sender, MD, the founder of the Society for Adolescent and Young

Adult Oncology (SAYAO), and director of the combined adolescent and young adult cancer program at Children’s Hospital of Orange County and Uni-versity of California, Irvine. Dr. Send-er added that AYAs often do better on more rigorous pediatric protocols than adult protocols, but many doctors are not aware of this.

A 2007 study on AYA cancer trends offers some sobering statistics on just how wide the survival gap has become

in this vulnerable patient population. Fourteen cancer types in AYA patients have five-year survival rates that are sig-nificantly lower than rates in younger patients, the authors reported (CA Can-cer J Clin 57;242-255). Of those, six can-cer types have survival rates that lag behind both younger and older patients.

Moreover, “cancer kills more 20- to 30-year-olds than any other disease except depression-induced suicide,”

Young Cancer Patients Getting More AttentionOrlando, Fla.—In recent years, a niche of medicine has sprung up to address the needs of adolescent and young adults (AYA) with cancer.

Table 1. The Most Common AYA Cancers per 100,000 People in the United States

Cancer TypeAges 15-39 Years

Females

Breast cancer 20.4

Thyroid cancer 14.6

Melanoma 9.5

Cervix and uterine cancer

9.1

Hodgkin’s lymphoma

3.7

Colorectal cancer 3.4

Males

Gonadal germ cell tumors

10.1

Melanoma 5.5

Non-Hodgkin’s lymphoma

4.7

Colorectal cancer 3.6

Thyroid cancer 2.9

Source: SEER Cancer Statistics Review, 1975-2008, national Cancer institute. Bethesda, MD. http://seer.cancer.gov/csr/1975_2008, based on november 2010 SEER

see YOUTH, page 26

®

Now Available...

Co-ChairsTessa Cigler, MD, MPHAssistant Professor of Medicine, Weill Cornell Medical CenterAttending Physician, NewYork-Presbyterian HospitalNew York, New York

Paula D. Ryan, MD, PhDAssociate Professor, Clinical Investigator, Section of Breast Oncology Medical Oncology, Fox Chase Cancer CenterPhiladelphia, Pennsylvania

Target AudienceOncologists, physicians, physician assis-tants, and other health care professionals involved in the treatment of patients with metastatic breast cancer (MBC). � ere are no prerequisites or fees.

Credit DesignationGlobal Education Group designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physi-cians should claim only the credit commen-surate with the extent of their participation in the activity.

Learning ObjectivesUpon completion of this activity, participants will be better prepared to:1 Review recent studies that may have clinically important therapy implications for

patients with locally recurrent breast cancer or MBC.2 Describe a treatment algorithm that refl ects evidence-based management of

advanced human epidermal growth factor receptor 2 (HER2)-negative and HER2-positive breast tumors and novel strategies for circumventing treatment resistance.

3 Explain core guideline-recommended approaches to MBC management that take into consideration the heterogeneity of patient and tumor characteristics.

4 Compare the mechanisms, synergies, and evolving roles of current and emerging targeted therapies with activity in MBC, particularly in terms of novel combina-tions and sequences.

Accreditation Statement� is activity has been planned and implemented in accordance with the Essen-tial Areas and policies of the Accreditation Council for Continuing Medical Edu-cation (ACCME) through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide CME for physicians.

Method of ParticipationTo receive CME credit, participants should complete the pre-test, read the mono-graph, and complete the post-test and evaluation either online at www.CMEZone.com (enter keyword MN113). Completed forms also can be faxed to (303) 648-5311 or mailed to 5575 S. Sycamore Street, Suite 200, Littleton, CO 80120. CME certifi cates will be issued within 6 to 8 weeks upon receipt of completed evalua-tions. A score of at least 70% is required to complete this activity.

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN113”

Release Date: October 1, 2011 Expiration Date: October 1, 2012

This activity is based on a live educational symposium held May 21, 2011, in Philadelphia, Pennsylvania.

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN113”

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Community Oncology

the authors noted. “Yet cancer in young adults has been under-recognized and frequently not considered” by clinicians who often come into contact with these patients—“including oncologists.”

Major Culprit: Clinical Trials Access

According to Dr. Parsons, the factor most responsible for this lack of progress in AYA oncology is inadequate access to clinical trials. “During the period of 1997 and 2003, approximately 70% of children were enrolled in an NCI-sponsored clin-ical trial,” she said. Unfortunately, “this level of clinical trial participation drops dramatically as you span into the AYA age range and falls to less than 2% [for patients] between 20 and 39 years of age.” The new AYA NCCN guidelines strong-ly advise that AYA patients be placed on clinical trials and referred to cancer cen-ters with experience in treating cancer patients in this age group.

Dr. Parsons said that a 20-year-old Marine with osteosarcoma was recent-ly referred to her hospital because it has been gaining a reputation as a cen-ter with AYA expertise. Her hospital was able to place him in a clinical trial. “We don’t need a fancy facility to care for these patients,” she said. “In my practice at the University of Alabama, we don’t neces-sarily have a formal program, although we are moving that way, but over the past few years, we have had a lot more phone calls and discussions between our physi-cians and our pharmacy colleagues about managing AYA patients.” Dr. Parsons pointed out that strides are being made in terms of getting AYAs into clinical tri-als for sarcoma. The percentage of AYA patients enrolled in NCI clinical trials for sarcoma was 5% during 1998 and 1999 and 19% during 2004 and 2005, she said.

In addition to inadequate research opportunities, poor access to health care, delayed diagnosis and treatment and poor adherence to treatment regi-mens also play a role in the survival rates of AYAs not improving over the years. She noted that a 2010 Gallup poll identi-fied AYAs as the most underinsured age among all age ranges.

Signs of Progress

All is not dire, however, in the field of AYA cancer. Since 2006, the NCI has collaborated with the Lance Arm-strong Foundation and published a series of reports on AYAs with can-cer, in an effort to bolster awareness. In 2010, Dr. Sender helped found the SAYAO. In 2011, the quarterly Journal of Adolescent and Young Adult Oncology was launched. The NCCN AYA oncolo-gy guidelines released in March are the latest big development in this growing

field (Table 2). The guidelines aim to help improve the diagnosis, treatment and survivorship care of AYAs. (Access to the NCCN Guidelines for AYA Oncol-ogy or any of the NCCN guidelines is available free of charge at NCCN.org.)

According to Dr. Parsons, physi-cians can do their part by paying par-ticular attention to toxicity and dosing

considerations in this population because of different pharmacokinetics. The oral clearance of dexamethasone and meth-otrexate, for example, is twofold greater for young children than for adolescents, and there is an inverse relationship in AYAs between age and clearance of eto-poside and busulfan. Pharmacists should be aware that when using dactinomycin,

the area under the curve is lower in ado-lescents than in young children, she said.

Through acute lymphoblastic leukemia (ALL) clinical trials run by the Children’s Oncology Group, researchers have found that patients between the ages of 16 and 30 years experience higher rates of tox-icities than children aged 1 to 15 when it comes to hyperglycemia (22% vs. 15.4%), hyperbilirubinemia (6.7% vs. 3.7%), oral mucositis during interim maintenance therapy (18.5% vs. 11.3%) and periph-eral neuropathy (11.5% vs. 7.4%; Blood, ASH Annual Meeting abstracts, 2011;118: Abstract 1510). Osteonecrosis is far more prevalent in ALL patients 10 years or older than in patients younger than age 10 (19.6% vs. 3.1%; J Clin Oncol 2011;29: Abstract 9504).

Survivorship Issues Need To Be Addressed

AYAs have specific survivorship issues that need attention, including financial pressures, psychosocial issues and med-ical concerns such as fertility. Accord-ing to Dr. Sender, psychological distress is significantly greater in AYAs than in younger children and older patients with cancer. Thus, health care work-ers need to focus on managing the psy-chosocial issues of this particular group of patients. The AYA NCCN guidelines echo the need for specific attention to psychosocial issues.

Dr. Parsons stressed that there still is a need to increase the overall awareness among the medical community as well as the lay community about the specif-ic needs of AYA patients. “The AYAs rep-resent a unique enough cancer diagno-sis that argues for the emergence of AYA oncology as a specialty practice in medi-cine,” she said.

Dr. Sender agreed and said practitio-ners can dive into the subject matter using online resources. “With Google and PubMed, you can bring yourself up to speed pretty quickly, if you know [how] to look for it. You need to know that the term ‘young adult’ needs to be put into a search when you have a leuke-mia or a sarcoma,” he said. He hopes the growing awareness of AYA oncology will spur health care providers to specialize in the niche. “There is a really rewarding career in doing young adult medicine,” Dr. Sender said.

—Kate O’Rourke

Table 2. Highlights From the NCCN Adolescent and Young Adult Oncology Guidelines

AYA patients usually are more tolerant of intensive therapies than older patients.

Monitoring of cumulative dosing for certain medications (anthracylines, epi-podophyllotoxins, cisplatin, ifosfamide) associated with irreversible organ damage may be essential when certain lifetime exposure is encountered.

Fertility preservation should be an essential part in the management of AYAs with cancer.

AYA patients with cognitive dysfunction or other psychiatric symptoms (e.g., depression or anxiety) should be referred to a mental health provider and community-based resources serving AYA patients.

All AYAs should have a survivorship care plan.

AYAs with cancer need long-term follow-up care for monitoring and treat-ment of late effects long after completion of treatment. This can include screening for pulmonary, thyroid, cardiovascular and audiologic issues; breast, colorectal and bladder cancer; acute myeloid leukemia; myelo-dysplasia; and kidney disease.

