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Chemotherapy in Primary Liver Cancers

Chemotherapy in Primary Liver Cancers. Hepatocellular Carcinoma Biliary adenocarcinomas. Jennifer J Knox Medical Oncology, Princess Margaret Hospital Assistant Professor of Medicine, University Of Toronto. Objectives.

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Chemotherapy in Primary Liver Cancers

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  1. Chemotherapy in Primary Liver Cancers Hepatocellular Carcinoma Biliary adenocarcinomas Jennifer J Knox Medical Oncology, Princess Margaret Hospital Assistant Professor of Medicine, University Of Toronto

  2. Objectives • Appreciate the challenges in treating primary liver cancers and the limitations to older trial data • Develop an approach to choosing appropriate patients who may benefit from therapies • Appreciate the recent advances in systemic therapy for both HCC and biliary cancers. HCC

  3. Hepatocellular Carcinoma • Fifth most common cancer globally • 5 year survivals < 10 % • Incidence is rising • NA: #8, (ahead of gastric/esophageal ca) • Ontario incidence more than doubles every decade

  4. HCC in TorontoN = 329 over 4 years Series from M. Sherman

  5. Hepatocellular Carcinoma: The Challenge • Two diseases: malignancy and chronic liver disease. • a virulent cancer and a dysfunctional liver • Heterogeneity: etiology & prognosis • both tumor and liver factors determine survival in this highly variable patient population

  6. Heterogeneity: CLIP Score(Cancer of the Liver Italian program) • Calculate a score based on • cirrhosis: Child-Pugh: (albumin Bili, PT, ascites, enceph) • tumor size (>50% 0f liver) • single vsmultinodular tumors • AFP (>400) • portal vein thrombosis (presence) score: 1 2 3 4 5/6 med survival 32 16.5 4.5 2.5 1.0 (months) n = 435 Gallo et al. 1998

  7. New HCC case UHN Tumor Boards Resection candidate? Yes, resect (10%) No Transplant candidate? No Yes Transplant (10%) RFA candidate? No (70% !! ) Yes, RFA (10%) Recurrences Trial Candidate? New Agents/ approaches TACE Candidate ? • local ds • portal vein patent • Childs A • good PS • extrahepatic ds • or aggressive local ds • Childs A • good PS NO Supportive / palliative Care

  8. Hepatocellular Carcinoma HCC’s are vascular tumors:

  9. TACE • Specialised local therapy in HCC • Carefully selected patients • Local disease • Child’ A • No PVT • Platelets > 50 • Preserved organ function • Mod PS • Interventional radiology and admission to hospital • High dose doxorubicin (75 mg / m2) and lipiodol,+/-gelfoam • Good f/u care Trans-Arterial Chemoembolization

  10. TACE improves survival vs. best supportive care Hong Kong (HBV) 2 yr survival of 31% vs 11 % Lo et al.Hepatology 2002; 35: 1164-1171 • Patients: • CPT A • No PVT • PS 0-2 UHN/PMH experience 2 yr survival of 55% Molinari et al. ClinOncol 2006 2 yr survival 63% vs 27% Llovet et al. Lancet 2002; 359: 1734-1739 Barcelona (HCV)

  11. 53 yo woman, HBV, CPT A, multifocal HCC. no PVT, good PS On transplant list...waiting TACE as a bridge to transplant • Catheterization of R hepatic artery and injection with • Doxorubicin 75/mg/m2 • Lipiodol 10cc in 20cc total volume Disease control at 10 months

  12. Should patients with HCC, not suitable for radical treatments, be considered for systemic treatments? • Older series suggest these patients have med OS of 3 months - chemo has no role. • But heterogeneity within patient population studied not recognized

  13. Single agent doxorubicin • 16 trials, 734 patients, ORR: 18% • myelosuppression, ↑ hyperbilirubin • 1 RCT doxo vs BSC (n=60) • Med surv 10.6 wks vs 7.5 wks • Rx-related death of 25%. Lai et al. Cancer 1998. • Other anthracyclines • mitoxantrone, epirubicin are similar, ? improved toxicity • Liposomal doxo - 2 trials - disappointing

  14. CLIP ScoreWhat patients were enrolled on these trials ? • Calculate a score based on • cirrhosis: Child-Pugh: (albumin Bili, PT, ascites, enceph) • tumor size (>50% 0f liver) • single vsmultinodular tumors • AFP (>400) • portal vein thrombosis (presence) score: 1 2 3 4 5/6 med survival 32 16.5 4.5 2.5 1.0 (months)

  15. Phase III trial of Nolatrexed vs. Doxorubicin in advanced HCC • 1st Modern trial in HCC (CLIP 0-3) • Med surv of 8 months with Doxo ! Gish et al JCO July 2007

  16. Doxorubicin combinations • Numerous combinations – toxic • 470 patients : RR 14% Exception: PIAF (cisplatin, INFα doxo, 5-FU) • Phase II RR 26% • 9 patients downstaged to surgery • 4 of 9 had path CRs!Leung et al. Clin Can Res 1999. • chemosensitivity and radiological underestimation true response • significant toxicity: Rx-related deaths

  17. Phase III Trial of PIAF vs Doxo in inoperable HCCYeo et al. J Natl Cancer Inst 2005 180 patients:one of the largest chemo trials in HCC Doxo PIAF ORR 11% 20% p=0.09 SD 40% 31% Med surv 7.1 mo 8.4 mo p=0.87 *PIAF: Septic death rate of 4 %, febrile neutropenia > 40%

