the march 2013 digital edition of clinical oncology news

Today, oncology practices interested in becoming oncology medical homes (OMHs) are lucky in one respect: They don’t have to reinvent the wheel. They can seek

advice from existing OMHs and oncology management consultant groups. So, what is involved in transforming a clinic?

There isn’t one formula, but several common themes emerged when Clinical Oncolo-gy News talked to experts about what it takes to create an OMH, a patient-focused sys-tem that delivers quality, coordinated and efficient cancer care. Key aspects include the use of team-based care, streamlined electronic medical records, software that allows tracking of physician compliance with pathways and prompting for real-time evidence-based decision making, and a telephone triage system. At the foundation, the transition

‘We Prevent Complications, Rather Than Chase Them’Medical home model begins to change community oncology practiceIn October 2012, my

office manager an-nounced that I can no longer give IV cyclo-phosphamide to Medi-care patients because I will lose about $100 on every 500 mg given. For a large lymphoma patient, this can add up to a loss of $400 for each dose of R-CHOP chemotherapy given, far more than I get paid for caring for this patient. Medicare rules forbid me from billing the patient as a result of

Vogl, NY...

CyclophosphamidePrices SkyrocketCauses and effects

INSIDE

Bevacizumab effective, tolerablein older CRC patients .................. 18

Cabozantinib promising for castration-resistant prostate cancer ...... 19

REVIEWS & COMMENTARIES

Manish Kohli, MDAxel Grothey, MD

Expert Insights From Mayo Clinic Cancer Center

SOLID TUMORS

Gastrointestinal Cancers SymposiumColorectal subtypes:

Ready for prime time? ...... 13

ESMODebate: Should neoadjuvant

data be used to accelerate

drug approval? ................... 20

Multi-targeted TKI promising

second-line neuroendocrine

option ...................................... 24

Stage III colorectal cancer:

Adding cetuximab gives

no benefit .............................. 24

HEMATOLOGIC DISEASE

Phase III data supports

bendamustine in NHL

and MCL ................................... 4

Rituximab Improves B-Cell

Lymphoma Survival ............ 16

CURRENT PRACTICE

Maurie Markman, MD:

Diagnostic imaging:

A double-edged sword ...... 3

FDA drug actions ............... 26

Clinical Conundrums ......... 29

see MEDICAL HOME, page 8EE �

see VOGL, NY, page 5 YY �

NEW ColumnThe Tumor Board: Is

laparoscopic distal

pancreatectomy the new

‘gold standard’? ................ 10

Steven Vogl, MD

“Blossom Tree,” an alternate view of mucinous carcinoma.

Independent News on Advances in Hematology/Oncology

CLINICALONCOLOGY.COM • March 2013 • Vol. 8, No. 3

on the cover

Our cover features the artwork of Marie Sicari, MD, a pathologist, visual artist and performer whose digital art

photography project focuses on the imagery of human disease. Dr. Sicari specializes in the fields of anatomic pathology and dermatopathology.

Dr. Sicari’s digital abstract art explores the fantastic imagery of microscopic pathology as a potential tool to access and explore the mind-body-spirit connection. Her work reflects the paradigmshift occurring in medicine towards the inclusion of holistic approaches and the role of creative arts in the healing process.

If you are interested in purchasing this piece or otherwork from her collection, Dr. Sicari may be reached at www.behance.net/MarieSicari

2 CLINICAL ONCOLOGY NEWS • MARCH 2013CURRENT PRACTICE

EDITORIAL BOARD

Solid TumorsBone Metastases

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

Breast Cancer

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

Maura N. Dickler, MDMemorial Sloan-KetteringCancer Center,Weill Cornell Medical CollegeNew York, NY

Gastrointestinal Cancer

Edward Chu, MDUniversity of PittsburghCancer Institute, University of PittsburghPittsburgh, PA

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

Leonard Saltz, MDMemorial Sloan-KetteringCancer Center,Weill Cornell Medical CollegeNew York, NY

Gastrointestinal Cancer and Sarcoma

Ephraim Casper, MDMemorial Sloan-KetteringCancer Center,Weill Cornell Medical CollegeNew York, NY

Genitourinary Cancery

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

Gynecologic Cancery g

Maurie Markman, MDCancer Treatment Centers of AmericaPhiladelphia, PA

Lung and Head and Neck Cancersg

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

Lung Cancer, Emesisg ,

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 ProstateCancer 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 AlabamaBirmingham, AL

Shaji Kumar, MDMayo Clinic Rochester, MN

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

Syed A. Abutalib, MDCancer Treatment Centers of AmericaZion, Illinois

Community OncologyJohn W. Finnie, MDMercy Medical CenterSt. Louis, MO

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

Steven Vogl, MDMedical OncologistNew York, NY

Symptom Control and Palliative Care

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

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

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

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

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

Oncology Nursing

Betty Ferrell, RN, PhDCity of HopeNational Medical Center Duarte, CA

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

Pharmacy

Cindy O’Bryant, PharmDUniversity of ColoradoCancer Center Denver, CO

Sara S. Kim, PharmDThe Mount SinaiMedical Center New York, NY

BioethicsJoseph P. DeMarco, PhDCleveland State University Cleveland, OH

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

Policy and ManagementMary Lou Bowers, MBAThe Pritchard Group Rockville, MD

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

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

Editorial PhilosophyThe Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears inthe 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 seach 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 andhematologists in providing the best possible care for their patients.

The potential harm resulting fromoverexposure to ionizing radiation

as a result of our substantial increase indiagnostic imaging strategies is among the most complex health-related discus-sions within our society.1-3 There are a number of components of this dilemma that increase the difficulty of develop-ing an objective and rational consensusregarding these strategies.

First, the dangers associated withradiation have been well known to thepublic for more than 60 years, beginning with the decision to drop atomic bombson Japan to hasten the end of World WarII and continuing through the “ColdWar” era and into the present in frequentnational discussions regarding the wisdomof building and/or maintaining nuclearpower plants. Furthermore, any discussionof the risk factors for common and lessserious skin cancers (e.g., localizedbasal cell carcinoma) or potentially farmore deadly conditions (e.g., malignantmelanoma) includes the major roleof exposure to natural radiation fromthe sun.

Second, any discussion of the concept of relative risk—including the well-estab-lished potential for radiation-associated malignant disease—versus benefit either at the societal level or for the individu-al patient is fraught with hazard as that theoretical ratio (“risk/benefit”) actual-ly relates to a population of patients or members of society and not to a particu-lar patient or individual.

Finally, this issue is made even more complex as we increasingly understand that this theoretical risk is clearly cumu-lative in nature. As a result, it may not be this particular test (e.g., a computed tomography [CT] scan to evaluate non-specific but persistent abdominal pain lasting for two weeks) that is worrisome, but rather the multiple procedures per-formed over many years or decades in a single individual that are of greatest con-cern. In fact, each individual imaging procedure performed over this extended period of time may have been medically justified, but adding up the total radiation exposure over time may lead one to ques-tion whether several or even many proce-dures could have been avoided.

Thus, when attempting to answer the question of the potential benefit-ver-sus-risk of a single routine (e.g., chest radiograph, mammogram, CT scan of the abdomen/pelvis) or more innova-tive (e.g., CT/PET [positron emission tomography] scan) imaging procedure, the answer may be less than satisfacto-ry in terms of objective data relevant to that patient.

The issues associated with

radiographic imaging present an even more unique challenge in oncology. In addition to the general issues noted above, there are questions of how fre-quently radiographic imaging should be undertaken to detect the presence, con-firm the absence or document the pro-gression of a malignancy.

In addition, as our imaging strategies improve in both sensitivity and specific-ity, and the effectiveness of “earlier inter-vention” as a result of “earlier detection” is confirmed through the conduct of appropriately designed clinical investiga-tions, it is virtually certain these diagnos-tic approaches will be employed increas-ingly in routine oncologic care. This includes a likely increase in both overall utilization and more frequent use in indi-vidual patients.

Several strategies can potentially reduce concerns about the radiograph-ic risks associated with increased use of diagnostic imaging. First, it is crit-ical that the utility of any suggested need for increased radiation exposure be unequivocally documented through well-designed clinical studies. Second, considerable effort should be undertak-en by those involved in the diagnostic imaging field to develop paradigms that maximize the opportunity to obtain use-ful clinical data while minimizing the radiation exposure required in the gen-eration of such data.

Finally, despite the recognized benefits associated with the information obtained from procedures that expose patients to forms of radiation (both external and

internal), it will be important for researchefforts to continue exploring diagnostic strategies that are not dependent on suchexposure (e.g., ultrasound).

It also will be important for oncologists to have a clearer understanding of the potential risks associated with obtaining particular types of imaging (e.g., CT scan vs. CT/PET scan) in different settings (e.g., adjuvant therapy with anticipated long-term survival vs. metastatic disease with expected shorter survival) and the impact of cumulative exposures over time. This will be relevant for both the individual decisions that physicians are called on to make when ordering diagnostic or screen-ing radiographic studies, as well as for dis-cussions they (hopefully) will be having with their own patients about the relativerisks and benefits of these procedures.

References1. Brenner DJ, Hall EJ. Computed tomogra-

phy–an increasing source of radiation expo-sure. N Engl J Med. 2007; 357:2277-2284, PMID: 18046031.

2. Linet MS, Slovis TL, Miller DL, et al. Can-cer risks associated with external radia-tion from diagnostic imaging procedures. Ca Cancer J Clin. 2012; 62:75-100, PMID: 22307864.

3. Smith-Bindman R, Miglioretti DL, John-son E, et al. Use of diagnostic imaging studies and associated radiation expo-sure for patients enrolled in large integrat-ed health care systems, 1996-2010. JAMA. 2012;307:2400-2409, PMID: 22692172.

Diagnostic Imaging in Oncology

A (Potential) Double-Edged Sword

If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor

Gabriel Miller at

[email protected]

Comments or feedback

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

EDITORIAL BOARD COMMENTARY

CLINICAL ONCOLOGY NEWS • MARCH 2013 3CURRENT PRACTICE

McMahon Publishing is a 41-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) ispublished monthly by McMahon Publishing,545 West 45th Street, New York, NY 10036. Corp. Office, 83 Peaceable Street, Redding CT 06896Copyright© 2013 McMahon Publishing, New York, NY. All rights reserved.

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Atlanta—Results from BRIGHT(Bendamustine Rituximab Investiga-tional Non-Hodgkin’s Trial) support theuse of bendamustine (Treanda, Cepha-lon) plus rituximab (BR) in the first-linetreatment of advanced indolent non-Hodgkin’s lymphoma (NHL) or man-tle cell lymphoma (MCL). The PhaseIII trial found that BR was noninferiorto the standards of care, R-CVP (ritux-imab, cyclophosphamide, vincristine andprednisone) and R-CHOP (rituximab,cyclophosphamide, doxorubicin, vin-cristine and prednisone). BR also causedless alopecia and neuropathy.

Ian Flinn, MD, PhD, the director of the Hematologic Malignancies ResearchProgram at the Sarah Cannon ResearchInstitute in Nashville, Tenn., presentedthe results at the annual meeting of theAmerican Society of Hematology (ASH;abstract 902).

According to Joshua Brody, MD, anassistant professor of hematology andmedical oncology at Mount Sinai Schoolof Medicine in New York City, who wasnot involved in the research, BRIGHT“is extremely important” and confirmsresults of the German Study Group Indo-lent Lymphomas (StiL) NHL 1 trial.

“The STiL study, presented by Dr.Mathias Rummel at ASH 2009 andupdated at ASCO [American Society of Clinical Oncology] 2012, was the firstlarge, randomized study to show that BR is at least as effective or possibly betterthan the R-CHOP regimen and appar-ently better tolerated in some impor-tant ways. The use of R-B [BR] increasedsignificantly in 2010 after that data waspresented, although that study has yetto be published in a peer-reviewed jour-nal for more thorough review,” Dr. Bro-dy said. “Personally, our clinical prac-tice changed at that time to incorporate R-B for the majority of our patients whomight have previously received R-CHOPor R-CVP, and we have been generally happy with the results.”

Jennifer Brown, MD, PhD, anattending physician with the Chronic

Lymphocytic Leukemia & Lympho-ma Program at the Dana-Farber Can-cer Institute in Boston, who also was not involved with BRIGHT, agreed. “This study adds to the evidence sug-gesting BR is a very effective regimen in MCL and indolent lymphomas, proba-bly as good and possibly more effective

than our older standard therapies,” she said. She doesn’t use BR for all of her patients, but her group is moving that way. “I think many people are using BR unless the person has very bulky dis-ease that might suggest occult trans-formation, in which case we would use R-CHOP,” she said. “BR often tends to

be better tolerated.”BRIGHT included treatment-naive

patients with indolent NHL or MCL,who were 18 years or older and satis-fied a need-to-treat criteria. Patients had CD20-positive disease, an East-ern Cooperative Oncology Group sta-tus of 0 to 2, and Ann Arbor stage of no less than 11. Patients were preassigned for randomization to either R-CHOP/BR or R-CVP/BR. The evaluable analy-sis included 213 patients who received BR and 206 patients who received R-CHOP or R-CVP.

The complete remission rate was 31% in the bendamustine arm compared with 25% in the R-CHOP/R-CVP arm, with a noninferiority P-value of 0.0225.The P-value for determining superiori-ty did not reach statistical significance (P(( =0.1269). The partial response rate was 65% in the bendamustine arm and 66% in the standard therapy arm.

BR was associated with a higher inci-dence of nausea and vomiting, pyrexia,chills, drug hypersensitivity, decreasedappetite, rash and pruritis (Tables 1 and 2). R-CHOP and R-CVP were associated with a higher incidence of constipation, paresthesia, peripheral neuropathy and alopecia. R-CHOP was associated with a higher incidence of febrile neutropenia and mucosal inflammation.

—Kate O’Rourke

Dr. Flinn disclosed research funding from Teva Pharmaceuticals. Drs. Brown and

Brody have no relevant disclosures.

Bendamustine Efficacy in NHL and MCL ConfirmedPhase III data supports clinical use following StiL NHL 1 trial

Table 1. Comparison of Adverse Events of Any Grade

BR, % R-CHOP, % BR, % R-CVP, %

Nausea 63 58 63 39

Vomiting 29 13 25 13

Constipation 32 40 27 44

Febrile neutropenia 3 6 3 4

Opportunistic infections 10 7 12 9

Peripheral neuropathy 4 20 4 26

Paresthesia <1 12 5 10

Peripheral sensory neuropathy <1 6 3 12

Rash 12 7 18 9

Alopecia 4 51 3 21

BR, bendamustine plus rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone;prednisone; R-CVP,R CVP, rituximab, cyclophosphamide, vincristine and prednisone rituximab, cyclophosphammide, vincristiine and prednisone

Table 2. Comparison of Grade ≥3 Adverse Events

BR, % R-CHOP, % BR, % R-CVP, %

Any event 59 69 58 51

Vomiting 5 0 2 0

Constipation 0 1 0 2

Drug hypersensitivity 3 0 2 0

Any infections 12 5 7 7

Peripheral neuropathy 0 2 <1 <1

Respiratory/thoracic disorders 7 2 7 2

White blood cell count 32 72 43 38

Absolute neutrophil count 39 86 49 56

Lymphocyte count 61 33 63 28

BR, bendamustine plus rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone;prednisone; R-CVP,R CVP, rituximab, cyclophosphamide, vincristine and prednisone rituximab, cyclophosphamidde, vincristinee and prednisone

The study adds weight

to the argument that

bendamustine plus

rituximab is as good,

and possibly better,

than older standard

therapies.

Send us your newsClinical Oncology News appreciates news tips and

suggestions for coverage from readers.

All submissions will be considered for publication.

Write to managing editor Gabriel Miller at

[email protected]

4 CLINICAL ONCOLOGY NEWS • MARCH 2013HEMATOLOGIC DISEASE

inadequate Medicare payments. Sincemy office can seek other sources to pay for the cyclophosphamide, what shesaid is not strictly true. However, every time I plan on giving cyclophospha-mide, I precipitate a crisis search forsome way to pay for the drug that willnot bankrupt my practice.

The history of the wholesale price of cyclophosphamide to one of my distrib-utors is shown in the Table. The pricerose ninefold in three years. It seemsclear that manufacturing costs for thisgeneric drug did not increase at thisrate. Only one company markets thedrug in the United States—Baxter Lab-oratories. The drug that is marketedhere is manufactured in Halle, Germa-ny. Baxter justifies the price increasesbased on the costs of making the drug,maintaining a stable supply and main-taining quality throughout the manu-facturing process.

Compared with the very, very highprices of new arrivals on the oncolo-gy drug market—increases that HagopKantarjian, MD, the director of the Leu-kemia Service at the University of Tex-as MD Anderson Cancer Center hascalled “obscene”—even the inflatedprice of cyclophosphamide is low. Com-pared with marginally effective drugslike eribulin (Halaven, Eisai), ixabepi-lone (Ixempra, Bristol-Myers Squibb),regorafenib (Stivarga, Bayer) and pra-latrexed (Folotyn, Allos Therapeutics),IV cyclophosphamide at $220 per 500mg is a bargain. The price itself, then, is

not the issue, but the rapid rise and its effects are big issues.

Cyclophosphamide given intrave-nously has a special place in the oncol-ogy armamentarium that makes it espe-cially difficult to substitute for it. It is an essential drug in the adjuvant treat-ment of resected breast cancer. Because it causes little or no acute leukemia at conventional doses, it is preferred over drugs like melphalan and thiote-pa. Huge studies have demonstrated that two-drug combinations contain-ing cyclophosphamide are more effec-tive than those without it.

