UPDATE ON HEPATOCELLULAR AND PANCREATIC CANCER FOR RESIDENTS 2014 KEVAN L HARTSHORN MD

SECTION OF HEMATOLOGY ONCOLOGY

HEPATOCELLULAR CANCER (HCC) General points to remember

Increasing incidence

Prognosis improving with screening, early diagnosis, more therapies for Hep B and C, more therapies for the cancer itself

Can be diagnosed without biopsy

Can be cured by transplant, surgery or in some cases local ablation

Some patients can live several years without treatment

Need to get sense of natural history

Increasing understanding of different biology of the cancer in different patients

Importance of multidisciplinary team including GI, surgery (transplant and liver surgeons), interventional radiology, medical and radiation oncology, support systems (navigators, nutrition, social work)

General Stats 5th most common cancer worldwide

Approx. 500,000 per year 3rd most common cause of cancer death

Asia and Africa due to HBV endemic Increased incidence in HIV but mainly

attributable to HCV and ETOH (large VA study)

HCV can also cause lymphoma Hep B vaccine reducing rate of HCC in Asia Hep B treatment also reducing rate of cancer Rise in US also fueled by steatohepatitis

which is an increasing cause of HCC

Each year, more than half a million people worldwide receive a diagnosis of hepatocellular carcinoma, and hepatocellular carcinoma related to HCV is the fastest rising cause of U.S. cancer-related deaths.

Recent NEJM review summarizes recent advances in prevention, surveillance, diagnosis, and treatment.

El-Serag HB. N Engl J Med 2011;365:1118-1127

Regional Variation in the Estimated Age-Standardized Incidence Rates of Liver Cancer.

El-Serag HB. N Engl J Med 2011;365:1118-1127

Age-Adjusted Incidence and 5-Year Survival Rates for Patients with Hepatocellular Carcinoma in the United States, 1973–2007.

El-Serag HB. N Engl J Med 2011;365:1118-1127

Etiology Hepatitis B, C

Can get without cirrhosis in Hep B Alcoholism Association with high body mass,

steatohepatitis, diabetes Statins and coffee drinking reduces risk

Hemachromatosis, Porphyria Cutanea Tarda (some types), auto-immune hepatitis

Wilson’s disease, α1 anti-trypsin deficiency Aflatoxin Common theme is persistent inflammation in

liver

Cumulative incidence of hepatocellular carcinoma by cumulative defined daily dose (cDDD) of statin use during the follow-up period in the cohort infected with hepatitis B virus.

Tsan Y et al. JCO 2012;30:623-630

©2012 by American Society of Clinical Oncology

General

Old criteria: AFP > than 400 in right context with liver lesion accepted as diagnostic

New Criteria: Arterial enhancing lesion with early washout (MR or CT); size 2cm or greater Need well done triple phase MRI or CT to get the early

arterial enhancement and the delayed wash out (tumor very dependent on arterial supply while rest of liver can be fed by portal vein)

If biopsy done useful to biopsy uninvolved liver to determine if cirrhosis is present Approx. 2.7 % rate of tumor seeding

Screening

Hep B carriers in China randomized to screening or not (19,000 subjects)

Screen with AFP and US q6 mos. 37% reduction in mortality related to HCC Another study did not confirm this Can get +AFP with active hepatitis and

cirrhosis itself El-Serag recommends screening in patients

with cirrhosis or advanced hepatic fibrosis irregardless of cause since they are the highest risk group for HCC

Types HCC: invasive, males 4-8 to 1 over females, <20% resectable;

90% have cirrhosis; 80% AFP +; mean age 55; molecular subsets being identified

Those with HBV less likely to have cirrhosis than those with HCV (although 70-80% do have cirrhosis) Concurrent risks for HBV: high viral load, HCV or delta virus co-infection, ETOH,

tobacco, early childhood infection)

Concurrent risk factors among HCV patients include increased age, male sex, HIV or HBV co-infection, probably diabetes and obesity

Fibrolamellar variant: circumscribed; Male:female 1:1; cirrhosis, HBV+, AFP+ only about 5%; 50-70% resectable; mean age 25

Note also that natural history varies between cases with some surviving 2 year or more with HCC and no rx.; mean surv. 6-9 mos for advanced HCC