Source: www.nccn.org

YOUTHcontinued from page 25

‘The AYAs represent a unique enough cancer

diagnosis that argues for the emergence of AYA

oncology as a specialty practice in medicine.’—Kerry Parsons, PharmD

‘You need to know that

the term “young adult”

needs to be put into a

[PubMed] search when

you have a leukemia or

a sarcoma.’

—Leonard Sender, MD


Community Oncology

Daily Aspirin Inhibits Metastatic Adenocarcinoma

Rothwell and colleagues have ana-lyzed data from five clinical trials

testing the reduction in cardiovascu-lar disease in patients receiving aspirin, and have shown a significant decrease in the incidence of metastatic cancer. The results of this trial are intriguing and offer insight into possible interventions to improve survival in patients with

cancer. With 17,285 participants in the trials, there were 1,101 cancers and 563 deaths due to cancer. There was a 12% reduction in risk for developing cancer in subjects receiving daily aspirin and a 23% reduction in death from cancer. In the 775 patients with a solid tumor and known metastatic disease status, there was a 36% reduction in known

metastatic disease in patients receiv-ing aspirin, with a decrease in metasta-ses to the lung, liver and brain, but not bone. The effect was most pronounced in patients with adenocarcinoma.

This data has limitations. These were trials assessing cardiovascular risk, not cancer prevention. It is possible that some tumors may have been missed or not diagnosed in a timely manner because this was not a goal of the trial. The presence of metastases was unclear in 20% of patients and the necessary dose and duration of aspirin for the effects observed is not known. This does, how-ever, reflect routine clinical use of aspirin.

What are the implications of this tri-al? Clinically, the reduction in inci-dence or development of metastatic disease is significant because metastat-ic disease is associated with increased

morbidity, heightened patient and fam-ily anxiety and reduced overall survival. The possibility of decreasing metastat-ic disease with aspirin, an inexpensive and easy-to-use therapy, is promising.

Clearly, aspirin is associated with risks, including stroke and gastrointesti-nal bleeding, and should not be used by patients at this time for cancer preven-tion due to risk for adverse effects and the unproven benefits in specific clini-cal trials. The mechanism by which aspi-rin reduced metastatic disease in the current trial remains unclear, but this offers an interesting area for research to understand how tumors grow and for development of future therapies.

Dr. Shepard reported no financial disclosures relevant to this study.

“CO.20 did not meet its primary end point of overall survival,” said Lillian Siu, MD, a senior staff physician in the Divi-sion of Medical Oncology and Hema-tology at Princess Margaret Hospital in Toronto, Ontario, Canada. She presented the study at the Gastrointestinal Cancers Symposium (ASCO-GI; abstract 386).

The NCIC Clinical Trials Group and Australasian Gastro-Intestinal Trials Group CO.20 study was based, in part, on a retrospective analysis of a Phase I/II trial that demonstrated that brivanib

improved the response rate in CRC patients with KRAS wild-type tumors. Patients who had not received any pri-or anti-epidermal growth factor recep-tor (EGFR) therapy were more likely to benefit (ASCO-GI 2009; abstract 375).

The CO.20 trial randomized patients with metastatic, chemotherapy-refrac-tory, KRAS wild-type CRC to receive cetuximab (Erbitux, BMS) with either brivanib (n=376) or placebo (n=374). To be included in the study, patients had to have KRAS wild-type tumors with prior

thymidylate synthase inhibitor thera-py (5-fluorouracil or capecitabine), be intolerant of or refractory to irinotecan and oxaliplatin, and have an Eastern Cooperative Group Study performance status of 0 to 2. One prior anti-vascu-lar endothelial growth factor (VEGF) therapy but no prior EGFR therapy was allowed. The two arms were well balanced in terms of patient character-istics. More than 90% of patients had received more than three lines of pri-or chemotherapy and 40% had received one prior anti-VEGF therapy.

At a median follow-up of 19 months, an intention-to-treat analysis showed that median overall survival was 8.8 months in the brivanib arm and 8.1 months in the

control arm, a difference that was not sta-tistically significant (hazard ratio, 0.88; P=0.12). Median progression-free sur-vival (PFS) was 5.0 months in patients who received brivanib compared with 3.4 months in patients who received placebo

Brivanib Fails in Phase III Colon Cancer TrialSan Francisco—The investigational agent brivanib (Bristol-Myers Squibb [BMS]) has failed in a Phase III trial of patients with colorectal cancer (CRC).

From The Lancet

An intriguing meta-analysis of five large, randomized cardiovascular

trials has found that patients who take daily aspirin (≥75 mg per day) have a reduction in the risk for cancer with distant metastasis, compared with con-trols. The finding has several implica-tions for clinical care.

The meta-analysis, undertaken by a group of researchers in the United Kingdom and headed by Peter Roth-well, FMedSci, included 17,285 partici-pants, of whom 987 had received a diag-nosis of a new solid cancer during trial follow-up (mean, 6.5 years). The study, published in The Lancet (2012;379:1591-1601; PMID: 22440947), found that those receiving daily aspirin had a

reduction in incidence of cancer with distant metastasis (all cancers: haz-ard ratio [HR], 0.64; 95% confidence interval [CI], 0.48-0.84; P=0.001; ade-nocarcinoma: HR, 0.54; 95% CI, 0.38-0.77; P=0.0007; other solid cancers: HR, 0.82; 95% CI, 0.53-1.28; P=0.39). The reduction was attributed mostly to the diminished proportion of adenocarci-nomas with metastatic compared with local disease (odds ratio, 0.52; 95% CI, 0.35-0.75; P=0.0006).

The meta-analysis found that aspi-rin reduced the risk for adenocarcino-ma with metastasis both at initial diag-nosis (HR, 0.69; 95% CI, 0.50-0.95; P=0.02) and at subsequent follow-up in those patients who did not present with metastasis initially (HR, 0.45; 95% CI, 0.28-0.72; P=0.0009). This effect was most pronounced in patients with

colorectal cancer (HR, 0.26; 95% CI, 0.11-0.57; P=0.0008).

Patients who took daily aspirin and developed adenocarcinoma had a reduced cancer-related death rate, par-ticularly in those with no metastasis at diagnosis (HR, 0.50; 95% CI, 0.34-0.74; P=0.0006). Therefore, aspirin reduced the overall risk for fatal adenocarcinoma in the five trial populations (HR, 0.65; 95% CI, 0.53-0.82; P=0.0002), although it did not lower the risk for other can-cer deaths (HR, 1.06; 95%, CI, 0.84-1.32; P=0.64; difference, P=0.003). The abso-lute benefit was greatest in smokers, although the beneficial effects of aspi-rin were independent of age and gen-der. The researchers noted that a low-dose, slow-release aspirin formulation, which inhibits platelets but has reduced systemic bioavailability, was as effective

as aspirin given in higher doses.The authors note several implica-

tions of this meta-analysis. First, the findings help explain the short-term reduction in cancer fatality in trials comparing daily aspirin with a con-trol. Second, the findings suggest that starting a course of aspirin after diagnosis also has a beneficial effect. Third, stopping aspirin after a diagno-sis of cancer, which is routine clinical practice, may indeed be detrimental. Fourth, pharmacologic intervention to prevent distant metastasis is a pos-sibility worth further study. They add-ed, “The effects of aspirin on metasta-sis are likely to be platelet-mediated, raising the prospect that more inten-sive platelet inhibition with combi-nation treatment might be even more effective.”

❖ Brivanib did not improve overall survival in metastatic, K-RAS wild-type colorectal cancer

❖ Grade 3/4 adverse events were 25% higher with brivanib

❖ The agent is currently being studied in no fewer than six cancer types

Dale Shepard, MD, PhDAssociate Staff Physician, Department of Solid Tumor OncologyCleveland Clinic Taussig Cancer InstituteAssociate Professor of Medicine atCleveland Clinic Lerner College of Medicine ofCase Western Reserve University

EXPERT INSIGHT

see BRIVANIB, page 28


Adenocarcinoma

Thromboembolism Risk Reduced With Semuloparin

The association between malig-nancy and VTE is well recognized.

Cancer patients receiving chemother-apy in the postoperative setting who experience a VTE are at twice the risk for dying within the first six months of initial hospitalization compared with those who do not.1 A meta-anal-ysis of several large randomized con-trolled trials concluded that although thromboprophylaxis with LMWH in

ambulatory cancer patients is effective

and results in a significant 46% rela-tive risk reduction of VTE, the abso-lute risk reduction with prophylactic anticoagulation is only 2.6%, with con-cerns remaining regarding an increase in major bleeding events.2

In the present study, Agnelli and colleagues report on semuloparin, a hemisynthetic, ultra-LMWH, and its use as thromboprophylaxis in cancer patients receiving chemotherapy. They found that during a treatment duration of approximately 3.5 months, fewer patients receiving the study drug had a VTE compared with a control group receiving placebo (1.2% vs. 3.4%; HR, 0.36; P<0.001). The incidence of clini-cally relevant and major bleeding was comparable between groups.

Hence, this report demonstrates a decreased incidence of VTE in patients receiving thromboprophylaxis during

chemotherapy, without an increase in major bleeding. However, semulopa-rin has not been compared with other currently available LMWH products. Moreover, the study was not pow-ered to demonstrate a survival ben-efit, and whether the lack of major bleeding observed in treated patients would have been realized if it had been is uncertain. Semuloparin, like other LMWHs, is administered subcutane-ously, therefore patients receiving this agent would need to be agreeable to a daily injection.