Similarly, curative therapy for diffuse large B-cell lymphoma and Burkitt’s lymphoma depends on intravenous cyclophosphamide backbones in com-plicated regimens. No other drug can be substituted in terms of either safe-ty or efficacy.

Monopoly and Its Consequences

With a ninefold increase in price for cyclophosphamide, it is unclear why other generic drug manufacturers have not entered the market, broken the monopoly and undercut Baxter’s price.

The FDA tells me that there is no regu-latory reason that only Baxter can mar-ket IV cyclophosphamide.

Following a change in Medicare laws, Medicare now pays for physi-cian-administered medication based on a number called “average sales price” (ASP), which is calculated from the actual money collected six monthsearlier for the drug. Medicare pays 106% of this number. This means that every time the price of a drug rises, adjusted reimbursement to physicians lags by six months. This matters very

Table. The WholesalePrice of IVCyclophosphamide (500 mg)

January 2010 and before

$25.28

February 2010 $31.47

June 2010 $44.06

February 2011 $69.43

July 2011 $75.65

January 2012 $123.74

October 2012 $220.88

VOGL, NYcontinued from page 1 ��

see VOGL, NY, page 6 YY �

Steven Vogl, MDMedical Oncologist,New York City

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little for drugs that cost $1 or $2, ordrugs whose prices rise by 1% to 2% ata time. Rises in price of 80% for evenmodestly expensive drugs lead to pro-hibitive losses that practices cannottolerate if they intend to survive andpay their employees.

It is possible that Baxter found itself ina monopoly, decided it could and shouldraise the price, and did so progressive-ly on the assumption that a gradual rise

in price every few months would cause less market disruption and less fuss than a huge price rise of 900% at once.

A Baxter spokesman denies that the slow but large price increase was designed to manipulate where patients get their chemotherapy, to shift who pays for the drug, or to shift the cost to a payer who pays more.

I wondered if Baxter would make more money if patients were sent to pharmacies to buy their IV cyclophos-phamide using their prescription plans. Because of deductibles, copays and the “doughnut hole,” this will increase

patient costs significantly. Many drugs are a lot more expensive for Medicare Part D prescription plans than for phy-sicians. It turns out that IV cyclophos-phamide is not one of these, at least in 2013. Baxter charges retail pharmacies and Medicare part D prescription plans approximately the same as it charges physicians via their wholesalers.

Many Hospitals Profit on Drugs While Physicians Lose!

It also turns out that hospitals serv-ing poor or uninsured populations—which now comprise one-third of all

U.S. hospitals according to a recent New York Times article—by law get a discount of 20% to 50% on cancer ther-apeutics in a program called 340B.1

Because this discount applies to allpatients treated at the hospital, hos-pitals in the 340B program now make a tidy profit on giving chemotherapy drugs, a profit that grows with the cost of the drugs. According to The New York Times, about $6.9 billion worthof drugs now moves annually through the program. A money-losing oncolo-gy practice could instantly become a profit center if taken over by a 340B

VOGL, NYcontinued from page 5 ��

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hospital, provided it gives a sufficientquantity of expensive drugs discount-ed under the 340B program.

In one of my more paranoidmoments, it occurred to me that anunscrupulous hospital or group of hos-pitals might have sought to manipulatethe way the price of cyclophospha-mide was increased so that reimburse-ment to physician offices is always wellbelow cost. If the resulting loss drivesthe physician practice to sell out tothe hospital—very cheaply, since thepractice is losing money—the hospi-tal wins. If the physician struggles on,

maintaining his practice, but sends his patients to the hospital to receive che-motherapy, the hospital wins because of its 340B discount.

Large hospitals could have significant influence on Baxter because they are the major customers for its large line of intravenous solutions and tubing, as

well as needles and syringes. The curi-ous pattern of large stepwise increases in the price of intravenous cyclophos-phamide that benefits 340B hospitals justifies an investigation by the Fed-eral Trade Commission, as should the continued Baxter monopoly on intra-venous cyclophosphamide, which

presumably is now very profitable.

Unintended Consequences for Sick Patients

Medicine, unfortunately, is quite dif-ficult. Every patient encounter is illu-minated by that patient’s ultimate mor-tality. If the patient is very ill with a disseminated lymphoma of a type that can be cured if treatment is careful-ly, quickly and appropriately admin-istered, it is a pity that the efforts of the physician and his office have to be diverted to dealing with cost and reim-bursement issues, especially for a rela-tively cheap drug like IV cyclophospha-mide. It is no help that many insurance companies take several days to confirm reimbursement policies even when the patient is acutely ill.

Skeptics will argue that unscrupu-lous physicians, in the past, chose che-motherapy regimens to maximize their profits. That this probably occurred is no reason to now divert the attention of conscientious physicians away from thecare of sick patients.

What Can Be Done?

Given the paralysis in Congress, it is futile to suggest changing the ASP + 6%Medicare reimbursement formula now in place. Encouraging another gener-ic drug manufacturer to enter the U.S.IV cyclophosphamide market or allow-ing imports from abroad would end theBaxter monopoly and presumably loweror at least stabilize prices. Indeed, regu-latory actions to encourage a free mar-ket for injectable generic drugs at prices sufficiently high to ensure several sourc-es of supply would go a long way towardresolving the recurring drug shortagesthat have plagued medical oncology inthe past several years.

Reference1. Pollack A. Drug industry sees abuse in dis-

count program. The New York Times. Febru-ary 13, 2013:B1.

Clinical Oncology Newswelcomes letters to the editor.

Do you have thoughts on Dr. Vogl’s commentary?

Please send comments to

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What areyour thoughts?

Regulatory actions to encourage a free market for injectable generic drugs at

prices sufficiently high to ensure several sources of supply would go a long

way toward resolving the recurring drug shortages that have plagued medical

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CLINICAL ONCOLOGY NEWS • MARCH 2013CLINICAL ONCOLOGY NEWS • MARCH 2013 77CURRENT PRACTICE

involves a culture change.“Oncology payments and thus most

of medical oncology care is focused on volumes of treatment. We have moved to several capitation models, as well as our modified fee-for-service medical oncology home pilot with Anthem Blue Cross. We are now dedicated to improv-ing patients’ health, not giving treat-ments,” said Linda Bosserman, MD, the president of Wilshire Oncology Medi-cal Group, who leads the group’s OMH in La Verne, Calif. “There has to be a cul-ture change, and it means two big things. You have to engage and you have to re-engineer. You have to fully engage every staff member at every level and re-engi-neer what their job is to be a team that delivers much better care, in and outside the clinic. You have to re-engineer your payer system and re-engineer how your patients interact with you.”

The culture shift involves an aggres-sive personal medicine approach aimed at anticipating symptoms and preventing them. “We now engage a patient’s kids or spouse or we will put their pills in a pill box or we will call them every day,” said Dr. Bosserman. “If we think the patient needs more support, we will figure out how they can get the support.”

Patient education is emphasized, espe-cially in end-of-life care. “The way our health care is organized right now is [doctors] are actively encouraged to treat, even when it is clear that those treatments are futile,” said Dr. Bosser-man. Patients with metastatic disease need to be educated that sometimes the best treatment is palliative relief of symptoms and that this can sometimes extend life, she said.

Another common theme is the use of pathways. Wilshire physicians meet monthly to evaluate the best of the National Comprehensive Cancer Net-work guidelines and program their com-puters to prompt doctors toward them. “Every month, we have meetings with the physicians, nurses and administrative staff, so everybody is on board delivering this quality product,” said Dr. Bosserman. “However, this is not a cookbook. We track warranted variations.” For exam-ple, avoiding a chemotherapy that causes peripheral neuropathy in a piano player is a warranted variation that a physician can note in a medical record.

Pathways are one of the quality mea-sures many insurers look for, but it’s not

where the real cost savings lie. “There isgoing to be a limited amount of savingsin pathways,” said Barbara McAneny, MD, chief executive officer of New Mex-ico Oncology Hematology Consultants (NMOH), an OMH with four centers in New Mexico. “When you start out, youcan identify people who are doing wildstuff and rope them in, but then there is no more to get. The real savings is keep-ing patients out of the hospital and out of the ERs [emergency rooms].”

This is where the telephone triage sys-tems come in. “Our telephone triage ser-vice has really been embraced by our patients,” said John Sprandio, MD, the lead physician at Consultants in Medi-cal Oncology and Hematology (CMOH),which has four offices in suburban Penn-sylvania. “When we first started mea-suring data in 2006, we had about 1,600clinical phone calls that were symptom-related. Last year, we had about 4,600.” CMOH is the only oncology practice toreceive recognition from the Nation-al Committee for Quality Assurance

(NCQA) as a level III patient-centered medical home. “Our model, based on theNCQA PCMH [primary care medical home] standards, has attracted nation-al attention from payers, providers and patients,” said Dr. Sprandio.

Oncology nurses man the telephonetriage lines in most OMH practicesand field symptom calls from patients. In some practices, calls are redirect-ed to an answering service after hours with an on-call nurse or physician field-ing patient questions. On-call staff can access the practice’s EMR remotely, allowing them to follow the same symp-tom management algorithms used by nurses during office hours.

“Do not have your phone answered by ‘if this is a medical emergency, hang up and call 911,’ because people do it. Then you have someone in the ER for some-thing that you could have quite easily managed in the office,” said Dr. McAne-ny. “The key is to provide aggressive man-agement of cancer and its treatments, so that we can prevent complications rath-er than chase them. We can have people come to us, instead of going to emergency departments.” She points out that condi-tions such as neutropenia or a stable pul-monary embolus is better treated for less money in an oncology office.

This takes extra effort from physicians.“It requires physician work. It requires that physicians are willing to see patients the same day,” said Dr. McAneny. If a patient has an event in the middle of the night, NMOH doctors will get out of bed

to direct admit them to a hospital. “It is just part of what you have to do,” said Dr. McAneny. “When you admit to a hospi-talist who doesn’t know your patient, you have all of the transition-of-care issues, but also, the hospital isn’t part of your system and doesn’t know that, for exam-ple, when you get somebody with neutro-penic fever stabilized, you can complete their therapy in your office.”

Alternatively, Dr. Bosserman reported that Wilshire oncologists partner with other specialists and hospitalist teams at each of the 12 regional hospitals they serve. Hospitalists and ER doctors active-ly work with oncologists to participate in cost-effective management, discuss-ing management strategies during eval-uations, admissions and discharge. If a patient is admitted, Wilshire oncologists work actively with hospitalists to set goals and oversee care plans that minimize unnecessary workups and minimize hos-pital stays. “We function as a team with the oncologist as quarterback for the can-cer patients,” said Dr. Bosserman.

Although physicians have more responsibilities in some areas of the OMH model, they can achieve significant

efficiencies. Minimizing irrelevant activ-ities for physicians is essential. “We haveminimized a lot of the tedious data col-lection that physicians are often engagedin. We increased the efficiency of docu-mentation and communication,” said Dr.Sprandio. His practice uses seasonedoncology nurses and 5.6 full-time equiv-alents (FTE) per physician comparedwith the national average of 8.3 FTE.“We developed a medical home enabling software overlay that has allowed us tointegrate our workflow with delivery of care, documentation and meaningful userequirements,” said Dr. Sprandio.

With the efficient and streamlinedused of EMRs and their software over-lay, called Iris, CMOH patient navigatorshave become stewards who ensure thatall ordered tests are conducted, treat-ment plans followed and nothing slipsthrough the cracks. The patient naviga-tor also is critical in the outcome mea-surement process. Dr. Sprandio has illus-trated that documenting reductions inhospital stays, ER visits and other healthcare costs is essential for insurers to con-sider paying for the new model.

“We have one active contract and we

Table. Oncology Medical Home Quality and Value Measures Developed by the Community Oncology Alliance

Patient Care Measures

% of cancer patients who received a treatment plan prior to the administration of chemotherapy.

% of cancer patients with documented clinical or pathologic staging prior toinitiation of first course of treatment.

% of chemotherapy treatments that have adhered to NCCN guidelines andpathways.

% of cancer patients undergoing treatment with a chemotherapy regimen with a ≥20% risk for developing neutropenia and also received granulocytecolony-stimulating/white cell growth factor.

Antiemetic drugs given appropriately with highly emetogenic chemotherapy treatments.

Resource Utilization

# of ER visits per chemotherapy patient per year.

# of hospital admissions per chemotherapy patient per year.

Survivorship

% of cancer patients who received a survivorship plan within a defined period of days after completion of chemotherapy.

% of chemotherapy patients who received psychosocial screening and received measurable interventions as a result of the psycho/social screening.

Survival rates of stage I-IV breast cancer patients.

Survival rates of stage I-IV colorectal cancer patients.

Survival rates of stage I-IV non-small cell lung cancer patients.

End of Life

% of patients who have stage IV disease and have end-of-life care discussions documented.

% of patient deaths where the patient died in an acute care setting.

Average number of days on hospice care (home or inpatient) at time of death.

A measurement of chemotherapy given near end of life.

ER,, emergency room;e e ge cy oo ; NCCN,CC , National Comprehensive Cancer Networkat o a Co p e e s ve Ca ce etwo

MEDICAL HOMEcontinued from page 1 ��

The focus in the medical home model is on

treatment pathways as well as anticipating and

preventing the symptoms that ultimately put

patients in the hospital or the ER.


are anticipating two additional con-tracts, one national payer and one local payer,” said Dr. Sprandio, who added that insurers agree to consider proposed payment reform after confirming their data and the practice’s commitment to standardizing the process of care.

CMOH has lowered ER visits by 68%, hospital admissions per chemothera-py patient per year by 51% and hospi-tal length of stay for admitted patients by 21%. The practice also noted a 22% overall reduction in outpatient visits per hematology and oncology patient peryear and a 12% reduction in outpatient visits per patient per year in the chemo-therapy subpopulation. Savings to CMOH payers is estimated to be in the range of $1 million per physician per year (Am J ((Manag Care 2012;18[5 Spec No. 2]:SP98-SP, PMID: 22693989). Dr. Sprandio said that his group was able to complete this practice transformation through innova-tion, without formal outside funding.

This is not true for all practices. Anthem Blue Cross increased its fee-for-service payment rates to cover the esti-mated care planning, management and coordination work for Wilshire Oncol-ogy’s OMH pilot, which launched in August 2011. The pilot has been extend-ed to August 2014. In summer 2012, Dr. McAneny’s company Innovative Busi-ness Solutions received a $19.7 million grant from the Centers for Medicare & Medicaid Services to test the NMOH medical home model in seven oncology practices across the country.

Dr. Sprandio said that practices seek-ing to become an OMH should study the NCQA’s PCMH standards; the NCQA patient-centered specialty practice standards are expected to be published this month. He pointed out that prac-tices also could seek guidance from a growing number of consultants. These include Oncology Management Servic-es in Drexel Hill, Pa., the team of pro-fessionals assembled by Dr. Sprandio to facilitate the transformation of other practices to an OMH. “Oncology prac-tices should be able to transition much more quickly than we did,” said Dr. Sprandio.

Additional tools are being developed. In January, the Community Oncology Alliance (COA) launched a website brim-ming with resources for practices aiming to become OMHs (www.medicalhome-oncology.org). The site is a byproduct of COA’s Oncology Medical Home Steering and Implementation Committee, which includes providers, payers, administra-tors, patients, nurses, pharmacists and cancer care advocates. The committeehas released a list of quality and value measures for OMHs (Table). “What we are trying to do is put the common glue together, by getting people to agree what the measures of quality and value are,” said Ted Okon, MBA, executive director of the Washington D.C.-based COA.

He said more resources will be addedto the site and that an implementationteam has been canvasing the hardware,software and different processes thatOMHs are using. The aim is to create a self-assessment that practices can use todetermine what they need to change tobecome a medical home.

According to Mr. Okon, cancer cen-ters need to change to OMHs to sur-vive and prosper. “The government haspushed the ball down the hill and it isrolling and gaining more moss or snowdepending on the season, and it is rolling toward having [medical practices] provethat they are providing high-quality,

efficient cancer care. … It is what oncol-ogy practices do right now. It’s just that they haven’t gone to the next level and nobody has really been measuring it.”

—Kate O’Rourke

Dr. McAneny is CEO of Innovative Business Solutions. Dr. Sprandio

disclosed a financial interest in CMOH and Oncology Management Services and active engagement with the NCQA in the

development of the Patient-Centered Specialty Practice recognition program.

Dr. Bosserman and Mr. Okon have no relevant disclosures.

‘Our model, based on the NCQA PCMH standards,

has attracted national attention from payers,

providers and patients.’—John Sprandio, MD

®

Now Available...

Chair

Julie M. Vose, MD, MBA

Neumann M. and Mildred E. Harris Professor

Chief, Division of Hematology/Oncology

Professor of Medicine

Nebraska Medical Center

Omaha, Nebraska

Faculty

John P. Leonard, MD

Clinical Director, Center for Lymphoma and

Myeloma

Professor of Medicine

Weill Medical College of Cornell University

NewYork-Presbyterian Hospital

New York, New York

Jonathan W. Friedberg,

MD

Professor of Medicine and Oncology

Chief, Hematology/Oncology Division

James P. Wilmot Cancer Center

University of Rochester Medical Center

Rochester, New York

Learning ObjectivesReview optimal therapy for the management of

newly diagnosed and relapsed/refractory follicu-

lar lymphoma (FL) and diff use large B-cell lym-

phoma (DLBCL), taking into consideration the

heterogeneity of patient and tumor characteristics.