Clinical features

Bruit approx. 25% Right upper quad pain, mass and wt

loss; Tumor fever can occur Liver failure symptoms as presentation

also: mainly due to replacement of already reduced liver parenchyma

Propensity for vascular invasion and this can contribute to liver failure

Clinical features GI bleeding: if from varices this has poor

prognosis: In one study 25% of HCC deaths were due to variceal hemorrhage

Tumor rupture can occur at presentation (2-5%) and these can be rescued surgically or through embolization (see series in JCO)

If jaundice is from biliary obstruction by tumor this has better prognosis than from liver failure

Hypoglycemia, erythrocytosis, hypercalcemia, PCT, hypertrophic osteoarthropathy, virilization

Clinical features

Mets: lung, peritoneum, adrenal gland, bone

Triple phase MRI or CT best overall testBe aware of vascular invasion and

multicentricity Importance of staging liver function:

Child’s classification A-C

Barcelona Staging

Factors in liver function and stratifies according to treatments appropriate for each stage Very early stage

PS0; Child’s A; one lesion <2cm Early stage

1 to 3 lesions <3cm; PS0; Child’s A Intermediate stage

Multinodular disease; PS0; Child’s A Advanced stage

Advanced stage Vascular invasion, M1, N1, PS1-2

Terminal Stage Child’s C; PS>2

Other staging systems: Okuda, CLIP not as useful

MRI Studies Showing the Effects of Hepatocellular Carcinoma at Different Stages of the Disease.

El-Serag HB. N Engl J Med 2011;365:1118-1127

A: Very early stage (one lesion 1.7cm), B: early stage (2 lesions 2.4 and 1.2 cm)

C: Intermediate stage (multiple lesions, Childs B), D: Advanced(large mass and ascites)

Therapy

Curative modalities first Resection, Transplant, Possibly RFA in early stage

lesions Modalities that extend overall survival second

RFA or chemoembolization (intermediate stage) Sorafenib (advanced stage but preserved liver

function: trials mostly Child’s A some B) Terminal Stage no evidence of survival benefit

Do no harm

Therapy: Surgery First question is resectability: functional reserve

and tumor location: 5yr surv about 30-40% <20% of pts with cirrhosis and HCC are

resectable Resectability greater with Hep B since they can

present with HCC without cirrhosis more often Is resection better than transplant?

Transplant cures cirrhosis and can remove other occult synchronous lesions

Downside of transplant is waiting time and need for immunosuppression; live donor transplant can shorten wait

Now do bridging therapy with TACE or RFA

Indications for Transplant

Tumor <5cm if single; <3cm if 1-3 tumors Expanded UCSF criteria lead to similar survival results but

not adopted thus far due to shortage of organs Absence of vascular invasion Not more than 3 nodules Better histology is associated with improved survival

post transplant Improved results of transplant since these were

adopted Lots of other restrictions: age <70, AFP not too

elevated, social factors (sadly)

Copyright © American Society of Clinical Oncology

Yoo, H. Y. et al. J Clin Oncol; 21:4329-4335 2003

Fig 3. Patient (A) and graft (B) survival by Kaplan-Meier survival analysis for patients transplanted for hepatocellular carcinoma at different time periods

Ablative therapies

RFA if approx 3.5cm diameter (can be up to 3 lesions) For RFA location important (heat dissipates if near vessels; hard

to do if near capsule of liver); Microwave ablation may be better; laparoscopic RFA may be needed in some cases

RFA proven better than ethanol injection Chemoembolization if larger but isolated to liver

The trials that showed benefit of this selected intermediate stage patients (no advanced liver disease; no vascular invasion; no shunting; no extrahepatic disease; largest tumor 4-7cm; can be multinodular)

Cyberknife: targeted radiation Little data as yet

Actuarial 5 year survivals: Local Therapies

Schwarz RE, Am J Surg 195: 829, 2008 Transplantation: 67% Resection: 35% Ablation: 20% No/incomplete local therapy: 3% If only cases meeting Milan Criteria were analyzed

resection improved to 43% and ablation went to 16% Population based study. Likely bias in favor of transplant

and resection by patient selection variables

RFA effectiveness: goal is complete necrosis 1,620 patients with hepatoma - mean follow-up 24 ± 6 months

Complete necrosis in:

• 1.0 - 3.0 cm - 82.3%• 3.1 - 5.0 cm - 64.9%• 5.1 - 7.0 cm - 32.4%• 7.1 - 9.0 cm - 12.5%• 9.1 - 13.0 cm - 0%

