update on hepatocellular and pancreatic cancer for residents 2014 kevan l hartshorn md section of...
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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
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