1 Identify the most recent data pertaining to

emerging single and combination therapies for

the treatment of relapsed/refractory NHL.

2 Explain the most signifi cant new data on con-

solidation and maintenance strategies in NHL.

3 Describe current and emerging prognostic clin-

ical and molecular markers to aid in treatment

decision making for NHL.

Intended AudiencesTh e intended audiences for this educational

activity are hematologists, community oncolo-

gists, oncology nurses, pharmacists, and other

hematology/oncology health care profession-

als. Th ese professionals constitute the core audi-

ence for this initiative as they direct treatment for

patients with NHL.

Statement of NeedTh e incidence of NHL is increasing steadily,

and new therapeutic strategies are needed; FL

remains incurable, and 30% to 40% of patients

with DLBCL still die from their disease. Th e

abundance of ongoing research into therapeu-

tic strategies for these conditions presents oppor-

tunities for improved patient outcomes as well as

challenges for clinicians, who must stay abreast

of the new data and be prepared to incorporate

emerging therapeutic strategies into their practice.

Course FormatInteractive Web-based monograph

Estimated Time for Completion: 60 minutes

Accreditation StatementTh is activity has been planned and implemented

in accordance with the Essential Areas and Poli-

cies of the Accreditation Council for Continuing

Medical Education (ACCME) through the joint

sponsorship of Global Education Group (Global)

and Applied Clinical Education (ACE). Global

is accredited by the ACCME to provide continu-

ing medical education for physicians.

Credit DesignationGlobal Education Group designates this endur-

ing activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only tthe credit commensurate with the extent of their

participation in the activity.

Method of PreparationTo receive CME credit, participants should read

the preamble, complete the pre-test, read the

monograph, and complete the post-test and eval-

uation. A score of at least 75% (in 3 attempts)

is required to complete this activity successfully.

CME certifi cates will be issued immediately

upon successful completion.

To participate in this FREE CME activity, log on to www.CMEZone.comand enter keyword “MM111”

This activity is jointly sponsored by Global Education Group and Applied Clinical Education. This activity is supported by educational grants from Genentec

in Non-Hodgkin’s LymphomaEvolving Treatment Paradigms

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MM111”Release Date: August 22, 2012 Expiration Date: August 22, 2013


Pancreatic Cancer: Is Laparoscopic Distal Pancreatectomy the New ‘Gold Standard’?

The Tumor Board

Welcome to the inaugural edition of The Tumor Board

This column aims to present readers with challenging cases and/or provide alternative treatment options

related to oncology and surgical oncology that are both timely and worthy of discussion. In addition to my commentary, the cases and/or alternative treatment options will be presented to other experts in related fields for “second opinions” regarding evaluation and treatment.

This first issue focuses on laparoscopy for distal pancreatectomy. I am very honored to have R. Matthew Walsh, MD, chairman of the Department of General Surgery at Cleveland Clinic Foundation in Cleveland, Ohio, kick off this first issue by providing an expert “second opinion.”

I hope readers enjoy the column and benefit from the timely discussions and multiple opinions presented as they relate to oncologic challenges and alternative—and

sometimes controversial—treatments.The focus is on discussion and I hope to hear from readers

with their opinions and comments on topics presented in each column. I also greatly welcome and encourage suggestions or case submissions for future issues.

Enjoy!

Conrad Simpfendorfer, MDEditor, The Tumor Board

Hepato-pancreato-biliary andTransplant SurgeonCleveland ClinicWeston, Florida

Case 1

A 66-year-old woman presents with a mass in the tail of the pancreas, discovered during evaluation for changes in bowel movement. Com-

puted tomography (CT) scan reports a 2.6-cm hypodense lesion in the tail of the pancreas (Figure 1). A follow-up magnetic resonance imaging (MRI) scan reports a 3μ2.3-cm heterogeneous mass in the tail of the pancreas. There is no evidence of distant metastasis.

An endoscopic ultrasound (EUS) reported a 3.5-cm heterogeneous mass in the distal body of the pancreas. The mass abuts the splenic artery and vein.

Fine-needle aspiration (FNA) of the mass reported a cystic neoplasm with papillary architecture. CA 19-9 level is greater than 3 U/mL.

Case 2

An 84-year-old healthy man presents with a massin the tail of the pancreas, discovered during

evaluation for abdominal pain. CT scan reports a 5.2-cm complex mass in the tail of the pancreas (Fig-ure 2). The mass is reported to have cystic and solidcomponents. No evidence of distant metastasis isnoted. The patient denies any history of pancreatitis.

CA 19-9 level is 84 U/mL.

Figure 1.

Figure 2.


Case Challenge

A 67-year-old man had elective

cholecystectomy with

intraoperative cholangiogram for an

episode of gallstone pancreatitis;

during surgery a thickened area was

noted at the fundus that resembled

impacted stones. The patient denied

fever, chills, jaundice or significant

weight loss. No significant past

medical or surgical history. All

preoperative labs were normal, as was

chest x-ray. Surgery was performed

uneventfully and the patient was

discharged home the next day. The

pathology report returned four days

later reported:

• Invasive moderately differentiated

adenocarcinoma of the fundus of

the gallbladder, 2.7 cm in greatest

dimension, infiltrating the entire

thickness of the gallbladder wall and

involving the surrounding soft tissue

• Focal perineural invasion is

identified

• No definitive evidence of vascular

invasion

• Cystic duct margin of resection is

free of invasive carcinoma

• Cystic duct margin of resection

is involved by highly dysplastic

epithelium

• Cholelithiasis

• Benign cystic duct lymph node

What would you do?

Dr. Simpfendorfer’s CommentaryHow would you treat these two patients?

I would advocate treating these patients based on the presumed pathology. The first patient would appear to have an asymptomatic lesion, and the description of the EUS findings is difficult to interpret.

The MRI is not presented, and the CT is of poor quality on one image. I am suspicious that the lesion is a serous cystadenoma that can appear incidentally as a “mass lesion” because the size of the cysts may be quite small. The other major diagnostic consideration would be a solid pseudopapillary neoplasm. I would review the imaging and FNA result, including cytology, in more depth before determining the exact approach.

The second patient is more concerning for a pancreatic neoplasm. The description of pain is nonspecific, and I would question the patient more closely on the symptoms, which in general can help guide the workup. The presence of a mass component is an indication for resection, and, for this patient, I would advise a distal pancreatectomy with splenectomy.

Would you perform open or laparoscopic pancreatectomy?

The operative approach should be guided by disease extent and presumed diagnosis, as well as surgeon experience. It is

unclear whether the patient in the first case requires resection, butthe patient in the second case should have a distal pancreatectomy with splenectomy, both due to the location of the lesion and pre-sumed carcinoma diagnosis. He is a suitable candidate for a laparo-scopic resection provided the surgeon has adequate experience. Thispatient appears to be quite thin and some of the advantages of a min-imally invasive approach may not be realized.

Is tissue diagnosis necessary before a planned surgery?

The patient in the first case has already undergone FNA, which should be reviewed for the cyto-logic features. “Papillary architecture” is an uncharacteristic cytologic feature that would need to

be reviewed with an experienced pancreatic cytopathologist. The patient presented in the second case has radiographic features of a mass component, which would be an independent indication for resection.

‘Second Opinion’:Expert Opinion by R. Matthew Walsh, MD

Advances in instrument technology and surgeon experience have made laparoscopic surgery the standard technique for

several abdominal surgical procedures. Minimally invasive sur-gery for the pancreas has been undertaken with more caution. Recently, laparoscopic distal pancreatectomy (LDP) has gained popularity. Studies comparing open distal pancreatectomy

(OPD) and LDP have reported advantages with minimally invasive surgery, includ-ing reduced postoperative pain, faster recovery, decreased wound complications, less intraoperative blood loss and fewer postoperative complications.1,2

A meta-analysis comparing LDP with OPD concluded that lower blood loss and reduced hospital length of stay were associated with the laparoscopic approach. LDP also was associated with a lower risk for overall postoperative complications and wound infection.3 A multicenter analysis comparing LDP with OPD for the treatment of adenocarcinoma of the pancreas reported similar short- and long-term oncologic outcomes between the two groups, suggesting that LDP is an acceptable approach for resection of pancreatic ductal carcinoma of the left pancreas.4

References

1. 1. Belli G, Fantni C, D’Agostino A, et al. Laparoscopic and open surgical treatment of left-sided pancreatic lesions: clinical outcomes and cost-effectiveness analysis. Surg Endosc. 2012;26:1830-1836, PMID: 22258300.

2. 2. Kooby D, Kneuertz P, Patel S, et al. Laparoscopic distal pancreatectomy: trends and lessons learned through an 11-year experience. J Am Coll Surg. 2012;215:167-176, PMID: 22632910.gg

3. 3. Wolfgang C, Venkat R, Edil B, et al. Laparoscopic distal pancreatectomy is associated with significantly less overall morbidity compared to the open technique: A systematic review and Meta-analysis. Ann Surg. 2012;255:1048-1059, PMID: 22511003.gg

4. 4. Kooby D, Hawkins W, Schmidt C, et al. A Multicenter analysis of distal pancreatectomy for adenocarcinoma: is laparoscopic resection appropriate? J Am Coll Surg. 2010;210:779-787, PMID: 20421049.gg

Resection of pancreatic body withautomatic suturing device

R. Matthew WalshChair, General SurgeryCleveland Clinic Cleveland, OH


Have comments or feedback on

The Tumor Board?

Would you like to suggest a case for an upcoming

column?

Email managing editor Gabriel Miller at

[email protected]

SUPPORT & INFORMATION FOR THE NEXT GENERATION OF ONCOLOGY PRACTITIONERS

oncologyfellowadvisor.com

ONCOLOGYFellowadvisor

Top-Tier Centers Share Tips s Share Tips

Hospitals in the United States are anxxious to be included in the annual US News and World Repport’s list of top

hospitals. To make the 2011 to 2012 cut, ccancer centershad to treat at least 254 inpatients withh high-level expertise in 2007, 2008, and 20099.1 The following are the top 10 cancer centerss in US News and World Report, in ascending orrder ofquality: University of Texas MD Andersonn Can-cer Center, Memorial Sloan-Kettering CCancer Center (MSKCC), Johns Hopkins (JH), Mayo Clinic, Dana Farber Cancer Institute/Briggham & Women’s Cancer Center, University of Washington Cancer Center in Seattlee,Massachusetts General Hospital, UCSFF Medical Center, Cleveland Clinic, andd Ronald Reagan UCLA Medical Center.1

Oncology Fellow Advisor spoke witthDaniel Spratt, radiation oncology trainee at Memorial Sloan-Kettering (No. 2 on tthe

Master Work–Life Balance

T raining to be an oncologist can be rough. In the face of long hours,

sleep deprivation, and patient suffer-ing, young oncologists may sacrifice hobbies, interests, and even relation-ships. Many fellows find comfort inreminding themselves that better days are ahead but experts say that they may be setting themselves up fordisappointment.

Oncologists who cope by looking to the future may miss opportunities in the present to shape their career to meet their needs.1 “Putting aside one’s personal needs or personal wellness can eventually come back in a negative

or unhealthy way that can lead toburnout,” said Charles M. Balch, MD, FACS, professor of surgery in the Divi-sion of Surgical Oncology at University of Texas Southwestern Medical Schoolin Dallas, Texas. “A successful medical career at the expense of personal well-being is not at all successful.”

One in 3 oncologists will experi-ence significant career burnout—described as emotional exhaustion, depersonalization, and a sense of low personal accomplishment that leads to decreased effectiveness at work.2

Some of its more tragic consequences



A DAY IN THE LIFE

We highlight the work of fellow-ship director Timothy Gilligan, MD. 4

FELLOWSHIP TRAINING

Experts discuss what to expect inthe first year of fellowship. 6

FELLOWSHIP TRAINING

Communication skills are crucialfor oncology fellows. 7

For the latest oncology fellow–related information,

please visit www.oncologyfellowadvisor.com

®

is brought to you as a professionalcourtesy. This content is selected and

controlled by McMahon Publishing and isfunded by Lilly USA.

SUPPORT & INFORMATION FOR THE NEXT GENERATION OF ONCOLOGY PRACTITIONERS



Vol. 3, Issue 3

PathsFellowship

TrainingMentorMemos

SurveySays

Physician Finance

Top-Tier page 5

see, Work–Life page 2

To obtain educational information for oncology fellows, please visit us online:

www.oncologyfellowadvisor.com

The classification of colorectal cancer(CRC) tumors into molecular sub-

types could lead to more targeted treat-ment strategies, according to two studiespresented at the 2013 GastrointestinalCancers Symposium.

“We have developed a diagnostic sin-gle-sample predictor that allows theclassification of colorectal cancer tumorsof different intrinsic molecular subtypes.These subtypes could be clinically rele-vant as they differ in their underlying biology and clinical outcomes and con-sequently require different treatmentstrategies,” said Josep Tabernero, MD,PhD, the director of the Vall d’HebronInstitute of Oncology in Barcelona,Spain, and lead investigator of one of thestudies (abstract 333).

Molecular classification systems couldbe most helpful in managing patientswith stage II CRC who have a variablerisk for relapse that is hard to predictwith current clinical and pathologic fac-tors. The goal of subtyping is not only toidentify the patients who need aggres-sive treatment, but also to pair the rightpatient with the right drug.

Dr. Tabernero and his team usedgene expression data taken from 188patients with CRC (stages I-IV) todevelop the classification system,which they subsequently validated in543 patients (stages II-III).

Three distinct molecular patterns wereidentified: 21.5% of the samples werecategorized as subtype A (32 genes),62% as subtype B (53 genes) and 16.5%as subtype C (102 genes). These subtypesdiffered according to three biologicalhallmarks of colorectal tumors: epitheli-al-to-mesenchymal transition (associat-ed with aggressive tumors); deficiency inmismatch repair genes (associated withgenetic alterations); and the rate of cellproliferation—features that are known toindependently affect outcomes, accord-ing to Dr. Tabernero.

“The subtypes were significantly associ-ated with prognosis and significantly cor-related with benefit from adjuvant 5-FU-based treatment,” Dr. Tabernero said.

Subtype A had a good prognosisregardless of whether chemothera-py was given. Ten-year survival rateswere approximately 65% without che-motherapy and 80% with chemother-apy (P(( =0.183). Subtype B had a pro-nounced benefit from chemotherapy,with 10-year survival rates of approxi-mately 55% without chemotherapy ver-sus 80% with chemotherapy (P(( =0.014).Subtype C, on the other hand, derivedno benefit from adjuvant chemotherapy,with 10-year survival rates of approxi-mately 65% without chemotherapy and

50% with chemotherapy The five-year overall survivence between types A and type C, was statistically sigicant (P(( =0.0166).

The study findings sug-gest that these groups would be treated different-ly: Subtype A would probably not require chemo-therapy; subtype B wouldreceive chemotherapy andsubtype C would require amore aggressive and perhanovel treatment. The study ers plan to evaluate these spatients who have receiverent regimens, especially ox

A separate study, presented by Josh-ua M. Uronis, PhD, of the Duke Insti-tute for Genome Sciences and Policy in Durham, N.C., found that deregula-tion of oncogenic signaling pathways can be used as a powerful tool to clas-sify patients with CRC into molecular subgroups. The researchers have devel-oped a preliminary set of biomark-ers that are prognostic, predictive of treatment response and applicable to patients who have undergone resection for primary or metastatic tumors.

The study (abstract 339) took micro-array data from 850 patients with pri-mary CRC, based on the activity of 19 oncogenic pathways, and generated patterns of pathway deregulation for each patient’s tumor. A molecular pro-file of CRC was created that identified six molecular subgroups of colorec-tal cancer (MSCCs) and found the sub-groups differed significantly in their risk for recurrence. For example, although recurrence-free survival approached 100% for MSCC 4, it fell to about 40% for MSCC 3 (P(( =0.0004). The model was then applied to a data set of 133 tumor samples of which 94 patients present-ed with metastatic disease and 34 with primary lesions. Again, the MSCC sub-groups differed in recurrence-free sur-vival (P(( =0.046), according to Dr. Uronis.

The unique patterns of pathway deregulation were translated into gene expression signatures and were used to measure the probability of pathway acti-vation in a panel of cell lines. With this

approach, the model also was predictiveof response to various drugs.

“We observed that MSCCs demon-strated differential sensitivity to specif-ic targeted agents, such as MSCCs 1, 2 and 3 to inhibition of HER2 by lapatinib and inhibition of the epidermal growth factor receptor by erlotinib,” said Dr. Uronis. “From this we gather that we can make basic predictions using path-way signatures.”

The study was validated using a murine model of drug sensitivity that took patient-derived CRC explants and implanted them into mice. This model showed that subgroups with high mam-malian target of rapamycin (mTOR)activity were highly sensitive to mTOR inhibitors and those with low mTOR expression were found to be resistant to these drugs. Researchers deduced that the combination of a genomic-based molecular profile of CRC and their pre-clinical murine model using patient-derived CRC explants can be used to develop a clinically relevant prognostic and predictive biomarker of CRC.

Representing the American Gastroen-terological Association at the symposium, William M. Grady, MD, the associate pro-fessor of medicine and chief of the gas-troenterology section at the University of Washington Medical Center in Seattle, said, “There has been considerable inter-est in determining whether molecular alterations in primary colorectal cancer are more accurate prognostic indicators

r’s pathologic stage, whichurrently used.”g on the study by Dr. Uronisd his colleagues, Dr. Grady aid, “They have used a unique approach to iden-

ify molecular alterations hat are predictive of recur-ent cancer, not only for non-metastatic disease but alsofor metastatic disease. If these results can be vali-ated, these molecular alter-

patterns have the poten-used as markers to identify ents should receive aggres-r surgical resection of both

metastatic colorectal cancer and to direct the specific chemotherapeu-tic agents they should receive.”