Transarterial Chemoembolization (TACE)

Doxo 75 mg not adjusted for BSA Other agents sometimes used: carboplatin, MitoC

Clinical pathway with anesthesia involvement, prophylactic antibiotics

Monitor for pain, fever, hepatic dysfunction Problem is proper selection reduces number of patients

who are eligible or get survival benefit Not clear yet if embolization alone is as good as

chemoembolization: trial pending Currently use drug-eluting beads so peak doxorubicin levels

low: this appears to be superior to prior approach with lipiodal and gelfoam

Chemo-embolization

Major risk is hepatic decompensation so avoid chemoembolization in advanced cirrhosis Other issues: post embolization syndrome (fever, nausea,

elevated LFTs); rare pancreatitis or cholecystitis due to embolization of other vessels

Portal vein involvement is not an absolute contra-indication although although major vessel involvement not included in the randomized trials

Two small randomized trials and a meta-analysis show survival benefit to chemoembolization LLovet et al, Lancet 2002; 359: 1734-39 Lo et al, Hepatology, 2002; 1164

TACE or RFA as bridge to transplant

Transplant waiting list can be long especially if lesion less than 2 cm MRI not considered diagnostic for lesions <2cm so

do not get the increased MELD points until >2cm Could wait for it to grow to >2cm which moves

patient higher on list or could RFA Chemoembolization can also be done as

bridge to transplant after patient is listed Lahey clinic requires 2 chemoembolization No real evidence base for the bridging approach

Advanced HCC: Sharp Trial: Phase III trial: Sorafenib:

first phase III showing a survival benefit low actual response rate a significant survival

extension of approx 3 months was found Limitations are that the group predominantly

had good liver function: ? Application to others We are working on summary of our experience

in a group of patients with less favorable starting characteristics

Kaplan-Meier Analysis of Overall Survival, the Time to Symptomatic Progression, and the Time to Radiologic Progression

Llovet JM et al. N Engl J Med 2008;359:378-390

Sorafenib: other studies Subgroup analyses of SHARP trial

Survival benefits for HCV positive = 6.1 months; for extrahepatic spread or macroscopic vascular invasion = 2.2 months; PS 1 to 2 = 3.3 months

Randomized trial of sorafenib in Asian patients (Lancet Oncology 2009 Vol10:p.25) Median overall survival sorafenib (#150 patients): 6.5 months Placebo median survival (#76 patients): 4.2 months Majority had Hep B (differs from SHARP) and probably as a group

more advanced disease accounting for lower survival

Future directions

Three trials open here for advanced HCC Adriamycin plus sorafenib vs sorafenib alone Sterotactic radiation plus sorafenib vs sorafenib alone TACE with or without sorafenib

Trials of other targeted agents Unfortunately several trials negative so far (sutent, everolimus, and

EGFR treatments)

Treatment of hep B and hep C (now with more tolerable regimens) Treatment of hep B reduces risk of HCC Those with hep C who have lower viral load have better prognosis

with HCC: maybe retreatment will reduce incidence or relapse of HCC

Pancreatic cancer

Incidence 32,180 new cases per yr USA As cause of cancer mortality: 4th (<5% 5yr surv) Causes: smoking, familial pancreatitis, BRCA2, HNPCC,

? Chemical exposures Head of pancreas better due to early presentation

with jaundice Diagnosis: CT best for staging (quality can vary

greatly based on technique and scanner), EUS for biopsy (avoid seeding: signif more seeding after CT guided bx than EUS guided in one study)

Pancreatic cancer

Poor prognosis if back pain, marked CA19-9 elevation, reduced performance status or weight loss

Hypercoagulability Mucins directly activate platelets via p selectin May explain why heparins more effective than

warfarin in adenocarcinoma related thrombosis Metastasis to liver and peritoneum most common Mets to brain or bone less common

CA19-9

The degree of elevation post op is predictive of long term survival

Patients that are Lewis antigen negative never have elevated CA19-9

CA19-9 is elevated by biliary obstruction per se and is elevated in other cancers (e.g., gastric, bladder…)