Whether thromboprophylaxis with semuloparin or other LMWHs becomes standard practice for ambu-latory cancer patients receiving che-motherapy remains to be seen. VTE in cancer patients and in those receiving chemotherapy remains a significant problem; yet, although risk reduction was demonstrated in this study, the

absolute degree was fairly small. Addi-tional studies will be needed to better risk-stratify this population and iden-tify those persons at highest risk for VTE in whom the risk– and cost–ben-efit ratios are maximal.

References

1. Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recurrent thromboem-bolic disease among patients with malig-nancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore). 1999;78:285-291, PMID: 10499070.

2. Kuderer N, Ortel T, Khorana A, et al. Low molecular weight heparin thomboprophy-laxis in ambulatory cancer patients: a sys-tematic review and metanalysis of ran-domized controlled trials. Blood (ASH Annual Meeting Abstracts). 2009;114:490.

Dr. Samaras reported no financial disclosures relevant to this study.

(HR, 0.72; P<0.0001), and more patients achieved a partial response with brivanib than placebo (13.6% vs. 7.2%; P=0.004).

The overall incidence of grade 3/4 non-hematologic adverse events was 78% in the brivanib arm and 53% in the control arm.

“There is no difference on the relative effect of brivanib against placebo in any of the subgroups tested,” said Dr. Siu.

Herbert Hurwitz, MD, an associate professor of medicine at Duke Cancer Institute in Durham, N.C., who was not involved in the study, noted that there

was a higher than expected rate of side effects, which led to patients dropping out of the study and significant dose reductions in both arms. This could have compromised the value not only of the experimental drug but cetuximab as well, he said. Nevertheless, the trial was clearly negative.

“There was a response-rate and PFS benefit, but this did not translate into an overall survival benefit. There was no meaningful crossover to confound these results,” said Dr. Hurwitz. He pointed out that the median PFS did not reflect the overall benefit of the drug in some patients, given that the survival curves splayed around the 50% mark. He called the 5% response rate

“potentially biologically interesting,” but not clinically significant.

According to Cristi Barnett, a spokes-woman for BMS, the company is current-ly investigating brivanib in four Phase III hepatocellular carcinoma trials, and a second Phase III trial is ongoing in CRC (NCT00640471). Brivanib also is being

tested in Phase I/II trials for gastrointes-tinal, kidney, endometrial, colorectal and cervical cancers.

“A decision on how best to continue the development [of brivanib] in CRC specif-ically, will be made after a careful review of the CO.20 study data from NCIC and other ongoing studies,” said Ms. Barnett.

—Kate O’Rourke

Dr. Siu disclosed research funding from Bristol-Myers Squibb. Dr. Hurwitz disclosed a consultancy or advisory role with Bristol-

Myers Squibb and Genentech/Roche; honoraria from Roche; and research funding

from Bristol-Myers Squibb, Cephalon, Genentech, GlaxoSmithKline, Novartis,

Pfizer, Roche, Sanofi, Threshold and Tracon.

From The New England Journal of Medicine

Semuloparin (Sanofi), an investi-gational antithrombotic agent,

reduces thromboembolic events in patients being administered cancer chemotherapy, while not increasing the incidence of major bleeding.

Venous thromboembolism (VTE) increases morbidity, mortality and cost in patients with cancer, requiring surgi-cal interventions, prolongation of hos-pital length of stay and additional med-ical care. There are many factors that increase risk for thromboembolism in patients with cancer, including the spe-cifics of the cancer itself, as well as the type of chemotherapy being admin-istered and its intensity, comorbidi-ties and performance status. However, there is little evidence from randomized

controlled trials that antithromboem-bolism prophylaxis should be given to ambulatory patients with cancer who are receiving chemotherapy.

This double-blind trial, undertaken by the SAVE-ONCO study group, sought to ascertain the safety and efficacy of sem-uloparin, an ultra-low-molecular-weight heparin (ultra-LMWH; 2,000-3,000 Da) with high anti-Xa activity and low anti-IIa activity, for prophylaxis against VTE in patients being administered che-motherapy for solid tumors. The lead author was Giancarlo Agnelli, MD, and the report, for which there were 414 collaborators at multiple international sites, was published in The New England Journal of Medicine (2012;366:601-609, PMID: 22335737). The study was fund-ed by Sanofi.

Patients with either metastatic or locally advanced solid tumors were

given subcutaneous semuloparin, 20 mg per day, or placebo for the duration of their existing chemotherapy regimen. The study recorded any symptomatic deep vein thrombosis, nonfatal pulmo-nary embolism or death from VTE as its primary efficacy outcome measurement. The principal safety outcome was any clinically relevant major or non-major bleeding. The median duration of treat-ment was 3.5 months.

VTE was noted in 20 of 1,608 (1.2%) patients in the semuloparin group and 55 of 1,604 (3.4%) patients in the pla-cebo group (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.21-0.60; P<0.001). Semuloparin was con-sistently effective across subgroups defined according to the cancer type and baseline risk for VTE. Clinically relevant bleeding was seen in 2.8% of the semuloparin group and 2% of the

placebo group (HR, 1.40). There was major bleeding in 19 of 1,589 (1.2%) patients receiving semuloparin and 18 of 1,583 (1.1%) patients receiving pla-cebo (HR, 1.05). Adverse events were similar in both groups. When com-paring the semuloparin group with the placebo group, findings were any adverse event (AE), 85% versus 84.6%; any AE related to the study drug, 15.2% versus 11.8%; any serious AE, 26.3% versus 25.5%; any AE leading to death, 12.1% versus 11.7%; and any AE lead-ing to the permanent discontinuation of the study drug, 15.2% versus 16.4%.

The study group concluded that semuloparin does reduce the inci-dence of thromboembolism in ambu-latory patients receiving cancer che-motherapy, and does so without a significant effect on the incidence of major bleeding.

Christy J. Samaras, DOAssociate StaffDepartment of Hematologic Oncology and Blood DisordersCleveland Clinic Taussig Cancer Institute

EXPERT INSIGHT

BRIVANIBcontinued from page 27


Thromboprophylaxis

has been a prevalent topic of research over the past five or 10 years,” said Dr. Shah.

The main risk factors for gastric can-cer are Helicobacter pylori, whose rates vary worldwide, tobacco use and family history. Several genetic syndromes pre-dispose individuals to the disease (Table 1). Gastric cancer also has different his-tologic patterns—intestinal versus dif-fuse—and is found in different digestive locations, such as gastroesophageal (GE) junction and the pyloric antrum.

A recent study compared a database of gastric cancer patients from Memo-rial Sloan-Kettering Cancer Center in New York City (n=711) with data from a hospital in Korea (n=1,646) from 1995 to 2005 (Ann Surg 2010;251:640-646, PMID: 20224369). “In the U.S., and cer-tainly in the Northeast and probably the West, proximal tumors, GE junction, distal esophagus and cardia tumors are much more prevalent than they are in Asia, about 40% of the population here versus 10% in Korea, whereas middle and lower tumors of the stomach are

more prevalent in Korea,” said Dr. Shah (Table 2).

This study also showed a difference in tumor stage at diagnosis. Nearly half (42%) of the patients in Korea had stage Ia, the earliest tumor stage, and more than half (60%) were stage I. In the Unit-ed States, there was more of an even split by tumor stage: Ia (28%), Ib (21%), II (20%), IIIa (16%) and IIIb (8%).

Thirty-day postoperative mortali-ty was higher in the United States (2%) than in Korea (0.2%), a difference that

could not be explained by differences in surgical volume or quality of surgi-cal care, said Dr. Shah. Patients in Korea had higher overall survival (OS; 81% vs. 58%; P<0.0001) and disease-specif-ic survival (DSS; 82% vs. 74%; P<0.0001)

than patients in the United States. After adjusting for all known confounding risk factors, the DSS for Korean gastric can-cer patients remained significantly better than that of U.S. patients by roughly 30% (hazard ratio [HR], 1.3; P=0.05).

“The study cannot exclude inherent biologic differ-ences between gastric cancer in the Unit-ed States and Korea that accounts for superior survival

in Korean patients,” said Dr. Shah.In areas where gastric cancer is most

prevalent, such as in China and Japan, intestinal gastric cancer, which has a glandular appearance and spreads through the stomach wall as part of a

tumor mass, is the most com-mon type. There is no region-

al variation in diffuse gastric cancer, which spreads as discohesive individual cells throughout the stomach wall and is less common than the intestinal type.

Dr. Shah pointed out that proximal and distal gastric cancers have two distinct epidemiologies. Cardia and GE junction cancers are five times more common in men than in women, twice as com-mon in blacks than in whites, occur in a

Table 1. Genetic Syndromes That Predispose Patients to Gastric Cancer

Hereditary diffuse gastric cancer syndrome (accounts for 3%-5% of gastric cancers)

Lynch syndrome (1%-2%)

Familial adenomatous polyposis (1%)

Li-Fraumeni syndrome (<1%)

Peutz-Jeghers syndrome (<1%)

CLASSIFIEDS

‘Not only do we have epidemiologic

evidence that there are different subtypes

of gastric cancer, we now have [gene]

expression evidence that there are different

subtypes of gastric cancer as well.’—Manish Shah, MD

see CHALLENGES, page 30

CHALLENGEScontinued from page 1

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Stomach

wide range of ages and are common in industrialized nations. Non-cardia can-cers (distal), which are more frequent in Korea, are twice as prevalent in males as in females, four times more common in blacks than in whites, and the incidence increases with age.