Jennifer Tseng, MD, chief of surgical oncology and the co-clinical director forsurgery at Beth Israel Deaconess Med-ical Center and an associate professor at Harvard Medical School in Boston, said, “The work [by Uronis et al] is criti-cal for colorectal care advancement, andsymbolic of the new age of cancer carein general. For example, we as surgeonscan surgically remove tumors to the best of our oncologic ability, and enable ourpartners, the pathologists, to stage the tumors and help determine the best treatment. However, currently, there are serious limitations. At the extremes,there is less controversy. There, there is no question that chemotherapy does not [for stage I] or does [for stage III or IV] help the patient, overall. But thevast majority of patients fall into those shades of gray, stage II especially, wherewe are weighing potentially toxic che-motherapy risks and benefits versus dis-ease recurrence risks and benefits. This type of study helps point us to person-alizing cancer care for the individual tumor, and thus the individual patient.”

—Caroline Helwick

Drs. Uronis and Tseng have no relevant relationships to disclose. Dr. Tabernero has

received research funding from Agendia; Dr. Grady previously reported that

he has served as a consultant or advisory board member for

General Electric, Illumina and Myriad.

2013 Gastrointestinal Cancers Symposium

Colorectal Cancer Subtyping: Predicting Outcomes‘If these results can be validated, these molecular alteration patterns have

the potential to be used as markers to identify which patients should receive

aggressive care after surgical resection of both primary and metastatic

colorectal cancer and to direct the specific chemotherapeutic agents they

should receive.’—William M. Grady, MD

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CLINICAL ONCOLOGY NEWS • MARCH 2013 13SOLID TUMORS

Mayo Clinic Cancer Center:

Continuing a Tradition of Excellence

Mayo Clinic Cancer Center is home to morethan 400 physicians and scientists who col-laborate across the full spectrum of cancer research and are dedicated to understand-ing the biology of cancer; to discovering new ways to predict, prevent, diagnose and treat cancer; and to transforming the quality of life for cancer patients today and in thefuture. More than 135,000 cancer patientsreceive treatment each year at Mayo Clinic Cancer Center’s three campuses—in Scott-sdale/Phoenix, Ariz., Jacksonville, Fla., and Rochester, Minn.

Cancer Patient Care

Mayo Clinic’s philosophy of patient care,laid out more than 100 years ago, emphasizes developing medicine as a cooperative sci-ence, with the clinician and the laboratory sci-entist uniting for the good of the patient. That philosophy, still relevant today, enables MayoClinic physicians and researchers to form pro-ductive collaborations across cancer programs and specialties. Their collective knowledge enhances the potential for breakthroughs in cancer research and treatment.

Mayo Clinic Cancer Center is one of 67 U.S. medical centers to be named National Can-cer Institute (NCI) cancer centers. Mayo Clinic has held this NCI designation since 1973, fol-lowing the creation of the Cancer Centers Branch of the NCI in 1971.

Mayo Clinic Cancer Center also has met even more rigorous standards for designation by the NCI as a comprehensive cancer center. These standards include the following:• Basic laboratory research• Participation in high-priority NCI clinical

studies• Applied and clinical research• Cancer prevention and control programs• Education and training of health care

professionals• Public information services• Community service and outreach

Mayo Clinic Cancer Center receives more than $140 million in competitive peer-reviewgrants, including the NCI’s highly sought Spe-cialized Programs of Research Excellence (SPORE) grants. The Cancer Center has fiveNCI SPORE grants and two SPORE grants that are shared with other institutions. These

SPORE grants support research in brain can-cer, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lymphoma and multi-ple myeloma.

Mayo Clinic Cancer Center has 10 major cancer research programs that translate sci-entific discoveries in the laboratory into leading-edge treatments and therapies for patients. These programs benefit from thecrucial infrastructure and scientific support of 15 shared resources, all of which further basic, clinical and population sciences research.

Cancer Clinical Trials

Mayo Clinic Cancer Center is a leader in translating knowledge gained from cancer research into better patient care. Patientshave access to hundreds of clinical trials ledby Mayo Clinic scientists. Trials are also avail-able through the Cancer Prevention Network, a clinical trial study group whose administra-tion and research is based at Mayo Clinic. Still more trials are available through cooperativeresearch agreements with the NCI, the Alli-ance for Clinical Trials in Oncology and other clinical trial groups.

Expert Insights From Mayo Clinic Cancer CenterEach month, Clinical Oncology News highlights key studies from the most important journals and provides perspectives from guest clinicians at a top cancer center.

Every four months, Clinical Oncology News features clinicians from a different U.S. center.This month we introduce Mayo Clinic Cancer Center, who will be providing expert commentaries in the next four issues of Clinical Oncology News.

We hope you find our Reviews & Commentaries section a valuable tool.

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14 CLINICAL ONCOLOGY NEWS • MARCH 2013REVIEWS & COMMENTARIES

From The European Journal of Cancer

Anew study lends support to the hypothesis that the fallopian tubes

are a primary site of pelvic high-grade serous cancer. The study was designed to test the theory by estimating the prevalence of occult cancers found in ovaries or fallopian tubes in a consec-utive series of women who were either BRCA carriers or were BRCA-negative high-risk patients.

Tissue samples were prospectively collected from asymptomatic, screen-negative, high-risk women between Jan-uary 2000 and March 2012. The study was undertaken by Welmoed Reitsma, MSc, and colleagues at the University

Medical Center Groningen, in Gronin-gen, the Netherlands. Results were pub-lished in the European Journal of Cancer(2013;49:132-141, PMID: 22921157).

Of the 360 women who underwent risk-reducing salpingo-oophorecto-my (RRSO), 188 were BRCA1 carri-ers, 115 BRCA2 carriers, and 57 were BRCA-negative, high-risk patients. The median age at surgery was 44 years (range 30-72 years). Patients were excluded from the study if the RRSO was part of their breast cancer therapy or if they had previous ovari-an/tubal cancer.

Gynecologic pathologists aware of the patients’ BRCA status reviewed the specimens. All tissue with positive

findings, as well as a sample of normal sections, were reviewed by a second pathologist who had no knowledge of patient information or the previous pathology report.

Histomorphologic results included occult invasive cancer in four wom-en: two with fallopian tube and two with ovarian cancers. All were BRCA1carriers, and all were over the age of 40 years. Four cases of serous intra-epithelial carcinomas (STIC) were detected, all in the fallopian tube: one in a BRCA1 carrier (age 60 years); two in BRCA2 carriers (ages 50 and 57) and one in a BRCA-negative high-risk patient (age 56) with an unclassified variant. The pathologists detected

atypical hyperplasia in 23 women: 13 BRCA1, nine BRCA2 and one BRCA-negative. These lesions were either located in the fallopian tube (17 of 23) or most likely derived from the fallo-pian tube (six of 23), suggesting this as the primary site.

These results found the prevalence of cancer to be 1.3% in BRCA carri-ers, whereas other published reports put the range between 2% and 12%. The present results do lend support to the hypothesis of the fallopian tube as a primary site of pelvic cancer ori-gin, as well as supporting the practice of RRSO before the age of 40 years in high familial-risk women with the BRCA mutation.

Pathogenesis of Serous Cancers Tied to Fallopian Tubes

The current publication by Reitsma et al is the latest article in the rap-

idly evolving field of ovarian cancer pathogenesis. Over the past several years, paradigm-shifting insights have emerged regarding the origin of serous ovarian cancer.

Approximately 50% of malignant ovarian cancers are serous. These cancers, which tend to be aggressive high-grade tumors that rapidly spread through the peritoneal cavity, make up the majority of ovarian cancers seen in BRCA1/2 mutation carriers.1

In a 2001 study, Piek et al first report-ed epithelial dysplasia within the fallo-pian tubes of six of 12 BRCA1/2 muta-tion carriers undergoing a risk-reducing bilateral salpingo-oophorectomy (RRBSO) when the surgical speci-mens were examined by thin section-ing.2 In 2006, Medieros et al conducted a similar study of 13 BRCA1/2 carriers undergoing RRBSO and established a technique termed sectioning and exten-sively examining the fimbria (SEE-FIM) to evaluate the fallopian tubes in their entirety at 2- to 3-mm intervals.3 This group discovered that 38% of thesewomen had STIC in the fimbria/dis-tal fallopian tube but none had carci-noma in the ovaries. Since that publi-cation, several studies have confirmed these findings, providing mounting evi-dence that serous cancer of the ovary may indeed stem from the distal fal-lopian tube and may better be termed

serous tumors of the pelvis.The present report by Reitsma et al

is the largest prospective study eval-uating the incidence of occult inva-sive and noninvasive carcinoma using the SEE-FIM method in RRBSO spec-imens of asymptomatic BRCA1/2 car-riers and other women at high risk for ovarian cancer. This study revealed four occult invasive cancers, four non-invasive STIC lesions and 23 cases of atypical hyperplasia. Each of these types of lesions provides the opportu-nity to gain new insight into the origin of serous tumors of the pelvis.

With four serous cancers, this cohort of women had a very low rate of occult cancer (1.1%), slightly lower than docu-mented in prior studies. Possible expla-nations include the slightly younger median age of women and the require-ment for a recent negative pelvic ultra-sound and CA-125 before the proce-dure. Unfortunately, of the four samples that did reveal occult cancers, two did not have the fallopian tube tissue avail-able for assessment of tubal lesions that could have given rise to the invasive cancers, although the other two cases did reveal fallopian tube origins.

All four STIC lesions and approxi-mately 74% of the atypical hyperpla-sia originated in the fallopian tube, with the remaining 25% of the atyp-ical hyperplasias consisting of tubal epithelium on the ovarian surface or within the lining of ovarian epithelial

inclusion cysts. Unfortunately, theshort median follow-up of the wom-en with STIC lesions (one year) makesit difficult to know the subsequentoutcome of these women. It is possi-ble that these early lesions might shedmalignant cells into the peritoneal cav-ity even at a preinvasive stage. Due tothe small number of STIC lesions dis-covered and the short follow-up, thelong-term implications cannot beassessed from this study.

An additional limitation is that a study of this type also requires sub-stantial pathology expertise that may not be available outside of tertia-ry medical centers. Two specializedpathologists who were aware of theobjectives of the trial reviewed all of the specimens. If there was any dis-crepancy, an independent pathologistwho was unaware of the patient his-tory was consulted. Because the STIClesions and atypical hyperplasia canbe quite subtle and the SEE-FIM tech-nique requires more time and exten-sive pathology experience, similarexamination may not be feasible atsmaller community-based centers.

Although this study is consistentwith the hypothesis that serous ovar-ian cancers originate in the tubes, thelow rate of lesions precludes using thistrial as definitive evidence of the fallo-pian tube model or reaching any con-clusions regarding the future impli-cations of STIC lesions, or screening practices. However, in combinationwith prior studies, some potentialpractice-changing possibilities havebeen raised.

One issue raised is the role of a risk-reducing bilateral salpingecto-my (RRBS) in high-risk women whorefuse RRBSO. As demonstrated in theReitsma article, approximately 48% of women with BRCA mutations or who

are otherwise at high risk opt not to undergo an RRBSO. In other investiga-tions, the rate ranges from 30% to 40%as well.4-6 Often the reluctance stems from the consequences of prematuremenopause, including increased risk for cardiovascular disease, osteoporo-sis, urogenital atrophy and decreased quality of life. Therefore, there may bea role for an RRBS in women at highrisk for a serous pelvic malignancy whoare unwilling to undergo a full RRBSO at age 35 to 40 years. It is important toremember that an RRBS would not pro-vide the approximately 50% risk reduc-tion for breast cancer that accompanies estrogen withdrawal,7 although pro-phylactic mastectomies often also are considered in these patients.

In summary, the report by Reitsma et al provides additional support forthe role of the fallopian tube in the pathogenesis of serous “ ovarian” can-cer. Further studies will be needed todetermine the rate of malignancies after identification of STIC lesions, and the implications on screening and risk reduction strategies.

References1. Mavaddat N, et al. Cancer Epidemiol Bio-

markers Prev. 2012;21:134-147, PMID: 22144499.

2. Piek JM, et al. J Pathol. 2001;195:451-456, PMID: 11745677.

3. Medeiros F, et al. Am J Surg Pathol. 2006;30:230-236, PMID: 16434898.

4. Kwon JS, et al. Obstet Gynecol. 2013;121:14-24, PMID: 23232752.

5. Friebel TM, et al. Clin Breast Cancer. 2007;7:875-882, PMID: 18269778.

6. Metcalfe KA, et al. Int J Cancer. 2008;122:2017-2022, PMID: 18196574.

7. Rebbeck TR, et al. J Natl Cancer Inst2009;101:80-87, PMID: 19141781.

Dr. Wahner Hendrickson reported no relevant financial disclosures.

EXPERT INSIGHT

Andrea Wahner Hendrickson, MDConsultant, Department of Medical Oncology, andAssistant Professor of Medicine,Mayo Clinic

CLINICAL ONCOLOGY NEWS • MARCH 2013 15REVIEWS & COMMENTARIES

From the Journal of Clinical Oncology

The addition of rituximab to a chlorambucil regimen has

improved both event-free survival (EFS) and complete response (CR) rates in a study of patients with B-cell lymphomas of mucosa-associated lymphoid tissue (MALT).

Initial chemotherapeutic treat-ment options for extranodal margin-al-zone B-cell lymphomas of MALT have been understudied. There is a preponderance of MALT sited in the stomach, and the eradication of Heli-cobacter pylori generally has been the sole initial treatment for localized gas-tric involvement. Surgical and radio-therapeutic options are available

should this fail, but there is no con-sensus on systemic chemotherapeutic options or how to proceed in the case of multiple or non-gastric sites. Eman-uele Zucca, MD, and an international group of colleagues from six countries and at 78 medical centers published their results in the Journal of Clini-cal Oncology (2013;31:565-572, PMID: 23295789).

Patients were enrolled in the Inter-national Extranodal Lymphoma Study Group 19 (IELSG-19) Phase III, ran-domized study (Randomized Trail of Chlorambucil Versus Chlorambu-cil Plus Rituximab Versus Rituximab in MALT Lymphoma) from January 2003 to October 2005. Patients were admitted with a histologic diagnosis

of CD20-positive MALT lymphoma, either newly diagnosed or relapsed. No prior systemic therapy was allowed, except in order to eradicate H. pylori. After inclusions and exclu-sions, the patient pool of 227 was ran-domly assigned (1:1) into two pools. The first received oral chlorambu-cil 6 mg/m2 daily for six weeks; those responding continued receiving the dosage of chlorambucil for 14 con-secutive days in 28-day cycles, for four cycles. The second arm added IV rituximab 375 mg/m2 daily on days 1, 8, 15, 22, 56, 84, 112 and 140.

EFS was the primary end point; sec-ondary end points included overall response rates, CRs, response duration, progression-free survival (PFS), overall

survival (OS), and acute and long-term toxicity. Both treatments were well tol-erated without unexpected toxicities.

At a median follow-up of 62 months, the five-year EFS of patients treat-ed in the rituximab arm was sig-nificantly better than those treat-ed with chlorambucil alone (68% vs. 50%; P=0.002). Patients in the ritux-imab plus chlorambucil arm had a higher CR rate as well (78% vs. 65%; P=0.025). Although PFS improved, it was not statistically significant, and the five-year OS was 89% in both arms.

In October 2006, the protocol was amended and reopened with a third arm, consisting of treatment with rituximab alone. This study is still in progress.

Addition of Rituximab Increases B-Cell Lymphoma Survival

This well-written and well-inten-tioned randomized controlled

trial compared alkylator therapy withchlorambucil versus rituximab andchlorambucil as treatment of extra-nodal marginal zone (MALT) lym-phoma in patients having indications

for systemic therapy.The primary end point of the trial

was EFS, and the two groups were well balanced for characteristics.

The study once again confirmed an increased depth of response with the combination versus chemotherapy

alone. Achievement of a CR correlat-ed with improved EFS but not with OS.

Numerous trials have shown ritux-imab plus chemotherapy (R-chemo) to be superior to chemotherapy alone in enhancing time-to-event end points by producing more CRs. R-chemo has become the standard treatment for CD20-positive lymphomas when a che-motherapeutic approach is needed.

This trial, like many others, failed to show long-term survival advantage. Indeed it seems EFS and PFS are poor surrogates for OS in low grade/indo-lent non- Hodgkin lymphoma, in part because of its long natural history and the ability to salvage patients at the

time of relapse.Newer drugs and radioimmunothera-

py are adding even more options in the upfront and relapsed setting and will no doubt further obscure our ability to define a treatment that provides a sur-vival advantage.

This trial does underscore the excel-lent outcomes for patients with MALT lymphoma and EFS may be a reasonable objective in a clinical trial. As physicians treating patients, however, we must real-ize that EFS may not always be the best goal for the individual patient.

Dr. Reeder reported no relevant financial disclosures.

From The European Journal of Cancer

To combat the toxicities associatedwith paclitaxel plus cisplatin ther-

apy in patients with platinum-resistantepithelial ovarian cancer, researchersare experimenting with a new com-bination—paclitaxel plus carboplatin (Paraplatin, Bristol-Myers Squibb)—and early results are promising.