Copyright © American Society of Clinical Oncology

Berger, A. C. et al. J Clin Oncol; 26:5918-5922 2008

Fig 2. Kaplan-Meier survival curve by CA 19-9 with 180 cutoff

Pancreatic Cancer: Clinical Surgery only curative modality but only 5-20% are resectable and only 20%

of these live 5 yrs; 40-45% metastatic at outset, 3-6 mos mean survival 40% locally advanced, 6-11 mos survival

Other histologies (islet cell, lymphoma) or cystic lesions have better prognosis

No screening modality: If positive family history can do CTs, be more aggressive approach cystic lesions like IPMN in this group Main branch IPMN more at risk for malignancy than side branch Cystic lesions can be aspirated by EUS to measure CEA

Laparoscopy initially to determine if there is peritoneal involvement not seen on CT

Tail of pancreas can do distal pancreatectomy and splenectomy (less morbid than Whipple)

Whipple procedure mortality highly related to experience of surgeon and center

Pathological, Radiologic, and Histologic Features of Pancreatic Cancer.

Hidalgo M. N Engl J Med 2010;362:1605-1617.

Copyright ©2002 AlphaMed Press

Wayne, J. D. et al. Oncologist 2002;7:34-45

Figure 2. Illustration of step 6 in the performance of pancreaticoduodenectomy

Pancreatic cancer: cases

Painless jaundice, tumor localized to pancreas by CT and EUS

Tumor involves SMV Solitary liver met Tumor involves SMA or celiac artery Positive peritoneal cytology otherwise

localized

Copyright ©2002 AlphaMed Press

Wayne, J. D. et al. Oncologist 2002;7:34-45

Figure 4. Illustration of superior mesenteric vein (SMV) resection

Controversy about adjuvant therapy: Some benefit but small, role of radiation unclear

Older US trials showed some survival benefit to chemoradiation (5fu)

Larger European trial (ESPAC-1) actually showed only benefit for chemotherapy with worse survival for radiation: Very controversial – problems with trial design Not standardized for radiation, split course, strange trial design, meta-

analysis shows similar result but this trial makes up many of the cases In Europe radiation not used

One very well done trial shows clear survival benefit to chemotherapy alone (gemcitabine) vs no therapy

USA centers still advocate chemoradiation: Last trial compared chemoradiation (fu during radiation) and either

gemcit or 5fu before and after radiation

Chua, Y. J. et al. J Clin Oncol; 23:4532-4537 2005

Fig 2. Kaplan-Meier estimates of survival according to whether or not patients received (A) chemoradiotherapy (CRT) or (B) chemotherapy (CT) for European Study Group for Pancreatic

Cancer 1 2 x 2 factorial design cohort

Figure 2. Disease-Free and Overall Survival (Intent-to-Treat Analysis).

Oettle, H. et al. JAMA 2007;297:267-277

Copyright restrictions may apply.

Figure 2. Survival Results by Randomized Treatment

Neoptolemos, J. P. et al. JAMA 2010;304:1073-1081

Copyright restrictions may apply.

Copyright restrictions may apply.

Regine, W. F. et al. JAMA 2008;299:1019-1026.

Overall Survival Among All Eligible Patients

Current trials

Head of pancreas cancer post resection trial open here Compare gem pre and post-chemorads (winning arm of last trial in

head of pancreas) to gem plus tarceva pre- and post-chemorads

The chemorads component uses 5fu as in prior trial

Large trial testing chemotherapy with and without radiation open at multiple centers Hope this will settle the question

Likely new trials will be developed based on newer more effective chemotherapies that have recently been discovered

If borderline resectable: Definition is tricky: partial involvement of key vessels (e.g.

superior mesenteric artery) Treatment in advance:

Has advantage of weeding out those who will have mets in short time frame,

Render someone resectable?: Not highly successful so far: In some series 2/16, 2/25, 6/47 and 2/87

were resectable mostly following chemoradiation

Newer chemotherapies (especially folfirinox) have higher objective response rates Trials looking at these folfirinox up front maybe followed by

chemoradiation if no distant mets

Locally advanced pancreatic cancer

Involvement of SMA or celiac; extensive nodal involvement; involvement of SMV/portal vein confluence

Back pain or highly elevated CA19-9 Note positive peritoneal washings has same prognosis as

metastatic disease so these patients considered metastatic and not locally advanced

Approximately 40% of newly diagnosed patients are locally advanced

Locally advanced has somewhat better prognosis (e.g. 1 year) than metastatic disease (6-8 months)