In 2010, investigators devised a clas-sification system for gastric cancer that divided the disease into three types (J Natl Compr Canc Netw 2010;8:437-447, PMID: 20410336). The first type, non-cardia gastric cancer, is linked to envi-ronmental factors such as high dietary salt, tobacco use and increasing age; clinical factors such as H. pylori infec-tion and use of nonsteroidal anti-inflammatory drugs; and genetic factors including immune regulatory single-nucleotide polymorphisms. The sec-ond type, diffuse gastric cancer, is asso-ciated with CDH1 mutation and family history and has no known environmen-tal or clinical factors. The third, proxi-mal gastric cancer, is caused by tobacco and alcohol use; has no known genetic link; and is associated with obesity, high body mass index and gastroesophageal reflux disease.

Probing the Genes

The classification system suggest-ed genetic differences between the dis-ease types, said Dr. Shah. “If you have clinical criteria that define three differ-ent diseases, they should have different molecular signatures as well,” he said.

Dr. Shah analyzed gene expression profiles from the primary tumors of 36 patients with gastric cancer and identi-fied gene signatures that could discrim-

inate three types of gastric tumors—proximal GE junction tumors, diffuse gastric tumors and distal intestinal type tumors—with 85% accuracy (Clin Cancer Res 2011;17:2693-2701, PMID: 21430069).

“Not only do we have epidemiolog-ic evidence that there are different sub-types of gastric cancer, we now have [gene] expression evidence that there are different subtypes of gastric cancer as well,” Dr. Shah said.

Additional evidence for diverse genetics comes from a Nature Genetics study in which researchers performed exome sequencing with 22 gastric

cancer samples (2011;43:1219-1223, PMID: 22037554). They found that 59% of gastric cancers had an error in chro-matin modification; 59% had an error in cell junction organization; and 77% had an error in cell cycle regulation.

In 2011, researchers also published a study analyzing gene expression pro-files for 37 gastric cancer cell lines and

identified two intrinsic subtypes, intes-tinal (G-INT) or diffuse (G-DIF), that they then validated in the primary tumors of 521 patients (Gastroenterolo-gy 2011;141:476-485, PMID: 21684283). They identified a 171-gene set that robustly classifies tumors into the two subtypes. In univariate and multivar-iate analyses, these intrinsic subtypes, but not subtypes based on Lauren’s his-topathologic classification, were prog-nostic of survival. The G-INT cell lines were significantly more sensitive to

5-fluorouracil (5-FU) and oxaliplat-in, but more resistant to cisplatin, than the G-DIF cell lines. The subtypes were also linked with survival following adjuvant, 5-FU–based therapy.

Restructuring Clinical Trials“The implication of all this is that gas-

tric cancer is not one disease. There are subtypes of gastric cancer and these subtypes may explain the differences in response to therapy and the differenc-es in prognosis,” said Dr. Shah. “If you accept that there are subtypes of gastric cancer, then you must accept that they

might have different molecular driv-ers and therefore they may respond to different molecular targets, and I think that is the future of gastric cancer.”

According to Wael El-Rifai, MD, PhD, a professor of surgery at Vander-bilt University Medical Center in Nash-ville, Tenn., a wide range of therapeutic drugs are in the pipeline in Phase I/II clinical trials for upper gastrointestinal (GI) cancer. These include inhibitors of crucial molecular targets and can-cer signaling pathways such as EGFR, VEGFR, HER2, HER3, aurora kinas-es, MET, BCL2, DNA methyltransfer-ases, histone deacetylases, heat shock proteins, AKT, mTOR and MEK.

“Upper GI cancers are complex with multiple genetic and epigenetic altera-tions. The complexity of signaling net-works in cancer cells is a challenge in developing successful therapeutics,” said Dr. El-Rifai. Genetic approach-es, he argued, are powerful in iden-tifying novel targets that could mod-ulate response to therapy, but given the complexity of signaling networks in cancer cells, single-agent therapies may not work for every patient. “Com-bined strategies that take into account the molecular and biological features of tumors are the future of personal-ized medicine in cancer therapy,” said Dr. El-Rifai.

He added that clinical trials need to consider the molecular defects in cancer cells of each patient to allow matching patients to therapies that are likely to block the effects of those spe-cific molecular alterations. However,

because of the complexity of the cancer genome, treatment response could vary from one patient to another.

In a recently reported Phase II trial, Dr. Shah and colleagues tested a modi-fied docetaxel, cisplatin, 5-FU and bev-acizumab (Avastin, Genentech) regimen in patients with metastatic gastroesoph-ageal adenocarcinoma (J Clin Oncol 2011;29:868-874, PMID: 21189380). The data was encouraging with a six-month progression-free survival (PFS) of 79%, a median PFS of 12 months and a medi-an OS of 16.3 months.

The results were more intriguing, however, when researchers looked more closely at subtypes. “If you divide by the subtypes we defined—proximal tumors, distal tumors and diffuse tumors—we see quite significant differences,” Dr. Shah said. The response rate was 85% in patients with proximal/GE junction tumors, 38% in diffuse tumors and 56% in patients with distal/intestinal tumors.

According to Dr. Shah, investiga-tors testing agents such as cetuximab (Erbitux, Bristol-Myers Squibb), pani-tumumab (Vectibix, Amgen), sorafenib (Nexavar, Bayer Healthcare Pharma-ceuticals) and trastuzumab (Herceptin, Genentech) have not examined the effectiveness of these agents by sub-types of gastric cancer.

“Many of these [agents] have been studied in gastric cancer, but virtually none have actually defined the diseases they have studied. They [the research-ers] have grouped them all togeth-er,” said Dr. Shah. He thinks clinical trials should be designed to address or account for disease heterogene-ity that occurs within a disease and also globally.

“Understand your target. Understand your disease,” he said. “I think we are approaching that in GI malignancies, and therefore the future is bright.”

—Kate O’Rourke

Dr. Shah disclosed receiving research funding from Genentech and Sanofi. Dr.

El-Rifai had no relevant disclosures.

❖ Gastric cancer incidence and stage at diagnosis differ widely by geography

❖ Epidemiology, risk factors, response to therapy, and genetic analyses suggest that gastric cancer may be an extremely heterogeneous disease

❖ Anticancer therapies including cetuximab, panitumumab, sorafenib and trastuzumab have not been well studied in gastric cancer subtypes, although studies suggest response rates may vary widely

Table 2. Differences In Pathologic Characteristics

Korea, %

United States, %

GE junction 0.4 18

Upper 9 21

Middle 36 27

Lower 54 33

Whole 0.4 2

Unknown 1 0

GE, gastroesophageal

Adapted from Strong VE, Song Ky, et al. Com-parison of gastric cancer survival following R0 resection in the united States and Korea using an internationally validated nomogram. Ann Surg 2010;251:640-646, PMiD: 20224369.

‘Upper GI cancers are complex with multiple genetic

and epigenetic alterations. The complexity of

signaling networks in cancer cells is a challenge in

developing successful therapeutics.’

—Wael El-Rifai, MD, PhD

CHALLENGEScontinued from page 29

‘If you accept that there are subtypes of gastric

cancer, then you must accept that they might have

different molecular drivers and therefore they may

respond to different molecular targets. I think that is

the future of gastric cancer.’—Manish Shah, MD


Stomach

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Recent Advances and Emerging TherapiesIn the Systemic Treatment of

Metastatic Melanoma

Although surgery offers a great cure rate for patients with early-stage melanoma, those who have either met-astatic disease or a high risk for recurrence are given a much poorer prognosis. In fact, the median overall sur-vival (OS) of patients with stage IV melanoma is only 6 to 9 months.2-4

Dacarbazine remains the only cytotoxic chemother-apy FDA-approved for the treatment of metastatic mel-anoma. However, dacarbazine has modest clinical efficacy, with a response rate of only about 10%.2,4-6 The FDA also has approved high-dose interleukin-2 (IL-2) for the treatment of advanced melanoma because of the agent’s ability to induce a durable response.

Unfortunately, this response is observed in only a small subset of patients, and IL-2 is associated with signifi-cant toxicities, such as capillary leak syndrome, that fre-quently require intensive monitoring in a dedicated unit or intensive care facility.7,8 Other agents—including temozolomide (Temodar, Schering-Plough), cisplatin, carboplatin, vinblastine, paclitaxel, carmustine, and lomustine (CeeNu, Bristol-Myers Squibb)—are common-ly used off-label to treat melanoma, but none of these agents or their various combinations have been found to offer a survival advantage over dacarbazine alone.9

Clearly, more active and less toxic drugs are needed for patients with advanced melanoma. In this article, we

JEFFREY T. YORIO, MDFellow, Hematology and Oncology

KEVIN B. KIM, MDAssociate Professor

Department of Melanoma Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, Texas

Melanoma, the malignant transformation of melanocytes, most

commonly occurs in the skin but also may arise from the mucosal

surfaces or in the choroid of the eyes. Melanoma is the fifth and

sixth most common cancer in men and women, respectively, in the United

States.1 In 2012, more than 76,000 people will be diagnosed with malignant

melanoma, and more than 9,000 people will die from the disease nationally.1

1INDEPENDENTLY D EVELOP ED BY M C M AH ON P U BL ISHIN G CL IN ICA L ON COLOGY N E WS • JUN E 2012

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COMBrought to you by the publisher of

review recent advances and emerging therapeutic approaches in the systemic treatment of metastatic melanoma.