In a study published online inDecember 2012 by the European Jour-nal of Cancer (2012 Dec 28 [Epub aheadof print], PMID 23276720), researchersidentified 108 patients with epithelial

ovarian cancer, of whom 43 were plat-inum resistant. Treatment consisted of six weekly induction cycles of 90 mg/m2 of paclitaxel plus area under the curve (AUC) 4 of carboplatin, both administered by one-hour infusion on days 1, 8, 15, 29, 36 and 43. Patients who demonstrated clinical benefit on the study regimen (stable disease, par-tial response and complete response) continued treatment with six mainte-nance cycles of 175 mg/m2 of paclitaxel in three-hour infusions plus AUC 6 car-boplatin in one-hour infusions admin-istered every three weeks. The study

end points included progression-free survival (PFS), overall survival (OS), response rate (RR) and toxicity.

Both the weekly and the three-weekly cycles of the study regimen were well tolerated. Treatment delay (median seven days) was required in 16% of the 633 weekly cycles admin-istered (these occurred mainly after the third or the fourth cycle) and in 29% of the 448 three-weekly cycles. Dose reduction was needed in only 2% and 15% of the cycles, respec-tively. During the 633 weekly cycles, reported grade 3/4 toxicities included

thrombocytopenia (8%), neutropenia (30%) and febrile neutropenia (0.5%).

Among platinum-resistant patients, the RR for the paclitaxel plus carbo-platin regimen was 58%. Median PFS and OS were eight and 15 months, respectively. Among platinum-sensi-tive patients, the RR was 76%, where-as PFS and OS were 13 and 26 months, respectively. Among 13 platinum-resis-tant patients who were started on week-ly paclitaxel plus carboplatin less than six months after progression had signif-icantly shorter PFS (four months) and OS (nine months).

Paclitaxel-Carboplatin for Platinum-Resistant Ovarian Cancer

Craig Reeder, MDConsultant, Hematology/Oncology, andAssistant Professor of Medicine,Mayo Clinic

EXPERT INSIGHT


From The New England Journal of Medicine

If a screening tool has merit, it shoulddetect more cancers at earlier, more

treatable stages and, as a result, catchfewer cancers at later stages. Research-ers undertook an analysis of mam-mography screening, in which theincidences of both early- and late-stagebreast cancers were reviewed over a span of more than three decades. Thereport, by Archie Bleyer, MD, and H.Gilbert Welch, MD, MPH, was pub-lished in The New England Journal of Medicine (2012;367:1998-2005, PMID:

23171096).Surveillance, Epidemiology, and End

Results (SEER) data from the National Cancer Institute were used to establishtrends in the incidence of early-stage breast cancer (i.e., ductal carcinoma in situ and localized disease) and late-stage breast cancer (i.e., both regional and distant disease) between 1976 and2008. The women in the SEER data analyzed in this study were all at leastage 40 years. In order to establish a baseline incidence of diagnosis without benefit of mammography, the authors chose the three-year period from 1976 to 1978.

Screening mammography has dou-bled the number of cases of early-stage breast cancer detected each year, from 112 to 234 cases per 100,000 wom-en, representing an absolute gain of 122 cases. At the same time, the rate at which women present with late-stage cancer has decreased by 8% (from 102 to 94 cases per 100,000 women). If a constant underlying disease burden is assumed, then only eight of the newly detected 122 additional early cancers would have progressed to a later stage. This implies an excess detection of 114 cases of breast cancer per 100,000 women—a “substantial overdiagnosis.”

The authors estimated that mam-mography over-detects tumors that would never have progressed to clinical symptoms. In 2008, early-stage breast cancer was overdiagnosed in about 70,000 women. Late-stage survivor-ship has decreased 28% (from 71 to 51 deaths per 100,000), but this is attrib-uted to a combination of improved treatment and screening mammogra-phy, with the former providing, in the authors’ estimation, a significantly larger contribution. The authors con-cluded that mammography has had only a small effect on the rate of death from breast cancer.

Overdiagnosis of Breast Cancer Found in SEER Data Review

The Bleyer and Welch study has renewed the debate over the

value of screening mammography. Its main criticism: Routine mammo-grams have led to overdiagnosis of breast cancer.

The problem is that we simply don’t have sufficient long-term data on

outcomes on the term overdiagnosis.And, we don’t have prospective data to be able to reliably counsel patients. Therefore, it’s important to put the study findings in a broader context for women.

The study did not account for addi-tional lifestyle or reproductive risk

factors that may increase the incidence of breast cancer that are unrelated to screening, such as obesity and women giving birth at an older age.

Additionally, it did not account for technological advances, such as the implementation of digital mammog-raphy. Much of the data reviewed in the study were based on film-detected mammograms.

Breast cancer is the leading cause of death for women in their 40s. We know that women are diagnosed with early-stage breast cancers because of mam-mography. We also know we are going to save lives and improve prognosis by detecting cancers early, regardless of false-positives, unnecessary mammo-grams or unnecessary biopsies.

As practitioners, we need to makesure we’re obtaining a thorough and accurate family history to assess forhereditary breast cancer risk andcounsel appropriately regarding sur-veillance and risk reduction options. However, it is just as important to remember that more than 50% of women diagnosed with breast cancerwill not have a family history of breastcancer. Additionally, practitioners areencouraged to inform and counselpatients about the benefits, risks andlimitations of having a mammogram,a nd they may be called back for addi-tional mammograms or a biopsy.

Dr. Pruthi reported no relevant financial disclosures.

Platinum-based chemotherapy is not only the standard front-line treat-

ment for ovarian cancer, it is disease defining. Indeed, sensitivity to platinum is a powerful prognostic tool, with plat-inum-resistant patients carrying a poor prognosis. Platinum-resistant ovarian cancer can be defined as cancer that has progressed within six months of prior platinum-based chemotherapy.

Although such patients may have a low RR, resistance is not absolute and may be overcome to varying degrees with combination chemotherapy, such

as paclitaxel, or by varying the sched-ule. This study published by van der Berg et al in the most recent issue of the European Journal of Cancer investigatesrweekly induction chemotherapy with paclitaxel (90 mg/m2) and carboplatin(AUC 4) for six cycles, followed by six cycles of every three-weekly paclitaxel (175 mg/m2)/carboplatin (AUC 6).

In summary, the authors concludethat given a 58% RR, eight-month PFSand 15-month OS for platinum-resis-tant patients, the treatment was effec-tive therapy for this patient population.

Additionally, there were no reported grade 4, nonhematologic toxicities and a low incidence of grade 3 toxicities, lead-ing the authors to conclude that the tox-icity profile of the regimen was reason-ably tolerable.

The seemingly paradoxical sensitivi-ty of platinum-resistant ovarian cancer to platinum is not a new area of investi-gation. Indeed, the authors draw com-parisons to several prior studies, which identify the current study as having the largest platinum-resistant cohort yet investigated. It confirms that longer platinum-free intervals increase sensi-tivity to platinum therapy and outcomes.

Technically, the study was conduct-ed soundly and demonstrated that there is a high RR, including 16% complete responses, in platinum-resistant ovar-ian cancer. However, this comes at a price—26 weeks worth of chemother-apy, including an initial six weeks of intensive treatment, for approximately 32 weeks of PFS.

Although the nonhematologic toxic-ities were very reasonable, as expect-ed, grade 3 or worse neutropenia wasnearly universal. Thus, a quality-of-life assessment may have been use-ful to determine if patients themselves felt combination chemotherapy wouldbe worth it to them at this point in thetreatment of their disease. As theseagents are clinically available for use inovarian cancer, this work does remindus that platinum combinations are a potential option for patients with plati-num-resistant disease.

In addition to assessing quality of life, future studies could stand to per-form correlative molecular analyses ontumor tissue to identify which patientsare most likely to benefit from platinum,such that we could better individualizetreatment for this group of patients indire need of better therapies.

Dr. Haluska reported no relevant conflicts of interest.

Sandhya Pruthi, MDConsultant, Breast Diagnostic Clinic, andAssociate Professor of Medicine,Mayo Clinic

EXPERT INSIGHT

Paul Haluska, MD, PhDOncologist, andAssociate Professor of Oncology,Assistant Professor of Pharmacology,Mayo Clinic

EXPERT INSIGHT


From Clinical Colorectal Cancer

First-line bevacizumab (Avastin, Genentech) plus chemotherapy

may be just as safe as chemotherapy alone in older patients with meta-static colorectal cancer (mCRC), a newreport has revealed.

Although the FDA initially approvedthe study drug for first-line therapy of mCRC in 2004, its use in this setting—particularly among older patients—hasbeen circumscribed due to the incidenceof adverse events (AEs), such as gastro-intestinal perforation, thromboembolic

events, hypertension, and wound-heal-ing complications, in some clinical tri-als. However, before this study, which was published online in December 2012 by the journal Clinical Colorectal Can-cer (2012 Dec 28 [Epub ahead of print], rPMID: 23276520), the relative safety of bevacizumab in older patients—partic-ularly those with preexisting medical comorbidities—had not been thorough-ly studied.

The authors of the study identi-fied 6,821 patients with mCRC aged 65 years and older from the Surveil-lance, Epidemiology and End Results

Program (SEER)-Medicare databaseand categorized them based on first-line treatment (none, chemotherapy alone, or chemotherapy and bevaci-zumab). Preexisting conditions knownto increase bevacizumab-related risksfor AEs were identified in the yearbefore diagnosis.

Among the patients selected for study,only 19% received first-line bevacizum-ab plus chemotherapy; those aged 75years or older who had a higher comor-bidity index or had preexisting cere-brovascular disease were less likely toreceive the drug. Among those patients

who did receive first-line bevacizum-ab, the incidence of AEs was not high-er compared with those who received chemotherapy alone (hazard ratio [HR], 0.97). Patients who received first-line chemotherapy without bevacizumab between 2005 and 2007 had the high-est AE incidence rate; however, AE inci-dence rates were comparable between patients receiving first-line chemother-apy between 2001 and 2003 (135 AEs per 100,000 person-days) and patients receiving first-line chemotherapy with bevacizumab between 2005 and 2007 (141 AEs per 100,000 person-days).

Bevacizumab Effective, Tolerable in Older CRC Patients

CRC ranks second in cancer deaths in the United States with about

51,000 patients expected to succumb to this disease in 2013.1 The majority of patients with CRC are over the age of 65 years at diagnosis, with a median age of 71. Bevacizumab, a monoclonal antibody against vascular endothelial growth fac-tor (VEGF), is a key component of stan-dard systemic medical therapy used in the metastatic setting.2 Some of the bevacizumab-related side effects—in particular, the higher rate of arterial thromboembolic events compared with placebo—might limit the use of this drug in elderly patients with clinically rele-vant comorbidities.3

The analysis presented by Shankaranand colleagues used SEER-Medicare data to get a better understanding of the risk–benefit ratio for bevacizumab as a compo-nent of CRC therapy in elderly patients. The study included more than 6,800 patients in the periods 2001 to 2003 and 2005 to 2007, which are before and after the FDA approval of bevacizumab.

One of the key findings was that patients over the age of 75 as well as patients with significant comorbidities and prior cerebrovascular disease were much less likely to receive bevacizum-ab as part of their therapy. In a retro-spective, pooled analysis, the rate of AEs was not higher in patients treated with

bevacizumab compared with patients treated with chemotherapy alone.

The study has several limitations that are related to the very structure of the SEER database, which only captures AEs associated with Medicare claims. Thus, the analysis cannot be a substitute for a prospective evaluation of bevacizumab in clinical studies. The key conclusions of the analysis, however, mirror the results obtained in subgroup analyses of large observational cohort studies in CRC, as well as a pooled analysis of randomized trials conducted with bevacizumab.4,5

It appears that if elderly patients are carefully selected based on their clinical status, comorbidities and medical histo-ry, bevacizumab can be safely adminis-tered in this patient population, produc-ing a similar treatment benefit from this drug to their younger counterparts.

The efficacy and tolerability of bev-acizumab in elderly patients has been confirmed in an elegant trial presented at the 2013 American Society of Clin-ical Oncology Gastrointestinal Sym-posium.6 In this international trial conducted exclusively outside of the United States, 280 patients with mCRC aged 70 years and older (median age 76) were randomized to capecitabine alone or capecitabine plus bevacizum-ab as first-line therapy. The addition of bevacizumab significantly improved

progression-free survival and response rates and led to a remarkable median overall survival of almost 21 months, which rivals results in younger patients. Except for a slight increase in venous and arterial thromboembolic events, no increased side effects were noted with the inclusion of bevacizumab. These results suggest that capecitabine plus bevacizumab could be considered one of the treatment standards for elder-ly patients with CRC. In the United States, however, most elderly patients receive an oxaliplatin-based combina-tion therapy like FOLFOX (leucovo-rin, 5-fluorouracil and oxaliplatin) or XELOX (capecitabine plus oxaliplat-in) as backbone for the addition of bev-acizumab.5 A prospective evaluation of oxaliplatin is still clearly warrant-ed in the context of fluoropyrimidine (capecitabine)-bevacizumab first-line therapy. A trial addressing this very question was initiated by the Inter-group (N0949, NCT01279681), but was unfortunately closed in December 2012 due to poor accrual.

In summary, the body of evidence confirms that bevacizumab can be safely and effectively used in elderly patients with CRC using clinical crite-ria to eliminate patients at higher risk for bevacizumab-related side effects. A fluoropyrimidine alone can be consid-ered as chemotherapy backbone for the addition of bevacizumab in first-line therapy in patients over the age of 70.

References

1. Siegel R, Naishadham D, Jemal A. Can-cer statistics, 2013. Ca Cancer J Clin.2013;63:11-30, PMID: 23335087.

2. Grothey A, Allegra C. Antiangiogene-sis therapy in the treatment of metastat-ic colorectal cancer. Ther Adv Med Oncol. 2012;4:301-319, PMID: 23118806.

3. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treat-ed with chemotherapy and bevacizum-ab. J Natl Cancer Inst. 2007;99:1232-1239,PMID: 17686822.

4. Cassidy J, Saltz LB, Giantonio BJ, et al. Effect of bevacizumab in older patients with metastatic colorectal cancer: pooledanalysis of four randomized studies. J Cancer Res Clin Oncol. 2010;136:737-743,PMID: 19904559.

5. Kozloff MF, Berlin J, Flynn PJ, et al. Clini-cal outcomes in elderly patients with met-astatic colorectal cancer receiving bevaci-zumab and chemotherapy: results from the BRiTE observational cohort study. Oncolo-gy. 2010;78:329-339, PMID: 20733336.

6. Cunningham D, Lang I, Lorusso V, et al. Bevacizumab (bev) in combination with capecitabine (cape) for the first-line treat-ment of elderly patients with metastat-ic colorectal cancer (mCRC): Results of a randomized international phase III tri-al (AVEX). ASCO Meeting Abstracts2013;31:337.

The Mayo Foundation received research funding from Genentech for studies

conducted by Drs. Hubbard and Grothey.

It appears that if elderly patients are carefully

selected based on their clinical status, comorbidities

and medical history, bevacizumab can be safely

administered in this patient population.

Axel Grothey, MDOncologist, andProfessor of Oncology,Mayo Clinic

Joleen M. Hubbard, MDOncologist, andAssistant Professor of Oncology,Mayo Clinic

EXPERT INSIGHT


From the Journal of Clinical Oncology

The orally bioavailable tyrosine kinase inhibitor cabozantinib

(Cometriq, Exelixis) has demonstrated clinical activity in patients with castra-tion-resistant prostate cancer (CRPC) in a Phase II randomized discontinu-ation trial with an expansion cohort. The FDA has already approved cabo-zantinib for the treatment of metastatic progressive medullary thyroid cancer.

The Phase II trial, the results of which were published in the Feb. 1 issue of the Journal of Clinical

Oncology (2013;31:412-419, PMID: 23169517), enrolled 171 men with CRPC; all patients received open-label treatment with cabozantinib during a 12-week lead-in stage. Initially, those with stable disease at 12 weeks were to be randomly assigned to cabozan-tinib or placebo; however, the study oversight committee recommend-ed suspension of randomization after enrollment of 122 patients because of “unexpected changes on bone scan and decrease in pain observed during the lead-in stage.” During the lead-in stage, 72% of evaluable patients on

cabozantinib had regression in soft tis-sue lesions and 68% had improvement on bone scan, including 12% with complete resolution. As a result, in all, 31 patients were randomly assigned to either receive cabozantinib or pla-cebo and 57 patients continued open-label treatment, whereas an addition-al 49 eligible patients were enrolled before closure of the cohort (of these, 28 remained on cabozantinib for more than 12 weeks).

Among those treated with the study drug for 12 weeks, median progres-sion-free survival (PFS) was 23.9

weeks compared with 5.9 weeks with placebo (P(( <0.001). In 57% of these patients, serum total alkaline phospha-tase and plasma cross-linked C-termi-nal telopeptide of type I collagen were reduced by at least 50%. On retro-spective review, bone pain improved in 67% of 116 evaluable patients, with a decrease in narcotic use in 56% of patients. The most common grade 3 adverse events reported during the trial were fatigue (16%), hypertension (12%) and hand-foot syndrome (8%). These resulted in dose reductions in 62% of patients.

Cabozantinib Promising in Castration-Resistant Prostate Cancer

Cabozantinib (previously known as XL-184) is an oral inhibitor of

MET and vascular endothelial growth factor receptor 2, both of which are overexpressed during the emergence of CRPC and both of which also play a critical role in the development of bone metastases. In Phase I trials, cabozan-tinib has shown broad activity against several tumor types, with acceptable toxicity profiles. The current Phase II study evaluated efficacy of cabozan-tinib in patients with metastatic CRPC who had an Eastern Cooperative Oncol-ogy Group performance status of 0 or 1 and had progressed on at least one stan-dard treatment.