Controversy regarding role of radiation in locally advanced disease also

Chemo-radiation vs chemotherapy aloneSmall old trial showed adding 5FU to radiation

improves survival compared to radiation alone but another trial showed 5FU alone was as good as 5FU+radiation

Recent trial did not show benefit to adding radiation in locally advanced disease

Mainly use palliation of pain as trigger for chemo-radiation as opposed to chemotherapy alone

New chemotherapy regimens are more effective and have higher response rates further putting into question role of radiation

Advanced pancreatic cancer Gemcitabine has modest survival benefit compared to

5fu; approved mainly for quality of life benefits (wt gain, decreased pain): med surv 5.65 mos for gem and 4.41 for 5fu; 1yr surv 18%vs 2%

Many dismal attempts to improve results with Gem alone: Long period of studies showing no benefit or minor benefit to adding

other chemotherapy agents to gemcitabine: included studies of adding cisplatinum, irinotecan, oxaliplatinum, and other agents

Addition of capecitabine barely better on metaanalysis Adding S-1 (oral 5fu related drug available in Japan) positive in Asian

study Add biological therapies to Gemcitabine: Small survival benefit to tarceva but anti-EGFR antibody and anti-

VEGF antibody (avastin) were negative

Gem vs S1 vs Gem+S1

JCO 2013 Japanese study Approx 280 in each arm S1≈Gem; S1+Gem better PFS but not OS but

many on Gem arm got S1 in second line OS Gem 8.8 mos, S1 9.7 mos, Gem+S1 10.1 mos

S1 in second line in Gem refractory (different trial) had shown 15% response rate

Is S1 better than capecitabine or 5fu leuk? Is there different pharmacokinetics in Japan?

Copyright © American Society of Clinical Oncology

Moore, M. J. et al. J Clin Oncol; 25:1960-1966 2007

Fig 1. Kaplan-Meier curves for (A) overall survival; (B) progression-free survival; and (C) overall survival in the 100-mg cohort

The tarceva study: to that time theonly study to show statistically significant added survival when combined with Gemcitabine

URGGHHH!!How to figure out who benefits??

Copyright © American Society of Clinical Oncology

Moore, M. J. et al. J Clin Oncol; 25:1960-1966 2007

Fig 3. Overall survival by grade of rash in erlotinib-treated patients

Meta-analysis in JCO, 2007(Prior to new regimens)

Chemo is better than supportive care in terms of survival

Gemcitabine better than 5FU Combinations of other drugs with

gemcitabine slightly superior to gem alone

Sultana, A. et al. J Clin Oncol; 25:2607-2615 2007

Finally some breakthroughs in last 2 years

Folfirinox regimen Nearly 3.6 month survival benefit compared to gemcitabine alone

Significant higher tumor response rate: approx. 30% partial response

Difficult regimen and patients treated from few centers in France with selection of younger patients with good performance status

Adding Abraxane (taxol bound to albumin “nanoparticle”) Survival benefit about 1.8 months more than gemcitabine alone

More tolerable regimen although neuropathy and cytopenias greater

Was tested in multicenter trial without age limit and with some patients who has somewhat lower performance status (although most still pretty fit)

Kaplan–Meier Estimates of Overall Survival and Progression-free Survival, According to Treatment Group.

Conroy T et al. N Engl J Med 2011;364:1817-1825

Gem abraxane

Med overall survival folfirinox vs Gem: 10.5 vs 6.9 mos. Gem abrax 8.5 mos (gem 6.7 mos in this trial)

RR 23% vs 7%PFS 5.5 vs 3.7 mosCan justify using Gem abraxane in older

patients

Von Hoff DD et al. N Engl J Med 2013;369:1691-1703

New agents Hedgehog inhibitor

Stroma is very dense and fibrotic in pancreatic cancer and is likely a very important factor in resistance to treatments

Stromal cells in cancer are different from normal tissue stroma and specifically nourish and send growth signals to the cancer cells

Hedgehog pathway is important in stromal proliferation

Folfox+Abraxane (Brown study)

Ruloxitinib

JAK2 inhibitor with some benefit in myefibrosis, oral and well tolerated generally

Trial we will open soon

Second line therapy for pancreatic cancer

Combination of ruloxitinib (Jak1 and 2 signaling) in combination with capecitabine

Jak activation is present in pancreatic cancer