Newly Approved Drugs For Late-Stage Melanoma

IPILIMUMAB

Immunotherapy has been used to treat melanoma for decades. Cancer cells, such as those that make up melanoma, have tumor-associated antigens that can be recognized by T cells. This recognition leads to a host response that targets the tumor cells.10 The stan-dard immunotherapy, high-dose IL-2, enhances this response but elicits a durable clinical response in only a small subset of patients.8,11,12 Accordingly, researchers have actively sought to identify and develop more effec-tive immunologic agents with better safety profiles.

Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human monoclonal antibody that binds to cytotox-ic T-lymphocyte antigen-4 (CTLA-4), a co-inhibitory receptor molecule found on the surface of activated T cells. T-cell activation begins when the T-cell recep-tor binds to an antigen presented by a major histo-compatibility complex on antigen-presenting cells, such as dendritic cells. Cluster of differentiation 28 (CD28), a co-stimulatory receptor molecule found on T cells, binds to B7 (CD80/CD86) found on antigen-presenting cells, leading to T-cell proliferation and IL-2 production. As T cells become activated, CTLA-4 is upregulated to the cell surface, where it competes successfully with CD28 for B7 to halt further cell pro-liferation in a self-regulatory mechanism. Ipilimumab blocks CTLA-4 on the cell surface, thereby preventing CTLA-4 from binding to B7 molecules and allowing CD28 to bind to these molecules instead, leading to further T-cell proliferation and IL-2 production.13,14 Ulti-mately, this can help increase the immune response to cancer cells.

Initial clinical studies revealed that ipilimumab could be a promising new therapy for metastatic mel-anoma.15,16 A Phase I/II trial of ipilimumab (≤10 mg/kg every 3 weeks) in 23 patients with metastatic melano-ma demonstrated a disease control rate of 39%, with at least 2 patients experiencing a durable response of longer than 21 months.15 These encouraging results led to several Phase III trials of ipilimumab in patients with metastatic melanoma (Table 1).17,18

In the first Phase III study of ipilimumab, 676 pre-viously treated patients with unresectable stage III or IV melanoma were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab with a glycoprotein 100 (gp100) peptide vaccine (n=403), ipilimumab alone (n=137), or the gp100 peptide vaccine alone (n=136).17 Ipilimum-ab was given at a dose of 3 mg/kg every 3 weeks for 4 doses. The median OS of patients who received ipi-limumab alone (10.1 months) was significantly longer than that of patients who received the gp100 vaccine alone (6.4 months; hazard ratio [HR], 0.66; P=0.003).

However, the median OS of patients who received ipi-limumab with the gp100 vaccine did not differ signifi-cantly from that of patients who received ipilimumab alone. The risk for disease progression in patients who received ipilimumab alone was 36% lower than that for patients who received the gp100 vaccine alone (P<0.001). The median progression-free survival (PFS) durations of the 3 groups were similar (2.76 months in the combination group, 2.86 months in the ipilimum-ab-alone group, and 2.76 months in the gp100 vac-cine-alone group). The results of this trial led to the FDA’s approval of the drug for the treatment of meta-static melanoma in March 2011.

In the second Phase III study of ipilimumab, 502 treat-ment-naive patients with metastatic melanoma were randomized to receive dacarbazine with or without ipi-limumab.6 During the induction phase, ipilimumab was given at a dose of 10 mg/kg every 3 weeks for 4 doses. During the maintenance phase, patients who did not experience severe toxicity during the induction phase were given additional doses of ipilimumab (10 mg/kg every 12 weeks). The median OS duration of the patients who received dacarbazine plus ipilimumab (11.2 months) was significantly longer than that of the patients who received dacarbazine alone (9.1 months; P<0.001). The 3-year OS rates in the dacarbazine plus ipilimumab group and the dacarbazine-only group were 20.8% and 12.2%, respectively. The risk for disease progression in the patients who received dacarbazine plus ipilimumab was 24% lower than that for the patients who received dacar-bazine alone (P=0.006).

As with other immune-stimulating agents, ipilim-umab induces immune-related adverse events (AEs). In the first Phase III trial, the most common immune-related AEs among those receiving ipilimumab alone were diarrhea (28%), pruritus (24%), rash (19%), and colitis (8%).17 Grade 3 or 4 diarrhea and colitis was seen in 5% of the patients. The addition of dacarbazine to ipilimumab in the second Phase III trial also resulted in notable elevations in serum liver enzyme levels. Of the 247 patients receiving the combination, elevations in alanine aminotransferase (ALT) and aspartate ami-notransferase (AST) were observed in 33% and 27% of the patients, respectively.6 Grade 3 or 4 elevations in ALT and AST were seen in 21% and 17%, respectively. Endocrine immune-related AEs such as hypothyroid-ism, hypopituitarism, and adrenal insufficiency were observed but were uncommon.

Patients who develop grade 2 diarrhea should be considered for treatment with oral steroids such as budesonide, whereas patients with grade 3 and 4 diar-rhea should discontinue ipilimumab and receive high-dose systemic corticosteroids until improvement.18 Infliximab, an anti-tumor necrosis factor-α antibody, has been used with some success to treat patients who are unresponsive to high-dose steroids. The use of high-dose IV corticosteroids also has been suggest-ed for grade 3 or 4 elevations in serum liver enzyme levels and endocrinopathies.

INDEPENDENT LY DEVELOP ED BY M C M AH ON P UBL ISHIN G2

VEMURAFENIB

The Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway is a key pathway for cell proliferation, particularly in cancer cells (Figure).19 In 2002, Davies et al reported that nearly 60% of melanomas harbor a mutation in BRAF, which codes for a serine-threonine protein kinase involved in the Ras/Raf/MEK/ERK path-way.20 Most BRAF mutations are the result of a single nucleotide substitution in which valine is replaced by glutamic acid at codon 600 (V600E) of exon 15, lead-ing to the constitutive activation of the MEK protein and ERKs, which are essential to melanoma cell prolifera-tion. Melanoma cells with the BRAF mutation do not require Ras activation to proliferate, indicating that the BRAF mutation is a driving force behind melanoma cell growth.

To inhibit the Raf/MEK/ERK pathway, researchers investigated sorafenib (Nexavar, Bayer), an inhibitor of multiple kinases, including BRAF, CRAF, and vascular endothelial growth factor receptor (VEGFR). However, 2 Phase II trials of sorafenib at a dose of 400 mg twice daily revealed that the drug elicited little or no response in patients with metastatic melanoma; additional-ly, the presence of the BRAF mutation was not corre-lated with response.21,22 Similarly, 2 large randomized Phase III trials revealed that the addition of sorafenib to front- or second-line carboplatin or paclitaxel yield-ed no additional clinical benefit in patients with meta-static melanoma.23,24

Despite the underwhelming results with sorafenib, researchers used scaffold-based drug design methods to develop increasingly selective inhibitors of the mutat-ed Raf kinase. One of these new drugs, PLX4032 (later

named vemurafenib [Zelboraf, Roche]), was found to have a high affinity for the mutant BRAF kinase.25 A first-in-human Phase I trial of oral vemurafenib enrolled 55 patients and found the maximum tolerated dose (MTD) of the drug to be 960 mg twice a day.26 Thir-ty-two patients with metastatic melanoma harboring a BRAF mutation were then enrolled in the dose-exten-sion cohort and received vemurafenib at a dose of 960 mg twice a day. Of these 32 patients, 26 had a partial or complete response (CR), for an overall response rate (ORR) of 81% with a confirmed response rate of 56% per Response Evaluation Criteria in Solid Tumors (RECIST).

Subsequently, a large Phase II study of vemurafenib was conducted in 132 previously treated patients who had metastatic melanoma harboring a V600E BRAF mutation.27 The ORR, which was validated by an inde-pendent review committee, was 53%, with a median PFS duration of 6.8 months, thus confirming the prom-ising results of the Phase I study.

A concurrent, large multicenter randomized Phase III trial was then conducted to compare the clinical benefit of vemurafenib with that of dacarbazine in treatment-naive patients with metastatic melanoma harboring a V600E BRAF mutation (Table 1).5 Six hun-dred seventy-five patients were randomized to receive either vemurafenib or dacarbazine, with the primary end points being OS and PFS. At the time of the inter-im analysis, the hazard ratio for death in the vemu-rafenib group was 0.37 (P<0.001), and the estimated median PFS duration of patients in the vemurafenib arm (5.3 months) was significantly longer than that of patients in the dacarbazine arm (1.6 months; HR, 0.26; P<0.001). The study was stopped at the time of

Table 1. Clinical Data From Positive Phase III Studies of Melanoma

Trial and Regimen NTreatment Setting

Primary End Point Results

Hazard Ratio (95% CI) P Value

NCT00094653

gp100 vaccine 136 Second-line OS, 6.4 mo Reference

Ipilimumab 137 OS, 10.1 mo 0.66 (0.51-0.87) 0.003

Ipilimumab + gp100 vaccine 403 OS, 10.0 mo 0.68 (0.55-0.85) <0.001

NCT00324155

Dacarbazine + placebo 252 First-line OS, 9.1 mo Reference

Dacarbazine + ipilimumab 250 OS, 11.2 mo 0.72 (0.59-0.87) <0.001

NCT01006980

Dacarbazine 338 First-line; V600E BRAF mutation

OSa Reference

Vemurafenib 337 OSa 0.37 (0.26-0.55) <0.001

Dacarbazine 338 PFS, 1.6 mo Reference

Vemurafenib 337 PFS, 5.3 mo 0.26 (0.20-0.33) <0.001

CI, confidence interval; gp100, glycoprotein 100; OS, overall survival; PFS, progression-free survival

a Inadequate number of patients in follow-up to provide reliable estimates of the survival curve

IN D E PE N D E N TLY D E VE LOPE D BY MCMA HON PUBL ISHING 3

the interim analysis so that patients in the dacarbazine arm could receive vemurafenib.