One of the key features of this study is its novel Phase II randomized “dis-continuation” design. This design attempts to maintain the ability to eval-uate tumors for response while mini-mizing exposure to placebo in tumors

with objective regression, while allow-ing for randomized evaluation where the activity is to prolong progression. In this study, therefore, all patients received an open-label treatment with 100 mg of oral cabozantinib dur-ing a 12-week lead-in stage followed by response assessments by Response Evaluation Criteria in Solid Tumors criteria, at which point patients with stable disease were randomly assigned to receive either cabozantinib or place-bo. These randomly assigned patients were then observed until they met study-defined progression criteria, at which point treatment assignment was unblinded. Patients were taken off study if they were receiving cabo-zantinib or were allowed to restart cabozantinib if on placebo. Patients restarted on cabozantinib after first progression on placebo were observed until subsequent progression.

The use of this adaptive design had an 80% power to detect a hazard ratio of 0.5 for evaluating efficacy, with the primary end point being PFS from the point of random assignment after com-pletion of the 12-week lead-in period, in those patients who demonstrated ini-tial stable disease at week 12.

By the 12-week lead-in period, 55 of the 171 patients enrolled had discontin-ued the cabozantinib treatments either due to drug toxicity or lack of response. However, the most interesting part of the results of this novel drug design lies elsewhere. After initially enrolling 171 patients for the 12-week lead-in peri-od and after randomizing 122 patients of these to cabozantinib or placebo, the study continuation was suspend-ed on the recommendation of the study oversight committee, as it was felt that unexpectedly positive results on bone scan and decrease in pain observed dur-ing the lead-in stage of random assign-ment made it unethical to continue randomization of patients to placebo

following the lead-in period.In this sense, the trial design and the

study results have been successful, as the results demonstrate that the drug is efficacious and so should be pursued vigorously in Phase III trials, which are well under way. Of note, com-mon all-grade adverse events included fatigue, decreased appetite, taste alter-ations, nausea, diarrhea, weight loss, and hand-foot syndrome in 62% of the study population.

Cabozantinib, although not yet ready for “prime-time” use as of yet, promis-es to be an extremely potent alternative for offering to CRPC patients in the future if these initial efficacy results hold out in on-going Phase III trials. The current need thus lies in encourag-ing patients to be directed to on-going trails with this drug, if and when the current standard treatments for treat-ing this stage have been exhausted.

Dr. Kohli reported no relevant conflicts of interest.

Cabozantinib, although not yet ready for

“prime-time” use as of yet, promises to be

an extremely potent alternative for offering

to CRPC patients.

Manish Kohli, MDOncologist, andAssociate Professor of Oncology,Mayo Clinic

EXPERT INSIGHT


Vienna—Can neoadjuvant breast can-cer data be used to accelerate drug development? At the recent annualmeeting of the European Society forMedical Oncology, a pro–con argumentwas conducted in a lively manner meantto incite controversy, convince audi-ence members to change their mindsand provide a few laughs in the process.PowerPoint slides even incorporatedimages of a bullfight with Jose Baselga,MD, PhD, in the arena.

Neoadjuvant Data: The Pro Argument

Dr. Baselga, the physician-in-chief atMemorial Sloan-Kettering Cancer Cen-ter in New York City, vehemently arguedthat pathologic complete response(pCR) can be used as a surrogate markerfor disease-free survival (DFS) and over-all survival (OS). Neoadjuvant trials, hesaid, provide an efficient trial design forassessing the efficacy of novel therapies.

They involve smaller sample sizes, fast-er trials and less money than large Phase III adjuvant trials.

Several studies speak to the strengthsof pCR as an end point in breast cancerpatients, said Dr. Baselga. The NOAH(NeOAdjuvant Herceptin) trial showedthat neoadjuvant trastuzumab (Her-ceptin, Genentech) induced a higherpCR in patients with HER2-positivebreast cancer than in those who receivedchemotherapy only and that this cor-related with improved DFS (Lancet((2010;375:377-384, PMID: 20113825).

In a recent meta-analysis, Dr. Baselga and his colleagues analyzed 30 publishedstudies involving neoadjuvant chemo-therapy in breast cancer patients to evalu-ate the association between pCR and sub-sequent DFS and OS (Bardia A, et al. AACR Advances in Breast Cancer ResearchConference. Oct 2011). The average pCR rate in the sample of 11,206 patients was22%, with a range of 3% to 27%, and pCR was associated with improved DFS (oddsratio [OR], 0.33; P<0.00001). The OR was0.37 in HER2-positive patients and 0.20in triple-negative tumors (P(( <0.00001).

pCR also was associated with improved OS (OR, 0.24) and was strongly correlat-ed in HER2-positive (OR, 0.09; P=0.02) and triple-negative disease (OR, 0.29; P<0.00001).

Additionally, the German Breast Group analyzed the association between tumor response at surgery and long-term outcome in patients with primary breast cancer receiving neoadjuvant anthra-cycline-taxane–based chemotherapy in seven randomized trials (J Clin Oncol ((2012;30:1796-17804, PMID: 22508812). pCR was associated with improved DFS in luminal B/HER2// -negative, HER2-positive/nonluminal and triple-negative tumors, but not in luminal A or luminal B/HER2// -positive breast cancer.

“pCR after neoadjuvant chemo-therapy is associated with significant-ly improved disease-free survival and overall survival, particularly for HER2-positive and the triple-negatives. pCR should be considered as a surrogate

marker for survival outcomes as new therapies are being evaluated in the neoadjuvant setting,” said Dr. Baselga.

He added that in patients with estro-gen receptor–positive breast cancer, cli-nicians need to think about using differ-ent biomarkers. Ki67 has been shown to be predictive in several clinical tri-als, including the RAD001 trial. This tri-al demonstrated that adding everolim-us (Afinitor, Novartis) to neoadjuvant letrozole treatment in postmenopaus-al women with operable ER-positive

breast cancer improved response rate, from 59.1% to 68.1% (J Clin Oncol((2009;27:2630-2637, PMID: 19380449). “At day 15, a large difference in Ki67 is seen between the everolimus plus letrozole and the placebo plus letrozole arms, which was not seen at baseline,” said Dr. Baselga.

He argued that the neoadjuvant data from the RAD001 trial should speed drug approval. “The fact that we can-not give everolimus in the adjuvant set-ting is ridiculous,” said Dr. Baselga. “If you have a patient with luminal disease that you know is going to recur with a high chance, we are doing a disservice to the community by not being able to offer it to them.”

Dr. Baselga pointed out that data from NEOALTTO (NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimi-zation) was not being allowed to influ-ence clinical practice. Researchers simul-taneously launched the ALTTO and NEOALTTO trials to investigate wheth-er dual HER2 blockade with trastuzumab and lapatinib (Tykerb, GlaxoSmithKline) is better than single-agent trastuzumab. The primary end point of NEOALTTO, in which the dual blockade was given in the neoadjuvant setting, was pCR (Lan-((cet 2012;379:633-640, PMID: 22257673). “The study accrued very rapidly, and

for over a year and a half now, we have known that combined HER2 block-ade induces a dramatic improvement in pathologic complete response,” said Dr. Baselga. Meanwhile, the ALTTO trial being conducted in the adjuvant setting involves 8,000 patients and is not expect-ed to report results for several years.

“Do we have any doubt that the out-come [of ALTTO] will be positive? No, we don’t,” said Dr. Baselga. “So, why are we depriving women of receiving dual HER2 blockade, which is clearly the way to go based on NEOALTTO?”

Dr. Baselga pointed out that the FDA recently released a draft guidance stating a drug may receive accelerated approvalbased on a surrogate end point that is rea-sonably likely to predict clinical benefit, and for neoadjuvant breast cancer treat-ment, that surrogate could be pCR.

“In case you don’t know, we are broke. We don’t have the resources to do10,000-patient clinical trials. We cannotwait for the results of adjuvant trials that we know are going to be positive,” said Dr. Baselga. “The day that the ALTTOtrial is positive, we are going to feel good, but we will also feel very sad and very bad, because we know that trastuzum-ab and lapatinib is better than trastu-zumab, yet how many lives have we lost? Was this necessary? It was totally unnecessary. There is not a single well-conducted neoadjuvant trial that has notbeen confirmed in the adjuvant setting.There are some that are suboptimal thathave never been confirmed, but that is an issue of science.”

Neoadjuvant Data: The Con Argument

Ian Tannock, MD, PhD, a professor of medical oncology at Princess Marga-ret Hospital in Toronto, Canada, argued strongly that neoadjuvant data should not be used to speed drug approval.

ESMO Debate:

Should Neoadjuvant DataBe Used To Speed Drug Approval?

FDA’s Rationale for Using Pathologic Complete Response as a Surrogate End Point in Neoadjuvant Trials

“We believe that use of pCR as an end point to support acceler-ated approval in high-risk populations in the neoadjuvant setting has the potential to help address unmet need in these populations in a far shorter time frame than would be required via the conventional approach to breast cancer drug development.”

From “Guidance for Industry: Pathologic Complete Response in Neoadjuvant Treatment of High-RiskEarly-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval.” U.S. Food and Drug Administration, May 2012.

‘The fact that we

cannot give everolimus

in the adjuvant setting

is ridiculous. If you have a

patient with luminal disease

that you know is going to recur with a high chance,

we are doing a disservice to the community by not

being able to offer it to them.’

—Jose Baselga, MD, PhD

see NEOADJUVANT, page 22TT �

‘pCR should be considered as a surrogate

marker for survival outcomes as new

therapies are being evaluated in the

neoadjuvant setting.’

—Jose Baselga, MD, PhD


®

Now Available...

ChairStefan Glück, MD, PhD,

FRCPSSylvester Professor, Department of MedicineDivision of Hematology/OncologySylvester Comprehensive Cancer CenterLeonard M. Miller School of MedicineUniversity of MiamiMiami, Florida

FacultyRuth O’Regan, MDProfessor and Vice Chair for EducationDepartment of Hematology/Medical OncologyChief of Hematology/Medical OncologyGeorgia Cancer Center for Excellence Grady Memorial HospitalDirector, Hematology Oncology FellowshipEmory UniversityChair, Louisa and Rand Glenn Family Breast Cancer ResearchDirector, Emory Breast CenterAtlanta, Georgia

Robert A. Burger, MDProfessor of Medicine and OncologyProfessor, Surgical OncologySection of Gynecologic OncologyDirector, Women’s Cancer CenterFox Chase Cancer CenterPhiladelphia, Pennsylvania

Samer I. Schuman, MD,

FACS, FACOGAssistant Professor, Obstetrics and GynecologyAssociate Director, Gynecologic Oncology FellowshipSylvester Comprehensive Cancer CenterLeonard M. Miller School of MedicineUniversity of MiamiMiami, Florida

Learning Objectives1 Identify recent major fi ndings in

breast and ovarian cancer research.

2 Describe how recent fi ndings may aff ect screening, diagnosis, and the use of biomarkers in breast andovarian cancer.

3 Discuss the implications of recent research for clinical practice in treating breast and ovarian cancer.

Intended AudiencesOncologists

Statement of NeedCancer is the second leading causeof death. Among women, breast andovarian cancers are particularly com-mon and have high mortality rates. Clinical needs have been identifi ed in the management of patients withthese conditions, including the dif-fi culty of translating the constant fl ow of newly presented data into daily physician practice; the quan-tity of information being released each year is considerably greater than the clinician can readily absorb. To close these gaps, education isneeded in reviewing the most impor-tant research in breast and ovar-ian cancers and clarifying how the new fi ndings may improve screening, diagnosis, and treatment.


Estimated Time for Completion90 minutes

Accreditation StatementTh is activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continu-ing Medical Education (ACCME)through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education(ACE). Global is accredited by the ACCME to provide continuing med-ical education for physicians.

Credit DesignationGlobal Education Group designates this enduring activity for a maximumof 1.5 AMA PRA Category 1 Credits™. sPhysicians should claim only thecredit commensurate with the extent of their participation in the activity.

Method of PreparationTo receive CME credit, participantsshould read the preamble, completethe pre-test, read the monograph, and complete the post-test and evalua-tion. A score of at least 75% is required to complete this activity successfully. CME certifi cates will be issued imme-diately upon successful completion.

To participate in this FREE CME activity, log on to www.CMEZone.comand enter keyword “MN122”

This activity is jointly sponsored by Global Education Group and Applied Clinical Education. This activity is supported by educational grants from Genentech, Inc.

on Breast and Ovarian CancersIntegrating Data, Improving Outcomes

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN122”Release Date: October 22, 2012 Expiration Date: October 22, 2013

Companies, he said, need to focus ondeveloping drugs that have a meaning-ful impact on survival, decrease symp-toms and improve quality of life. “Wehave to recognize that anything else isa surrogate end point, and while sur-rogate end points might be valuable,they must correlate with those out-comes,” said Dr. Tannock. “What we donot need are drugs that have a trivialimpact on survival with a high cost anda high toxicity.”

He said he accepted the fact thatpatients who achieve a pCR in neoad-juvant trials usually have better sur-vival, but that did not get around themain problem of giving a new drug withunknown safety to women. “Even largerandomized controlled trials are insuffi-cient to disclose serious toxicities whennew agents are prescribed. Nearly 60%of potential fatal adverse events are notin the initial FDA label,” said Dr. Tan-nock. “I think there are ethical questionsabout prescribing a new drug to patientsafter accelerated approval [is granted]based on a small neoadjuvant trial.”

He also said that if the confirmatory trial of a drug that has gained acceler-ated approval is an adjuvant trial, thereare ethical concerns about selling a drug to women who can afford it, while

recruiting others to a clinical trial. “Women will perceive benefit because of conditional approval, and they will be reluctant to take part in the clinical trial, so the whole process as proposed by the FDA may be retarded rather than accelerated,” said Dr. Tannock.

He pointed to a study in the Jour-nal of Clinical Oncology that provided a statistical argument as to why achiev-ing response may be correlated with improved survival, but that it should not be used to imply cause and effect (J ((Clin Oncol 2008:26;3913-3915, PMID: 18711176). One of the arguments put forth in this paper is that it is generally impossible to refute the possibility that response is just a marker that selects the good-prognosis patients, those who would have survived longer even if the therapy has no effect at all. The question is “is the surrogate end point of response reasonably likely to predict overall clini-cal benefit,” Dr. Tannock said.

In the RAD001 trial, everolimus improved response rate, but grade 3/4 toxicities increased from 4% to 23%. “Neoadjuvant trials involving new agents require the new drug to be giv-en to women with a potentially cur-able disease, [which is] not always a good strategy for potentially toxic new drugs,” said Dr. Tannock.

He pointed out that improvements in surrogate end points do not always trans-late into survival benefits. For example,

the FDA granted accelerated approv-al for bevacizumab (Avastin, Genen-tech) in metastatic breast cancer based on a 5.5-month improvement in PFS in the E2100 trial, but rescinded approval after several studies demonstrated that the drug only modestly improved PFS and did not increase overall survival. “Make no mistake: A drug that does not improve survival but does add toxicity is not a negative trial. That is a harmful tri-al,” Dr. Tannock said.

Although he lamented the fact that few drugs have been approved for breast cancer in the past five years, he said that speeding the approval of subpar drugs was not the answer. “We don’t need a process that increases the approval of marginal drugs,” said Dr. Tannock.

According to Dr. Tannock, one of the reasons that good drugs are not being developed is the FDA’s and the Europe-an Medicines Agency’s policy of approv-ing any new drug that improves OS or PFS, no matter how small the differ-ence, as long as it is statistically signif-icant. “What this has done is [it has]

encouraged Big Pharma to do very largetrials to detect trivial differences in out-come that allow drug registration,” saidDr. Tannock. “We don’t need those enor-mous trials to detect a truly effective drug.”

According to Dr. Tannock, the solu-tion to the problem of unwanted mar-ginal drugs is to require value-based pricing as a condition for approval, so that the price of new drugs is related totheir effectiveness. Future trials would become smaller and faster because sam-ple size depends on the effect size that a trial is designed to detect or exclude, and companies would be discouraged from developing marginally effective drugs.

—Kate O’Rourke

Dr. Baselga has served as an advisor or consultant for Exelixis, Merck, Novartis and Roche, and has received grants for clinical

research from GlaxoSmithKline. Dr. Tannock disclosed uncompensated consultant or advisory roles for and research funding

from Bayer, Eli Lilly, Exelixis, Genentech,Johnson & Johnson and Sanofi.

The Great Divide in Pain Medicine Access

At the European Society for Medical Oncology annual meeting, researchers presented preliminary data from the International

Collaborative Project to Evaluate the Availability and Accessibility of Opioids for the Management of Cancer Pain. The consortium evaluated opioid drug availability, cost to consumers and barriers that stand in the way of cancer patients trying to obtain these drugs. Data was gathered between December 2010 and July 2012 in 76 countries in Africa, Asia, theMiddle East, Latin America, the Caribbean and 19 Indian states.

Only 12 countries surveyed provided all seven of the opioid medications considered to be essential for the relief of cancer pain by the InternationalAssociation for Hospice and Palliative Care: codeine, immediate- and slow-release morphine, injectable morphine, oral oxycodone, oral methadone,and transdermal fentanyl. In many countries, opioids that were on a formulary were only available occasionally or half the time. Many countrieshave highly restrictive regulations that limit entitlement of cancer patients to receive prescriptions, limit prescriber privileges, impose restrictive limits on duration of prescription, restrict dispensing, and increase bureaucraticburden of the prescribing and dispensing process.