Overall, patients in the Phase III trial tolerated vemurafenib fairly well.5 The most common AEs were arthralgias, fatigue, and cutaneous events. Twelve per-cent of patients experienced grade 2 or 3 photosensi-tivity reactions, but the use of sunblock helped prevent the blistering typically observed in grade 3 reactions. Eighteen percent of patients developed either cutane-ous squamous cell carcinomas (SqCC) or keratoacan-thomas; fortunately, these were all treated by simple excision with no further complications or evidence of SqCC in other organs.

These SqCCs could have been the result of the par-adoxical activation of the Ras/Raf/MEK/ERK pathway in premalignant skin lesions that lack a BRAF muta-tion.28,29 Poulikakos et al demonstrated that the bind-ing of vemurafenib to BRAF, which forms a dimer with another Raf kinase, actually leads to transactivation of adenosine triphosphate (ATP)-bound Raf, causing the downstream activation of MEK and ERK in wild-type BRAF cells.30 Many vemurafenib-induced SqCCs harbor a mutation in Ras that ultimately becomes activated

when vemurafenib binds to wild-type BRAF.28,29

Based on the statistically significant improvement in both OS and PFS and the acceptable safety profile, in summer 2011 the FDA approved vemurafenib for the treatment of metastatic melanoma harboring a V600E BRAF mutation. However, despite the high response rate, a majority of patients will have disease progression with-in 1 year, and a long-term clinical benefit is expected only in a small subset of patients. Therefore, more effective therapeutic strategies are urgently needed.

Emerging Targeted Therapies

SELECTIVE RAF INHIBITORS

The successful development of vemurafenib has gen-erated great interest in the clinical evaluation of selec-tive Raf inhibitors in patients with metastatic melanoma harboring a BRAF mutation. One such agent, dabrafenib (GSK2118436, GlaxoSmithKline) is an orally available, highly potent ATP-competitive inhibitor of BRAF.31 In a Phase I/II study in patients with advanced solid tumors, dabrafenib was well tolerated, and the MTD was not reached.32 Dabrafenib inhibited the phosphorylation of

Figure. Commonly activated signal transduction pathways in melanoma.ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin

AKT

PI3K

p70

mTOR

IF4E

PTEN

Cell membranereceptor

Transcription factors

Cyclin D1 MMP-2

Tumor cell survival, proliferation, invasion

Nucleus

ERK 1/2

Raf

Ras

MEK 1/2


ERK in a dose-dependent manner, and based on the pharmacokinetics and pharmacodynamics of the drug and its early clinical activity in the Phase I study, inves-tigators recommended a dose of 150 mg twice daily for further studies. Of the 16 patients in the study who had metastatic melanoma harboring a V600 BRAF mutation and received at least 150 mg of dabrafenib twice daily, 10 (63%) had a partial response. Interestingly, of the 10 patients in the study who had active brain metastases measuring at least 3 mm at baseline, 7 also had a clinical response in the brain lesions.33

Subsequently, a Phase II study of dabrafenib enrolled 76 patients who had metastatic melanoma harboring a V600E/K BRAF mutation.34 Of these 76 patients, 45 (59%) had a confirmed response to dabrafenib, and the median PFS duration was 27.4 weeks. The common AEs associated with dabrafenib were arthralgia, pyrexia, fatigue, hyperkeratosis, and SqCC of the skin. A Phase III study (NCT01227889) is under way to compare dab-rafenib and dacarbazine with respect to PFS in treat-ment-naive patients with metastatic melanoma who harbor a V600E BRAF mutation (Table 2).

Another promising selective Raf inhibitor is LGX818 (Novartis). The results of a Phase I trial of the drug (NCT01436656) will be available shortly.

MEK INHIBITORS

Another approach to treating metastatic melanoma is to inhibit the mitogen-activated protein (MAP) kinase pathway at the level downstream of BRAF kinase. This pathway is commonly activated in melanoma and is induced not only by mutated BRAF, but also by kinase-activating NRAS mutations or other upstream aberra-tions, such as receptor kinase phosphorylation. In this signal transduction pathway, the MAP kinase kinase (MEK) protein is the direct substrate of activated BRAF kinase. Therefore, targeting the MEK protein can inhibit the MAP kinase pathway.

The results of clinical trials of first-generation MEK inhibitors were disappointing. For example, CI-1040 (Pfizer) and PD0325901 (Pfizer) had poor clinical activ-ity and caused significant AEs, including retinal vein occlusion, that resulted in the discontinuation of their development.35,36 Selumetinib (AZD6244, AstraZeneca) is an orally available, highly selective, allosteric inhibi-tor of MEK1/2. Although in vitro studies revealed that melanoma cell lines containing a BRAF mutation were particularly sensitive to selumetinib,37,38 a randomized Phase II study showed that the drug had no clinical ben-efit over temozolomide in chemotherapy-naive patients with metastatic melanoma.39 The differences in the median PFS duration (78 vs 80 days) and ORR (5.8% vs 9.4%) between the patients who received selumetinib and those who received temozolomide, respectively, were not statistically significant, and the response rates among patients with melanoma containing a BRAF mutation in each group were both the same, at 11%.

Clinical outcomes with the next-generation, hydro-gen sulfate (Hyd-sulfate) formulation of selumetinib,

which has better oral bioavailability than does the origi-nal crystalline formulation, are more promising. A Phase I dose-finding study revealed the MTD of Hyd-sulfate selu-metinib to be 75 mg twice daily.40 In a separate Phase I study of combination regimens containing Hyd-sulfate selumetinib, patients with metastatic melanoma with a BRAF mutation had a higher clinical response rate and longer median time to progression than did those with-out a BRAF mutation, suggesting that BRAF mutation is a positive predictive factor for Hyd-sulfate selumetinib.41 A randomized Phase II study comparing dacarbazine plus Hyd-sulfate selumetinib with dacarbazine alone in treatment-naive patients with BRAF-mutated melanoma (NCT00936221) recently completed patient accrual, and the results of this study are highly anticipated.

Another potent, highly selective, non–ATP-competitive MEK1/2 inhibitor is trametinib (GSK1120212, GlaxoSmith-Kline). Although a Phase I study revealed the MTD of tra-metinib to be 3 mg per day, 2 mg per day was chosen as the recommended dose for future studies on the basis of pharmacokinetic, clinical activity, and safety data.42 The results of a recent Phase II study of trametinib (2 mg/d) in 97 previously treated patients with metastatic melanoma harboring a V600 BRAF mutation are encouraging.43 In this study, of the 57 patients who had not been previously treated with a BRAF inhibitor (of whom 81% had a V600E

Table 2. Ongoing Phase III Clinical Trials for Metastatic Melanoma

Trial and Regimen

Treatment Setting

Mutation Criteria

Primary EndPoint N

NCT01227889

Dabrafenib (GSK2118436)versusdacarbazine

First-line V600E BRAF mutation

PFS 249

NCT01245062

Trametinib (GSK1120212)versusdacarbazine or paclitaxel

≤1 prior systemic chemo-therapy

V600E/K BRAF mutation

PFS 322

NCT01280565

Masitinibversusdacarbazine

First-line C-Kit (juxta-mem-brane)

OS 200

NCT01515189

Ipilimumab (3 mg/kg)versusipilimumab (10 mg/kg)

First-line Any OS 700

OS, overall survival; PFS, progression-free survival


BRAF mutation and 75% had M1c disease), 14 (25%) had a confirmed response, and the median PFS duration was 4 months (95% confidence interval [CI], 3.5-5.6 months). However, of the 40 patients who had previously received a BRAF inhibitor, none had a confirmed clinical response, and the median PFS duration was 1.8 months (CI, 1.8-2.0 months). The marked differences in clinical response and PFS between the 2 groups suggest that the mechanisms of resistance to BRAF inhibitors also might confer resis-tance to MEK inhibitors. The results of an open-label ran-domized Phase III study (NCT01245062) comparing the PFS associated with trametinib with those associated with dacarbazine or paclitaxel in patients with metastat-ic melanoma harboring a V600 BRAF mutation will be available shortly (Table 2).

Other MEK inhibitors in the early phases of clinical investigation include AS703026 (EMD/Merck Serono), E6201 (Eisai), MEK162 (Novartis), and GDC-0973 (Genentech).

The common AEs of MEK inhibitors include skin rash, diarrhea, nausea, vomiting, peripheral edema, and fatigue.35,36,39,40,42,43 Visual disturbances, such as blurry vision or flashing lights, are common but generally mild. Serious ocular toxicity, including central serous reti-nopathy and retinal vein occlusion, is uncommon. The decreased left ventricular ejection fraction associated with the use of MEK inhibitors is mostly asymptomat-ic and is reversible upon discontinuation of the drugs.

COMBINATION STRATEGIES USING TARGETED THERAPIES

Despite the high response rates observed with Raf inhibitors and the promising clinical activity of MEK inhibitors in patients with advanced melanoma har-boring a BRAF mutation, the durations of response to these drugs are relatively short because of acquired drug resistance. Recent studies have elucidated a number of mechanisms of resistance to these drugs, including acquisition of activating NRAS mutations,44 acquisition of activating MEK mutations,45 upregulation of upstream receptor kinases,46 upregulation of CRAF kinase,47 induction of splicing variants of BRAF kinase,48 increased Cot expression,49 and activation of PI3K/AKT signaling pathways.50,51 Loss of BRAF mutations and the development of secondary mutations to the drug-bind-ing domain of BRAF kinase have not been observed at the time of drug resistance, however.44,46

A recent study found that although vemurafenib universally inhibited the phosphorylation of tumoral ERK1/2 protein within 14 days of treatment, the phos-phorylated-ERK1/2 was re-upregulated at the time of disease progression in a subset of patients.52 This find-ing suggests that in at least some patients, the reacti-vation of the MAP kinase pathway is associated with resistance to the Raf inhibitors and can, at least partial-ly, bypass the inhibition of the BRAF mutations. In vitro studies have shown that the addition of a MEK inhibi-tor can delay the development of drug resistance to a selective Raf inhibitor.45

On the basis of these encouraging findings, a Phase I

study of dabrafenib plus trametinib (NCT01072175) was conducted in patients with metastatic melanoma. The clinical data generated from the study’s interim analysis are promising.53,54 Given at the recommended doses for a Phase II study, the combination of dab-rafenib (150 mg twice daily) and trametinib (1-2 mg per day) was well tolerated, with mild AEs, the most common of which were pyrexia, chills, nausea, diar-rhea, and fatigue.53 Skin toxicity, including the develop-ment of cutaneous SqCC, occurred much less commonly than was anticipated based on the safety data of dabrafenib treatment alone, suggesting that treatment with the selective Raf inhibitor paradoxical-ly activated MAP kinase in the normal skin, and the concurrent treatment with MEK eliminated this para-doxical MAP kinase activation. Of the 65 patients who had metastatic melanoma containing a V600E/K/D BRAF mutation and who had never received a BRAF inhibitor, 43 (66%) had objective responses, including 5 (8%) CRs.53 Additionally, of the 26 patients who pre-viously had been treated with a selective Raf inhibitor, 5 (19%) had partial responses.54

KIT INHIBITORS

Preclinical findings demonstrating the essential role of stem cell factor and its receptor, KIT tyrosine kinase, in the proliferation and survival of melanocyte precur-sors,55,56 and KIT’s frequent expression in melanoma spec-imens56,57 led investigators to conduct 3 studies evaluating the use of imatinib (Gleevec, Novartis) in patients with metastatic melanoma in the early 2000s.58-60 Unfortu-nately, imatinib had minimal clinical activity, with only 1 of 63 patients (who had not been selected on the basis of genomic biomarkers) responding to the drug.

Interest in KIT-targeted therapy in melanoma was renewed when Curtin et al showed that KIT mutation and/or amplification is more common in certain sub-types of melanoma than in others.61 In their analysis of 102 primary melanomas, they used a comparative genomic hybridization assay and found KIT mutations and/or increased copy numbers of KIT in 36% of acral lentiginous melanomas, 39% of mucosal melanomas, and 28% of melanomas that developed in chronical-ly sun-damaged skin. Following this novel discovery, a number of case reports have emerged showing that KIT inhibitors have clinical benefit in patients who have melanoma harboring KIT mutations.62-65 Additionally, the interim analysis of a Phase II study of imatinib in patients with advanced acral lentiginous melanoma, mucosal melanoma, or melanoma in chronic sun-dam-aged skin revealed that 5 of 10 patients with melanoma harboring a KIT mutation had a clinical response to the drug.66 However, none of 10 patients with KIT amplifi-cation without a mutation had a response.

In another Phase II study of imatinib in 43 patients with metastatic melanoma harboring a KIT mutation or amplification, 10 (23%) patients had an overall clinical response, and 9 of the 10 responders had a KIT muta-tion in exon 11 or 13.67 In a separate Phase II study of


imatinib in a similar population, 4 (16%) of 25 patients had a durable clinical response, including 2 patients who had CRs.68 The response rate among patients who had mutations affecting recurrent hotspots of the KIT gene or a higher KIT mutant-to-wild-type allele ratio (>1) was 40%, whereas the response rate among patients who did not have these features was 0% (P=0.05), suggesting that the presence of a func-tionally relevant KIT mutation is required for imatinib or other KIT inhibitors to have clinical benefit.

Emerging Immunotherapies

ANTI-PD1 ANTIBODY

Like CTLA-4, programmed death 1 (PD-1) is a mem-ber of the CD28 family. PD-1 is expressed in activated T cells, memory T cells, and regulatory T cells and is involved in T-cell regulation. Upon binding to its ligands, PD-L1 and PD-L2 (which are highly expressed in tumor cells and the antigen-presenting cells found in tumors), PD1 suppresses T-cell effector function. Tumoral PD-L1 expression has been associated with negative progno-sis in cancer patients.69,70

MDX-1106 (Bristol-Myers Squibb), a fully human immunoglobulin G4 monoclonal antibody against PD-1, can interrupt the binding of PD-1 with its ligands, there-by reactivating T-cell function.71 In a Phase I dose-esca-lating study evaluating a single dose of the drug (with 2 additional doses every 4 weeks allowed in patients in whom continued clinical benefit was observed), MDX-1106 was well tolerated with only one serious AE (colitis).72 Of the 39 patients in the study, 3 patients, including one with metastatic melanoma, had a clinical response to MDX-1106.

Another Phase I study evaluated the safety profile of a biweekly dosing schedule of MDX-1106 in patients with refractory metastatic non-small cell lung can-cer, renal cell carcinoma, melanoma, or prostate can-cer.73 The MTD of the drug was not reached up to a dose of 10 mg/kg every 2 weeks. Common AEs includ-ed fatigue, nausea, diarrhea, xerostomia, and pruritus, but grade 3 or 4 AEs were uncommon. In the prelim-inary response evaluation, 6 (38%) of 16 patients had objective responses; among these patients, 3 patients with metastatic melanoma had a partial response. The clinical investigation of MDX-1106 is ongoing.

ADOPTIVE T-CELL THERAPY

In the mid-1980s, Rosenberg et al found that tumor-infiltrating lymphocytes (TILs) isolated from murine sarcomas and colon adenocarcinomas that had been transplanted into syngeneic mice could be expanded with IL-2 in vitro. When infused back into the donor mice, the TILs could mediate the regression of meta-static tumors.74 They later reported the regression of metastatic melanoma lesions in 11 of 20 patients who were treated with the adoptive transfer of TILs and IL-2 infusion following a single dose of cyclophos-phamide.75 Other researchers found that when the

adoptive transfer of TILs and IL-2 infusion were pre-ceded by a 7-day regimen of cyclophosphamide and fludarabine, which depleted the number of endoge-nous regulatory cells and lymphocytes that would compete with the transferred TILs for growth-promot-ing homeostatic cytokines, 6 of 13 patients had a clin-ical response.76 Notably, this approach resulted in the persistent clonal repopulation of T cells, which pro-liferated in vivo and traveled to tumor sites in these patients.

In an expanded Phase II study conducted by the same group of investigators, lympho-depleting che-motherapy followed by TIL transfer and high-dose IL-2 infusion elicited a response rate of 51% among 35 patients with metastatic melanoma.77 When TIL trans-fer and IL-2 infusion were preceded by myeloablative chemoradiation (lympho-depleting chemotherapy plus 2 or 12 Gy of total-body irradiation), clinical activ-ity of the regimen was even better, with response rates of 52% and 72%, respectively.78 Of 20 patients who had CRs in these trials of adoptive TIL transfer, only 1 patient’s disease has relapsed. The other patients con-tinue to have CRs 3 to 7 years following the comple-tion of the treatment.78,79

In another study, CD4-positive T-cell clones tar-geting the DPB1*0401-restricted epitope of a peptide derived from NY-ESO-1 were isolated from the peripher-al blood mononuclear cells of patients with metastatic melanoma and expanded in vitro, and the antigen-spe-cific CD4-positive T cells were infused back into the patient.80 One patient had a complete resolution of lung and nodal metastases that was accompanied by the persistent presence of the NY-ESO-1–specific CD4-pos-itive T cells and lasted for at least 2 years. This finding suggests that the adoptive transfer of antigen-specif-ic CD4-positive T cells may be used to treat advanced melanoma.

ConclusionAfter a long drought in the development of suc-

cessful therapies, recent advances in targeted ther-apy and immunotherapy have set a new standard of treatment for metastatic melanoma. However, the arrival of ipilimumab and vemurafenib in the clinic has generated more questions and challenges. For exam-ple, it is not clear which of these agents, ipilimum-ab or vemurafenib, should be offered first in patients with metastatic disease, especially in those with lim-ited or slowly progressing metastatic lesions; in addi-tion, the optimal sequencing of high-dose IL-2 with these agents remains unknown. Whether a Raf inhib-itor should be added to subsequent therapy follow-ing the failure of BRAF inhibition is also unclear. The optimal combination of targeted drugs and/or immu-notherapeutic agents will need to be determined to maximize their clinical benefit in patients with meta-static melanoma. We hope that these important ques-tions soon will be addressed with rationally designed clinical studies.


References1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA

Cancer J Clin. 2012;62(1):10-29, PMID: 22237781.

2. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17(9):2745-2751, PMID: 10561349.

3. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18(1):158-166, PMID: 10623706.

4. Bedikian AY, Millward M, Pehamberger H, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006;24(29):4738-4745, PMID: 16966688.

5. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516, PMID: 21639808.

6. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarba-zine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517-2526, PMID: 21639810.

7. Rosenberg SA, Lotze MT, Yang JC, et al. Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol. 1989;7(12):1863-1874, PMID: 2685181.

8. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombi-nant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6 Suppl 1:S11-S14, PMID: 10685652.

9. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melano-ma. N Engl J Med. 2004;351(10):998-1012, PMID: 15342808.

10. van der Bruggen P, Traversari C, Chomez P, et al. A gene encod-ing an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991;254(5038):1643-1647, PMID: 1840703.

11. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 con-secutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271(12):907-913, PMID: 8120958.

12. Smith FO, Downey SG, Klapper JA, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vac-cines. Clin Cancer Res. 2008;14(17):5610-5618, PMID: 18765555.

13. Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol. 2001;1(3):220-228, PMID: 11905831.

14. Lee KM, Chuang E, Griffin M, et al. Molecular basis of T cell inactivation by CTLA-4. Science. 1998;282(5397):2263-2266, PMID: 9856951.

15. Weber JS, O’Day S, Urba W, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26(36):5950-5956, PMID: 19018089.

16. Hersh EM, O’Day SJ, et al. A phase II multicenter study of ipilim-umab with or without dacarbazine in chemotherapy-naive patients with advanced melanoma. Invest New Drugs. 2011;29(3):489-498, PMID: 20082117.

17. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723, PMID: 20525992.

18. Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncolo-gist. 2007;12(7):864-872, PMID: 17673617.

19. Peyssonnaux C, Eychene A. The Raf/MEK/ERK pathway: new con-cepts of activation. Biol Cell. 2001;93(1-2):53-62, PMID: 11730323.

20. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954, PMID: 12068308.

21. Eisen T, Ahmad T, Flaherty KT, et al. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer. 2006;95(5):581-586, PMID: 16880785.

22. Ott PA, Hamilton A, Min C, et al. A phase II trial of sorafenib in metastatic melanoma with tissue correlates. PLoS One. 2010;5(12):e15588, PMID: 21206909.

23. Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination

with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27(17):2823-2830, PMID: 19349552.

24. Flaherty KT, Lee SJ, Schuchter LM, et al. Final results of E2603: a double-blind, randomized phase III trial comparing carboplatin/paclitaxel (P) with or without sorafenib (S) in metastatic melano-ma. J Clin Oncol. 2010;28(15 suppl). Abstract 8511.

25. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467(7315):596-599, PMID: 20823850.

26. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809-819, PMID: 20818844.

27. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707-714, PMID: 22356324.

28. Oberholzer PA, Kee D, Dziunycz P, et al. RAS mutations are associ-ated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol. 2012;30(3):316-321, PMID: 22067401.

29. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207-215, PMID: 22256804.

30. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464(7287):427-430, PMID: 20179705.

31. Takle AK, Brown MJ, Davies S, et al. The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett. 2006;16(2):378-381, PMID: 16260133.

32. Kefford K, Arkenau H, Brown MP, et al. Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. J Clin Oncol. 2010;28(15suppl). Abstract 8503.

33. Long GV, Kefford R, Carr P, et al. Phase I/II study of GSK2118436, a selective inhibitor of v600 mutant (mut) BRAF kinase: evidence of activity in melanoma brain metastases (mets). Presented at: 35th European Society for Medical Oncology ESMO Congress 2011;21 (suppl 8). Abstract LBA27.

34. Trefzer U, Minor D, Ribas A, et al. BREAK-2: a Phase IIA trial of the selective BRAF kinase inhibitor GSK2118436 in patients with BRAF mutation-positive (V600E/K) metastatic melanoma. Pigment Cell Melanoma Res. 2011;24(5):1020. Abstract LBA 1-1.

35. LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al. Phase I phar-macokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res. 2010;16(6):1924-1937, PMID: 20215549.

36. Rinehart J, Adjei AA, Lorusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol. 2004;22(22):4456-4462, PMID: 15483017.

37. Yeh TC, Marsh V, Bernat BA, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007;13(5):1576-1583, PMID: 17332304.

38. Haass NK, Sproesser K, Nguyen TK, et al. The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res. 2008;14(1):230-239, PMID: 18172275.

39. Kirkwood JM, Bastholt L, Robert C, et al. Phase II, open-label, ran-domized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18(2):555-567, PMID: 22048237.

40. Banerji U, Camidge DR, Verheul HM, et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibi-tor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010;16(5):1613-1623, PMID: 20179232.

41. Patel SP, Lazar AJ, Mahoney S, et al. Clinical responses to AZD6244 (ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma. J Clin Oncol. 2010;28(suppl). Abstract 8501.


42. Infante JR, Fecher LA, Nallapareddy S, et al. Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212. J Clin Oncol. 2010;28(15suppl). Abstract 2503.

43. Kim KB, Lewis K, Pavlick A, et al. A phase II study of the MEK1/MEK2 inhibitor GSK1120212 in metastatic BRAF-V600E or K mutant cutaneous melanoma patients previously treated with or without a BRAF inhibitor. Pigment Cell Melanoma Res. 2011;24(5):1021 (Abst. LBA 1-3).

44. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468(7326):973-977, PMID: 21107323.

45. Emery CM, Vijayendran KG, Zipser MC, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20411-20416, PMID: 19915144.

46. Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18(6):683-695, PMID: 21156289.

47. Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68(12):4853-4861, PMID: 188559533.

48. Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480(7377):387-390, PMID: 22113612.

49. Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468(7326):968-972, PMID: 21107320.

50. Jiang CC, Lai F, Thorne RF, et al. MEK-independent survival of B-RAFV600E melanoma cells selected for resistance to apop-tosis induced by the RAF inhibitor PLX4720. Clin Cancer Res. 2011;17(4):721-730, PMID: 21088259.

51. Shao Y, Aplin AE. Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res. 2010;70(16):6670-6681, PMID: 20647317.

52. McArthur GA, Ribas A, Chapman PB, et al. Molecular analyses from a phase I trial of vemurafenib to study mechanism of action (MOA) and resistance in repeated biopsies from BRAF mutation-positive metastatic melanoma patients (pts). J Clin Oncol. 2011;29(suppl). Abstract 8502.

53. Infante JR, Falchook GS, Lawrence DP, et al. Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436). J Clin Oncol. 2011;29:(suppl). Abstract CRA8503.

54. Flaherty KT, Infante JR, Falchook GS, et al. Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who pro-gressed on a prior BRAF inhibitor. Pigment Cell Melanoma Res. 2011;24(5):1022. Abstract LBA 1-4.

55. Kawa Y, Ito M, Ono H, et al. Stem cell factor and/or endothelin-3 dependent immortal melanoblast and melanocyte popula-tions derived from mouse neural crest cells. Pigment Cell Res. 2000;13(suppl 8):73-80, PMID: 11041361.

56. Shen SS, Zhang PS, Eton O, Prieto VG. Analysis of protein tyrosine kinase expression in melanocytic lesions by tissue array. J Cutan Pathol. 2003;30(9):539-547, PMID: 14507401.

57. Went PT, Dirnhofer S, Bundi M, et al. Prevalence of KIT expression in human tumors. J Clin Oncol. 2004;22(22):4514-4522, PMID: 15542802.

58. Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer. 2005;92(8):1398-1405, PMID: 15846297.

59. Wyman K, Atkins MB, Prieto V, et al. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer. 2006;106(9):2005-2011, PMID: 16565971.

60. Kim KB, Eton O, Davis DW, et al. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer. 2008;99(5):734-740, PMID: 18728664.

61. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24(26):4340-4346, PMID: 16908931.

62. Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol. 2008;26(12):2046-2051, PMID: 18421059.

63. Lutzky J, Bauer J, Bastian BC. Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res. 2008;21(4):492-493, PMID: 18510589.

64. Quintas-Cardama A, Lazar AJ, Woodman SE, Kim K, Ross M, Hwu P. Complete response of stage IV anal mucosal melanoma expressing KIT Val560Asp to the multikinase inhibitor sorafenib. Nat Clin Pract Oncol. 2008;5(12):737-740, PMID: 18936790.

65. Handolias D, Hamilton AL, Salemi R, et al. Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT. Br J Cancer. 2010;102(8):1219-1223, PMID: 20372153.

66. Hodi FS, Friedlander P, Corless C, et al. Phase II trial of imatinib in KIT mutant/amplified melanoma. Presented at: 6th Annual International Melanoma Congress 2009: Boston, MA. Abstract.

67. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011;29(21):2904-2909, PMID: 21690468.

68. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305(22):2327-2334, PMID: 21642685.

69. Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prog-nostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104(9):3360-3365, PMID: 17360651.

70. Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 2006;66(7):3381-3385, PMID: 16585157.

71. Wong RM, Scotland RR, Lau RL, et al. Programmed death-1 block-ade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int Immunol. 2007;19(10):1223-1234, PMID: 17898045.

72. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immuno-logic correlates. J Clin Oncol. 2010;28(19):3167-3175, PMID: 20516446.

73. Sznol M, Powderly JD, Smith DC, et al. Safety and antitumor activ-ity of biweekly MDX-1106 (Anti-PD-1, BMS-936558/ONO-4538) in patients with advanced refractory malignancies. J Clin Oncol. 2010;28(15 suppl). Abstract 2506.

74. Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lympho-cytes. Science. 1986;233(4770):1318-1321, PMID: 3489291.

75. Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infil-trating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988;319(25):1676-1680, PMID: 3264384.

76. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298(5594):850-854, PMID: 12242449.

77. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemo-therapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346-2357, PMID: 15800326.

78. Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):5233-5239, PMID: 18809613.

79. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adop-tive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8(4):299-308, PMID: 18354418.

80. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 2008;358(25):2698-2703, PMID: 18565862.


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