“There is an urgent need for formulary review, improving affordability ofmedications, improving availability of opioids by better distribution and dispensing, careful examination of multiple drug control policies, and forrepeal of excessive restrictions, which are impeding this most fundamentalaspect of cancer care,” said Nathan Cherny, MD, head of Cancer Pain andPalliative Medicine, Shaare Zedek Medical Center, Jerusalem, Israel, whopresented the survey results.

numbersby the

TNEOADJUVANTcontinued from page 20 ��

‘Make no mistake: A drug that does

not improve survival but does add

toxicity is not a negative trial. That

is a harmful trial.’—Ian Tannock, MD, PhD

Austria

United States

Canada

Worldwidemorphine

consumption

Ukraine

Nepal

India

Mg/capita

123

75

75

6

0.64

0.19

0.09

0 30 60 90 120 150

Figure. Overall morphine consumption.

Based on 2009 and 2010 data from the International Narcotics Control Board.


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Vienna—Pazopanib (Votrient, Glaxo-SmithKline) may offer a treatmentoption for patients with locally advancedor metastatic pancreatic neuroendo-crine tumors (pNETs) that have failedtreatment with two of the most recent-ly approved drugs for this patient pop-ulation. This news comes from resultsof the Phase II PAZONET trial, whichwere reported at the annual meeting of the European Society for Medical Oncol-ogy (abstract 11570).

“Pazopanib is the first drug to showclinical activity in patients with neu-roendocrine tumors who have failed atleast one previous systemic treatmentbased on mammalian target of rapamy-cin (mTOR) inhibition or other multi-targeted agents,” said Enrique Grande,MD, from the Ramon y Cajal Universi-ty Hospital in Madrid, Spain, who pre-sented the results on behalf of the Span-ish Task Force for NETs. The mostrecent agents to be approved by the

FDA for pNETs are the vascular endo-thelial growth factor receptor inhibitor sunitinib (Sutent, Pfizer) and the mTOR inhibitor everolimus (Afinitor, Novartis). Both drugs were approved in 2011 based on progression-free survival data.

The new multicenter study included 44 patients with well- and moderately differ-entiated carcinoid or pancreatic islet cell, locally advanced or metastatic tumors that were not amenable to surgery, radi-ation or combined modality therapy with curative intent. Patients were treatment naive (21%) or had been treated with an mTOR inhibitor only (24%), a tyrosine kinase inhibitor (TKI) only (36%), or both a TKI and an mTOR inhibitor (24%). All patients had progressive disease within 12 months and the median number of pre-vious systemic treatments was two. Forty-two patients were evaluable for response.

The primary end point was clini-cal benefit rate, defined as complete response plus partial response plus

stable disease at six months by Response Evaluation Criteria in Solid Tumors. The clinical benefit rate was 85.7% (Table) and the median progression-free sur-vival was 10 months. Grade 3/4 toxici-ties included asthenia (19%), diarrhea (10%), hypertension (10%), transaminase

elevation (12%), hyporexia (2%) and hyperglycemia (7%).

According to Eric Baudin, MD, PhD, from the Institut de Cancerologie Gus-tave Roussy in Villejuif, France, an expert on NETs, the study suggests anti-tumor activity of pazopanib in a mixed population of well-differentiated NETs pretreated with multiple options includ-ing a TKI and/or an mTOR inhibitor in 80% of cases. He was encouraged by the safety data. “Sequencing of targetedmolecular therapies could be consideredan option in future protocols analyzing best sequencing strategy in NETs,” Dr. Baudin said.

—Kate O’Rourke

Dr. Grande disclosed he is on the advisory boards and has received honoraria from

IPSEN Pharma, Novartis Oncology and Pfizer Oncology and has received research

support from GSK Oncology. Dr. Baudindisclosed a relationship with HRA, Ipsen,

Novartis, Pfizer and Sanofi.

A Second-Line Option for Neuroendocrine TumorsMulti-targeted TKI pazopanib shows promise in mixed, pretreated patient population

Vienna—Adding cetuximab (Erbitux,Merck Serono) to FOLFOX4 does notimprove outcomes in patients withresected stage III colorectal cancer(CRC), according to results from thePhase III PETACC8 (Pan-EuropeanTrials in Alimentary Tract Cancer) tri-al, reported at the annual meeting of theEuropean Society for Medical Oncolo-gy (LBA4). The trial can be added to thegrowing list of studies that have shownthat CRC therapies that are effective inthe metastatic setting are not always suc-cessful in early stages of the disease.

In PETACC8, patients with fully resected stage III, KRAS wild-type CRCwere randomized to receive six monthsof adjuvant treatment with FOLF-OX4, either with or without cetuximab.

FOLFOX4 consists of oxaliplatin 85 mg/m2 administered as a two-hour infusion on day 1; leucovorin (200 mg/m2) admin-istered as a two-hour infusion on days 1 and 2; followed by a loading dose of 5-flu-orouracil (5-FU; 400 mg/m2) IV bolus, then 5-FU (600 mg/m2) administered via ambulatory pump for a period of 22 hours on days 1 and 2 every two weeks.

In an interim analysis of 1,602 patients, Julien Taieb, MD, PhD, from the Georges Pompidou European Hospi-tal-Paris Descartes University in Par-is, France, reported no difference in disease-free or overall survival. There were no survival differences in BRAFwild-type patients. A subgroup anal-ysis showed that patients with more aggressive pT4N2 tumors might bene-fit from cetuximab (hazard ratio, 0.555; P=0.0122).

Colon cancer expert Fortunato Ciardi-ello, MD, PhD, from the Second Uni-versity of Naples in Italy, offered sev-eral possible reasons for the negative results. First, perhaps in unselected, fully resected stage III CRC patients treated for six months with a combina-tion of a fluoropyrimidine and oxaliplatin, “a plateau of efficacy has been reached.” This would explain the negative results of the recent CRC trials investigating either bevacizumab or cetuximab, said

Dr. Ciardiello. A second possibility is that the FOLFOX chemotherapy back-bone is not the most appropriate combi-nation for cetuximab. Another potential explanation is that the biology of micro-metastases in fully resected stage III CRC patients is different from the biol-ogy of metastases in stage IV CRC and, therefore, anti-angiogenic drugs and anti-endothelium growth factor recep-tor drugs are not effective in the adjuvant setting. This latter hypothesis has been previously suggested to explain the neg-ative results of the AVANT and Nation-al Surgical Adjuvant Breast and Bowel Project CO-8 trials, both of which test-ed bevacizumab, as well as the North Central Cancer Treatment Group-N0147

trial that tested cetuximab.A fourth explanation, said Dr. Ciardi-

ello, is that the KRAS wild-type tumorgroup is a heterogenous biologic and pathologic group, and thus this groupneeds to be further divided to find effec-tive therapies. “I strongly encourage the authors to conduct further translational research studies in the PETACC8 KRASwild-type patients,” said Dr. Ciardiello.

—Kate O’Rourke

Dr. Taieb disclosed a consultancy/advisory role and honoraria from Merck KGaA. Dr. Ciardiello disclosed honoraria and

research funding from Bayer, Merck KGaA and Roche.

Adding Cetuximab Gives No Benefit in Stage III CRCPETACC8 trial reports negative results

Why They’re Not Working

Targeted therapies have now failed in a series of advanced colorectal cancer trials. Here are some theories as to why:

• FOLFOX provides a “plateau of efficacy” that targeted therapies cannot improve on in unselected patients

• FOLFOX does not pair well with bevacizumab or cetuximab

• Micrometastic disease in resected stage III patients is biologically different from metastases in stage IV disease

• The KRAS wild-type tumor group is heterogenous with subgroups Sof responders and non-responders that have yet to recognized

Table. Clinical Benefit Rate in NET Patients Receiving Pazopanib

Response by RECIST

Patients, %

Complete response 0

Partial response 7.1

Stable disease 78.6

Progressive disease 14.3

NET, neuroendocrine tumor; RECIST,Response Evaluation Criteria in Solid Tumorsespo se va uat o C te a So d u o s

Chemical structure of cetuximab.

24 CLINICAL ONCOLOGY NEWS • MARCH 2013SOLID TUMORS

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MCCON510.indd 1 1/29/13 5:12 PM

On Feb. 4, the FDA approved thefirst generic version of doxoru-

bicin hydrochloride (HCl) liposomeinjection to ease an ongoing shortage of the cancer drug, the agency announcedin a press release. For products on theFDA’s drug shortage list, the agency’sOffice of Generic Drugs uses a prior-ity review system to expedite review of generic applications.

The newly approved medication ismade by Sun Pharma Global FZE, and isthe generic equivalent to Doxil (JanssenProducts, LP). The drug will be avail-able in 20- and 50-mg vials, accord-ing to the press release. Doxorubicin

HCl liposome injection is administered intravenously and indicated, under certain conditions, for ovarian cancer, AIDS-related Kaposi’s sarcoma and multiple myeloma, according to the drug’s prescribing information.

“The agency is committed to doing everything we can to address drug shortages so that patients can get the medicines they need when they need them,” Capt. Valerie Jensen, RPh, the director of Drug Shortage Staff at the FDA’s Center for Drug Evaluation and Research, said in a statement. “For the past year, the FDA has been working to ensure that supplies of doxorubicin

hydrochloride liposome injection were not interrupted.”

Part of those efforts by the agency included a decision in February 2012 to allow temporary importation of Lipo-dox, a branded version of doxorubi-cin HCl liposome injection that also is produced by Sun Pharma, along with its distributor, Caraco Pharmaceutical Laboratories Ltd. The FDA stressed, however, that Lipodox is not approved for marketing in the United States; the agency used its regulatory enforcement discretion to allow importation of the drug during the Doxil shortage.

For the present time, the FDA will

continue to allow importation of Lipo-dox. However, once supplies of Sun Pharma’s approved version of the drug are sufficient to meet projected demand,the agency said it expects to reinstate itsban on importing any unapproved doxo-rubicin HCl liposomal product.

Janssen Products, which is the sole U.S.-based supplier of doxorubicin HCl liposome injection, has stated that manufacturing issues are to blame for the ongoing shortages of Doxil. Updates on the drug’s availability can be obtained at http://www.doxilsupply.com/index.html.

—George Ochoa

On Feb. 8, the FDA approvedpomalidomide (Pomalyst, Celgene

Corporation) for patients with multi-ple myeloma who have received at leasttwo prior therapies, including lenalid-omide and bortezomib, and have dem-onstrated disease progression within 60days of the last treatment, according toan agency press release.

“Treatment for multiple myeloma is tai-lored to meet individual patient’s needs,and today’s approval provides an addi-tional treatment option for patients whohave not responded to other drugs,” Rich-ard Pazdur, MD, director of the Office of

Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.

A thalidomide analog, pomalidomide was approved under the FDA’s acceler-ated approval program and was grant-ed orphan product designation. Accord-ing to FDA and Celgene press releases, pomalidomide’s safety and effectiveness were evaluated in a Phase II, random-ized, open-label trial of 221 patients with relapsed or refractory multiple myeloma. Patients were randomized to pomalid-omide alone or pomalidomide with low-dose dexamethasone. In patients

treated with pomalidomide alone, 7.4% achieved objective response rate (ORR). The median duration of response has not yet been reached in this arm. In patients treated with pomalidomide with low-dose dexamethasone, 29.2% achieved ORR; median duration of response was 7.4 months.

Approval is based on response rate, according to the Celgene press release. Clinical benefit, such as improvement in symptoms or survival, has not been verified.

Pomalidomide carries a boxed warn-ing stating that it is contraindicated

in pregnancy because it causes severe birth defects or embryo-fetal death; andthat it can cause venous thromboembo-lism. Because of the embryo-fetal risk,pomalidomide is available only throughthe Pomalyst Risk Evaluation and Mit-igation Strategy program. Common adverse reactions include fatigue and asthenia, neutropenia, anemia, consti-pation, nausea, diarrhea, dyspnea, upper respiratory tract infections, back pain and pyrexia.

—Based on FDA and Celgene press releases

FDA Approves Generic Version of Doxil To Ease Shortage

Pomalidomide Approved for Advanced Multiple Myeloma

On February 22, the FDA approved trastuzumab

emtansine (T-DM1, Roche) under the agency’s priority

review pathway for women with HER2-positive, metastatic

breast cancer (mBC) who have been previously treated

with trastuzumab (Herceptin) and a taxane chemotherapy,

either separately or in combination.

T-DM1 is a novel antibody-drug conjugate—the cytotoxic

agent mertansine (DM1) is attached to the antibody

trastuzumab using a biochemical link designed by the

biotechnology company ImmunoGen. The theory is that an

antibody, by targeting surface proteins like HER2 or CD56,

will deliver a cytotoxic “payload” directly to cancer cells

wherever they may be throughout the body.

T-DM1 is only the first in a series of drugs in clinical

development using conjugate technology, a concept that

stands to have a significant impact on cancer treatments.

T-DM1 is already being tested in a Phase II/III study of

gastric cancer and Roche has reported that the company

has approximately 25 antibody-drug conjugates in their

development pipeline alone.

The Table highlights a handful of conjugate compounds

in development that are using ImmunoGen’s technology.

Therapeutic developments: Antibody-drug conjugates

Table. Clinical-stage compounds with ImmunoGen’s antibody-drug conjugate technology.

ADC Compound Disease Type Development Stage Company

HER2+ breast cancers Ph III/registration Roche

HER2+ gastric cancers Ph II

SAR3419 B-ALL Ph II Sanofi

Diffuse large B-cell lymphoma Ph II

IMGN901 Small-cell lung cancer Ph II ImmunoGen

BT062 Multiple myeloma Ph I/II Biotest

IMGN853 Ovarian, lung cancers Ph I ImmunoGen

SAR566658 Solid tumors Ph I Sanofi

IMGN529 Non-Hodgkin’s lymphoma Ph I ImmunoGen

BAY 94-9343 Solid tumors Ph I Bayer

AMG 595 Gliomas Ph I Amgen

Amgen 2 Undisclosed Ph I Amgen


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Ultrasound should be the primary imaging modality in women aged

30 to 39 years with focal breast signs orsymptoms, according to a large study.

Adjunct mammography adds littlevalue and should be reserved for cer-tain high-risk cases, such as patientswith a highly suspicious lesion on ultra-sound, a known gene mutation or a strong family history for the malignan-cy, according to the study authors (AJR((2012;199:1169-1177, PMID: 23096195).

“We studied women under 40 withpalpable breast lumps to see how best todiagnose cancer. This hasn’t been stud-ied carefully,” lead author Constance D.Lehman, MD, PhD, a professor of radi-ology at the University of Washington inSeattle and the director of imaging forSeattle Cancer Care Alliance, told Clin-ical Oncology News. “This is the largeststudy to date of breast ultrasound andadjunct mammography in women 30 to39 years of age who present with focalbreast signs or symptoms of cancer inthe United States.”

In the retrospective, single-cen-ter study, the researchers identified allwomen in their 30s who underwentultrasound examination with corre-sponding mammography between Jan. 1,2002 and Aug. 31, 2006, for focal breastsigns or symptoms. The total cases iden-tified were 1,208 in 954 patients (meanage, 35 years). Outcomes were benignin 1,185 cases (98.1%) and malignant in23 cases (1.9%). Ultrasound found 22 of the 23 cancers, whereas mammography found 14 of 23. Breast ultrasound provedto have 95.7% sensitivity for cancer detec-tion at the site of focal breast concern,89.2% specificity, 99.9% negative pre-dictive value (NPV) and 13.2% positivepredictive value (PPV). Mammography had a sensitivity of 60.9%, specificity of 94.4%, NPV of 99.2% and PPV of 18.4%.Mammography detected one additionalmalignancy in an asymptomatic area in

a patient who subsequently was found to have a BRCA2 gene mutation.

“Before our study, in the United States we were doing mammography first in women ages 30 to 39,” said Dr. Lehman. “We found that best practice is to start with ultrasound. Ultrasound is the bet-ter primary tool in these women.” The current American College of Radiology

(ACR) Appropriateness Criteria for wom-en 30 years of age or older with a palpable breast mass recommend mammography as the first imaging modality, followed by ultrasound. Dr. Lehman thinks the crite-ria should be revised. “ACR is reviewing our data and other available evidence, and considering changes to their guidelines.”

Andrew D. Seidman, MD, an attending

physician at Memorial Sloan-Kettering Cancer Center in New York City, who is not associated with the study, comment-ed: “It is an important study because it represents the largest analysis of the utility of ultrasonography and diagnos-tic mammography in patients between30 and 39 years of age who present with breast signs or symptoms. It suggests that a change in guidelines and practiceis warranted, specifically that ultrasound should be the first ‘go to’ radiologic exam-ination, and that mammography might belargely abandoned for patients in this agegroup, in this specific clinical scenario.”

Regarding the study’s limitations, Dr. Lehman said, “It’s a single-site study. Andthe ultrasound was performed by radiolo-gists specialized in the use of breast ultra-sound.” Dr. Seidman noted these and other limitations, including the study’s retrospective design and its insufficient “special handling” of patient subgroupsat higher baseline risk for having breast cancer or ductal carcinoma in situ.

Dr. Seidman did not agree, however, that the current ACR Appropriateness Criteria should be revised on the strength of this study. “While it would appear thatmammography may indeed add very little to ultrasonography for the woman aged 30 to 39 who presents with breast signs or symptoms, it is hard for me to imagine that under such circumstances, patients and their physicians will forgo mammog-raphy. The time of breast pain or a lump is an anxious moment for most women, anda retrospective, single-institution study,no matter how robust, does not seem suf-ficient to either change guidelines or dis-suade patients and their physicians fromproceeding with mammography, or even [magnetic resonance imaging], for thatmatter.”

—George Ochoa

Drs. Lehman and Seidman reported norelevant financial conflicts of interest.

Breast Ultrasound Best for Evaluating Young WomenSingle-center study suggests an unlikely change in imaging guidelines

‘It suggests that a change in guidelines and practice

is warranted, specifically that ultrasound should be

the first “go to” radiologic examination, and that

mammography might be largely abandoned for

patients in this age group, in this specific clinical

scenario.’—Andrew Seidman, MD

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.

Right breast ultrasound from a 35 year-old patient with bilateral palpable breast masses. The ultrasound documented a 19×14-mm hypoechoic mass. She was found to have metastatic disease to her breast from a lung neuroendocrine carcinoma.

Vaughan et al. World Journal of Surgical Oncology 2007

28 CLINICAL ONCOLOGY NEWS • MARCH 2013SOLID TUMORS

QUESTIONS

1. True or False. In Hodgkin lympho-ma (HL), 10% to 15% of patients withearly-stage and 20% to 30% of those withadvanced-stage disease fail to achievedurable remissions, ultimately dying of resistant or recurrent HL.

2. True or False. The German Multi-center Study Group for Adult Acute Lym-phoblastic Leukemia (GMALL) report-ed that the administration of single-agent blinatumomab (MT103, Microm-et) improved relapse-free survival (RFS)in patients with B-cell adult acute lym-phoblastic leukemia (ALL) with persis-tent or recurrent minimal residual dis-ease (MRD).

3. True or False. Tiziano Barbui, MD,and colleagues at the Research Founda-tion at Ospedali Riuniti di Bergamo inItaly, reported a hazard ratio (HR) of 1.0for thrombosis in patients with essential thrombocytosis (ET) who are harboring the JAK2V617F mutation.

4. True or False.Using the new three-tiered Internation-al Prognostic Score of thrombosis in the essential thrombocy-themia (IPSET-throm-bosis) model, the risk for thrombosis was 1.03% patients per year in the low-risk group, 2.35% in the interme-diate-risk group and 3.56% in the high-risk group.

5. True or False. On Feb. 8, 2013, the FDA granted accelerated approv-al to pomalidomide (Pomalyst, Cel-gene) for the treatment of patients with multiple myeloma (MM) who have received at least two prior ther-apies, including lenalidomide (Rev-limid, Celgene) and bortezomib (Vel-cade, Millennium), and have demon-strated disease progression within 60 days of completion of the last therapy.

6. True or False. Chris-tian Gisselbrecht, MD, on behalf of the COR-AL (Collaborative Trial in Relapsed Aggressive Lym-phoma) study, reported significant improvement in event-free survival (EFS) with rituximab mainte-nance therapy following autologous hematopoiet-ic stem cell transplantation (auto-HSCT) in patients with relapsed CD20+ dif-fuse large B-cell lymphoma (DLBCL).

7. Patients with angioimmunoblastic T-cell lymphoma (AITL) may have all of the following characteristics except:a. hemolytic anemiab. skin rashc. hypergammoglobulinemiad. presence of T-cell receptor gene rear-

rangements in 100% of the patients

8. True or False. Quantitation of hematogones at engraftment is useful

to predict prognosis of patients treated with allogenic HSCT (allo-HSCT).

9. True or False. In newly diagnosedMM, IgH translocations are detectable in approximately 20% of patients.

10. True or False. Currently, theone subgroup of patients with DLBCL who should be considered for alternate initial therapy, outside of a clinical trial,is the subset with a concurrent translo-cation involving BCL2 and MYC.

11. True or False. Gene expres-sion profiling (GEP) studies have iden-tified several molecular subtypes within DLBCL with distinct intracellular onco-genic pathways.

Clinical ConundrumsClinical Hematology Review: Highlights from ASH 2012 and NEJM, Blood and JCO

How easy is it for patients and physicians to access newly approved cancer drugs? It depends on what country you live in. At the European Society for Medical Oncology annual meeting, experts discussed access issues. One physician, Heinz

Zwierzina, MD, of Innsbruck Medical University in Austria, highlighted the differences in average time delay between marketing

approval of cancer drugs and effective market access. Germany, the United States and the United Kingdom came out on top.

Figure. Access to New Drugs Based on data from Ann Oncol 2007;18 Suppl 3:iii1-iii77.l

numbersby the

for answers see CONUNDRUMS,SS page 30 �

Prepared by

Syed A. Abutalib, MD

Assistant DirectorHematology& Stem Cell

TransplantationProgram

Cancer TreatmentCenters of America

Zion, Illinois

Primum non nocere.(First, do no harm.)

United States

United Kingdom

Germany

Norway

Switzerland

Portugal

Spain

Hungary

France

Slovenia

Italy

Belgium

Average time delay in days between approval of cancer drugs and market access

Co

un

try

0

0

0

0

123

148

271

338

390

404

431

447

235

100 200 300 400 500

123

148

271

338

390

404

431

235


ANSWERS

1. True. There remains an unmet need for a valid method to predict the completeness of therapeutic response and ultimately patient outcomes in HL. Ideally before treatment, or early in treatment, identifying a patient sub-set in which continuing standard ther-apy would be ineffective is preferable in order to institute a more effective ther-apy to achieve complete response. Pos-itron emission tomography (PET)/com-puted tomography has yielded high-ly promising results as a surrogate test for determining tumor chemosensitiv-ity and outcomes. Several ongoing pro-spective trials are exploring the feasibil-ity of treatment de-escalation strategies in patients with a negative interim PET, as well as therapy escalation in patients with advanced-stage HL who have a positive interim PET result.

Gallamini A, Kostakoglu L. Interim FDG-PETin Hodgkin lymphoma: a compass for a safe navi-gation in clinical trials? Blood. 2012;120:4913-4920,PMID: 22932799.

Hutchings M, Mikhaeel NG, Fields PA, et al. Prognostic value of interim FDG-PET after two or three cycles of chemotherapy in Hodgkin lympho-ma. Ann Oncol. 2005;16:1160-1168, PMID: 15939713.

2. True. In this Phase II study report-ed on behalf of GMALL, blinatumomab demonstrated excellent activity against MRD in virtually all patients with B-pre-cursor ALL, including patients with Philadelphia chromosome-positive ALL harboring the T315I mutation and older Iadults. These positive results are being confirmed in the larger ongoing trials.

Topp MS, Gökbuget N, Zugmaier G, et al. Long-term follow-up of hematological relapse-free survival in a phase II study of blinatumomab inpatients with minimal residual disease (MRD) of B-precursor acute lymphoblastic leukemia (ALL). Blood. 2012;120:5185-5187. PMID: 23024237.

Bassan R. Toward victory in adult ALL: blinatumomab joins in. Blood. 2012;120:5094-5095, PMID: 23258898.

3. False. The HR for patients har-boring JAK2V617F was 2.0, indicat-ing a 100% increase in risk for throm-bosis compared with individuals with-out the JAK2V617F mutation. The HRs for thrombosis for patients aged 60 years or older, those with cardiovas-cular (CV) risk factors and those with a history of thrombosis were 1.5, 1.6

and 1.9, respectively. In the new three-tiered prognostic model for thrombosis in ET, patients aged 60 years or older or those with presence of CV risk factors are assigned 1 point, whereas patients with history of thrombosis or presence of JAK2V617F mutation are assigned 2 points. The low-risk group for thrombo-sis is defined as a total score of less than 2 points; intermediate risk, 2 points; and high risk, greater than 2 points. The investigators recommend cytoreductive therapy in patients of any age who have a history of thrombosis, or in patients with advanced age with either CV risk factors or JAK2V617F-positive muta-tional status.

Barbui T, Finazzi G, Carobbio A, et al. Devel-opment and validation of an International Prog-nostic Score of thrombosis in World Health Organization–essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120:5128-5133,PMID: 23033268.

4. True. In the two-tiered “conven-tional” classification, risk for thrombosis was 0.95% patients per year in the low-risk group and 2.86% patients per year in the high-risk group. Only 48% of previ-ously defined low-risk patients are con-sidered at low risk with the new classi-fication, whereas the remaining 52% are classified as intermediate risk. The majority of patients classified at high risk, according to conventional risk fac-tors, are now reclassified at intermedi-ate (31%) or even at low thrombotic risk by IPSET.

Barbui T, Finazzi G, Carobbio A, et al. Devel-opment and validation of an International Prog-nostic Score of thrombosis in World HealthOrganization–essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120:5128-5133, PMID: 23033268.

5. True. The approval was based on the results of the CC-4047-MM-002 clinical trial, a multicenter, random-ized, open-label study in 221 patients with relapsed and refractory MM. The efficacy results demonstrated an over-all response rate of 7% in patients treat-ed with pomalidomide alone and 29% in those treated with pomalidomide plus low-dose dexamethasone. The median response duration was not evaluable in the pomalidomide-alone arm and was 7.4 months in the pomalidomide plus low-dose dexamethasone arm. The recom-mended dose and schedule for pomalid-omide is 4 mg taken orally on days 1 to 21 of repeated 28-day cycles until disease progression.

American Society of Hematology. FDA grantsaccelerated approval to pomalidomide for patientspreviously treated for multiple myeloma. http://www.hematology.org/News/2013/9811.aspx.Accessed February 9, 2013.

6. False. In total, 477 patients with CD20+ DLBCL who were in their first relapse or were refractory to initial ther-apy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the respond-ing patients received high-dose che-motherapy followed by hematopoiet-ic cell rescue. There were 242 patients randomly assigned to either rituximab every two months for one year or obser-vation. After auto-HSCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year EFS rates after auto-HSCT were 52% and 53% for the rituximab and observation groups, respectively (P(( =0.7).

Gisselbrecht C, Schmitz N, Mounier N, et al.Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20+ diffuse large B-cell lymphoma: final anal-ysis of the collaborative trial in relapsed aggres-sive lymphoma. J Clin Oncol. 2012;30:4462-4469,PMID: 23091101.

7. D. AITL is a rare clinicopatholog-ic entity characterized by an aggressive course and dismal outcome with current therapies. Five-year overall and failure-free survivals are 33% and 18%, respec-tively. The International Peripheral T-Cell Lymphoma Project was under-taken to better understand the subtypes of T-cell and natural killer–cell lympho-mas. Twenty-two institutions in North America, Europe and the Far East partic-ipated in the study. From 1,314 patients, 243 (18.5%) were diagnosed with AITL. At presentation, generalized lymphade-nopathy was noted in 76% of patients and 89% had stage III to IV disease. Skin rash was observed in 21% of patients. Hemolytic anemia and hypergammo-globulinemia occurred in 13% and 30% of patients, respectively. T-cell receptor gene rearrangement is negative in up to 30% of patients with AITL.

Federico M, Rudiger T, Bellei M, et al. Clinico-pathologic characteristics of angioimmunoblas-tic T-cell lymphoma: analysis of the international peripheral T-cell lymphoma project. J Clin Oncol.2013;31:240-246, PMID: 22869878.

8. True. Transient marrow expan-sion of normal B-cell precursors, termed hematogones, is occasionally observed

after allo-HSCT. In the study by Taka-hiro Shima, MD, and colleagues, hema-togones that comprised greater than 5% of bone marrow mononuclear cells con-stituted a group of patients with sig-nificantly prolonged overall surviv-al and RFS, irrespective of their prima-ry disease or donor cell source following allo-HSCT.

Shima T, Miyamoto T, Kikushige Y, et al. Quan-titation of hematogones at the time of engraft-ment is a useful prognostic indicator in allogene-ic hematopoietic stem cell transplantation. Blood. 2013;121:840-848, PMID: 23233661.

9. False. In newly diagnosed MM, IgH translocations are detectable in approximately 40% of patients. There is a notable diversity of chromosom-al partners involved in IgH transloca-tions. The most frequently involved loci are 11q13 (CCND1) in 15%, 4p16 (FGFR3/MMSET) in 15% and 16q23 (MAF) in 5% of cases. Other recurrent loci, including 6p21 (CCND3) and 20q11 (MAFB), occur less frequently.

Bergsagel PL, Mateos MV, Gutierrez NC, et al. Improving overall survival and overcom-ing adverse prognosis in the treatment of cyto-genetically high-risk multiple myeloma. Blood. 2013;121:884-892, PMID: 23165477.

10. True. Patients with dual trans-locations have a worse outcome and should be considered for alternate thera-pies. Although it remains unclear which alternate approach will prove beneficial, these patients have a remarkably poor outcome after R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vin-cristine and prednisone) regimen, with a median survival of less than one year.

Sehn LH. Paramount prognostic factors thatguide therapeutic strategies in diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Pro-gram. 2012;2012:402-409, PMID: 23233611.

Johnson NA, Slack GW, Savage KJ, et al. Con-current expression of MYC and BCL2 in diffuselarge B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine,and prednisone. J Clin Oncol. 2012;30:3452-3459, PMID: 22851565.

11. True. Despite our improved understanding of the diversity of DLBCL, management strategies remain remarkably uniform. The GEP analysis has paved way for novel clinical trials with agents targeting dominant biolog-ic pathways in molecularly determined DLBCL.

Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med. 2010;362:1417-1429, PMID: 20393178.

CONUNDRUMScontinued from page 29 ��


®

Now Available...

ChairLinda T. Vahdat, MD

Associate Professor of Clinical MedicineNewYork Presbyterian HospitalWeill Cornell Medical CenterNew York, New York

FacultyAdam Brufsky, MD, PhD

Assistant Professor of MedicineUniversity of Pittsburgh School of MedicineCo-Director, Comprehensive Breast Cancer CenterMedical Director, Women’s Cancer CenterMagee Womens Hospital/UPCIPittsburgh, Pennsylvania

William J. Gradishar, MD

Professor of MedicineDivision of Hematology and Medical OncologyDepartment of MedicineFeinberg School of MedicineNorthwestern UniversityChicago, Illinois

Learning Objectives1 Appraise recent studies that may have clinically

important therapy implications for patients

with locally recurrent breast cancer or meta-

static breast cancer (MBC).

2 Describe a treatment algorithm that refl ects

evidence-based management of advanced

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 combinations and sequences.

Intended AudiencesOncologists

Statement of NeedComplexities in the management of MBC are

substantial, and the optimal approach to therapy

remains unclear. Toxicity, resistance, and hypersen-

sitivity reactions limit the use of cytotoxic drugs in

mainstay treatment regimens, and improved ther-

apeutic options are needed for this heterogeneous

disease. Th ere are encouraging data on novel treat-

ment approaches, including combinations and

sequencing regimens, but clinicians face challenges

in integrating this potentially practice-changing

data. For these reasons, oncologists require educa-

tion on clinically relevant recent studies, against a

backdrop of evidence- and consensus-based treat-

ment recommendations.


Estimated Time for Completion: 60 minutes

Accreditation StatementTh is activity has been planned and implemented

in accordance with the Essential Areas and poli-

cies of the Accreditation Council for Continuing

Medical Education (ACCME) through the joint

sponsorship of Global Education Group (Global)

and Applied Clinical Education (ACE). Global is

accredited by the ACCME to provide continuing

medical education for physicians.

Credit DesignationGlobal Education Group designates this enduring

activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit tcommensurate with the extent of their participa-

tion in the activity.

Method of PreparationTo receive CME credit, participants should read

the preamble, complete the pre-test, view the pro-

gram, and complete the post-test and evaluation.

A score of at least 75% is required to complete

this activity successfully. CME certifi cates will be

issued immediately upon successful completion.

To participate in this FREE CME activity, log on to www.CMEZone.comand enter keyword “MM112”

This activity is jointly sponsored by Global Education Group and Applied Clinical Education. This activity is supported by educational grants from Genentech, Inc

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MM112”Release Date: October 22, 2012 Expiration Date: October 22, 2013

Individualizing Therapy in Metastatic Breast Cancer

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mation on radiation oncology. The wide range of entries is written by leading experts. They will provide basic and clinical scientists in aca-demia, practice and industry with valuable information about the field of radiation oncology.

6 Manual of Clinical Oncology: Seventh EditionDennis A. Casciato

May 9, 2012 This guide is a concise pocket manual that incorporates basic science, clinical findings and available technology into the diagnosis and man-agement of cancer. It focuses on information useful for participating inrounds and for making diagnostic and therapeutic decisions at the bed-side of cancer patients.

7 MD Anderson Manual of Medical Oncology, Second Edition

Hagop M. Kantarjian; Robert A. Wolff; Charles A. KollerApril 22, 2011

This book details the personalized multidisciplinary approach to cancermanagement pioneered by The University of Texas MD Anderson Can-cer Center. It is intended to bring a pragmatic approach to cancer man-agement that can serve as a guide for oncologists around the world.

8 Surgical OncologyDavid Bartlett; Pragatheeshwar Thirunavukarasu; Matthew D. Neal

May 4, 2012 Surgical Oncology incorporates the basic tenets of surgical practice withy

the innovations of modern technology in an evidence-based fashion.Thebook presents the opinions of experts in the field alongside an analytical and unbiased review of the evidence. Each chapter contains not only a summary of the relevant data, but also presents succinctly a list of land-

g ymark studies for disease or organ system.

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the march 2013 digital edition of clinical oncology news

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