  18. Other Cytotoxics No other drug appears better. All RRs < 10% • Fluoropyrimidines • Infusional or capecitabine maybe best • Taxanes • Not well studied…but appear toxic • Topoisomerase inhibitors • CPT-11 toxic • Etoposide better • Nucleoside analogues • Gemcitabine inactive alone / combinations (?SD) • Gem/ cisplatin combo more promising • TS inhibitors • Nolatrexed stable disease in phase II • ...phase III worse than single agent doxo

  19. Other Agents in HCC

  20. HCC: Promise of Targeted Agents • appropriate to test new agents • better tolerated in patients with liver dysfunction • promising targets: • angiogenesis inhibitors ( sorafenib, Avastin) • growth factor inhibitors (EGFR, Ras ,Raf) • apoptosis and cell cycle modifiers • unique antigens or receptors (HGF)

  21. Vascularity and Angiogenesis in Multistep HCC Carcinogenesis low grade dysplastic high grade dysplastic HCC H/E SMactin CD34 Park et al. Arch Pathol Lab Med 2000; 124:1061

  22. Sorafenib (Nexavar) in HCC • Few responses seen in early trials • TTP of 6 months in phase II thought encouraging (most phase IIs in HCC TTP is 2 months) • 3 randomised trials completed Phase III: 1)Nexavar vs BSC (SHARP trial) :2) Asian-Pacific Phase II: 3) Doxo vs Doxo + Nexavar

  23. Eligibility criteria • Histologically/cytologically confirmed, unresectable and/or metastatic disease • Child-Pugh A • Measurable disease • ECOG PS 0 or 1 • Good organ function • Prior TACE allowed (1:1) Randomization Stratification SHARP: SorafenibHepatocellular Phase III Study Design • Major endpoints • Survival • PFS • QOL Sorafenib400 mg bid Placebo Opened 2005

  24. Hand–foot skin reactionpalmar plantar erythrodysethesias (PPE) • Acral Erythema • painful, edematous, • erythematous • parathesias • hyperkeratosis • desquamation

  25. SHARP HCV subgroup c/w SHARP : OS 10.7 vs 7.9 mo, HR 0.69 20% HBV subset? Bolondi et al. GI ASCO 2008

  26. Asia-Pacific phase III Cheng et al ASCO 2008

  27. Cheng et al ASCO 2008

  28. 2nd trial:Doxorubicin +/- sorafenibrandomized phase II

  29. Period 1 Period 2 Sorafenib400 mg po bid 6 cycles of: • Doxorubicin 60 mg/m2 IV* Day 1 in 21-day cycles • Sorafenib 400 mg po bid Eligibility • Child-Pugh A • ECOG PS: 0, 1, 2 Continue until withdrawal, PD, or death (1:1) Randomization (N~96) Placebo2 tablets po bid 6 cycles of: • Doxorubicin 60 mg/m2 IV* Day 1 in 21-day cycles • Placebo 2 tablets po bid Study Design Doxorubicin total allowed 360 mg/m2 and in approved circumstances 450 mg/m2, after which sorafenib versus placebo can be continued as single agent

  30. Results Definitive analysis (data from March 2007 cutoff, independent assessment, TTP: 38 events, OS: 50 events, PFS: 70 events )

  31. Exploratory Comparison Per Protocol: Overall Survival Median OS: Doxorubicin + sorafenib: 13.7 (95% CI: 10.4-can not be estimated) Doxorubicin + placebo: 6.5 (95% CI: 4.9-9.5) Hazard Ratio: 0.45 p= 0.0049 Total # of events: 50 1.00 0.75 0.50 Survival Distribution Function 0.25 0.00 20.0 months 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 Months From Randomization Doxorubicin plus sorafenib Censored treatment: Doxorubicin + sorafenib STRATA: Censored treatment: Doxorubicin + placebo Doxorubicin + placebo

  32. 29% Percent Change in Target Lesion From Baseline (Independent Assessment) Doxorubicin + sorafenib (n=47) 100 Doxorubicin + placebo (n=49) 80 60 62% 40 20 Change in Target Lesion From Baseline (%) 0 -20 -40 -60 -80 -100 • March 2007 data cut-off • Based on independent radiological assessment population: subjects valid for ITT

  33. Safety and Study Drug Administration

  34. CALGB 80802 : Phase III trial of sorafenib ± Doxorubicin in advanced HCC • PI: GhasanAbou-Alfa • 600 patient trial, same patient population.... • randomized sorafenib vs sorafenib/doxorubicin combination. • Primary endpoint is OS • Includes radiological correlate • protocol at CTEP review, ? NCIC.

  35. 72 yo woman, HBV+, recurrent biopsy-proven multifocal HCC, +PVT, 8 months post resection. Child A, good PS. Enrolled on phase II trial of Doxorubicin + Sorafenib Baseline triphasic CT

  36. 72 yo woman, HBV+, recurrent biopsy-proven multifocal HCC, +PVT, 8 months post resection. Child A, good PS. Enrolled on phase II trial of Doxorubicin + Sorafenib C-2, slight progression, SD C-4, SD Dox held baseline C-6, hypodense minor response, SD by RECIST C-10, all more hyperdense PD by RECIST C8, ongoing SD What is the mechanism of drug resistance ?

  37. HCC Sorafenib Trials Summary

  38. Sorafenib in HCC • Body of evidence supports sorafenib as the new reference standard of care in advanced HCC (Child A, good PS) • This has launched many new studies… • Adjuvant setting ( surgery/ RFA) • ECOG 1207: Peri TACE (+/- sorafenib) • Combinations with other targeted agents and dox • Other HCC populations (Child B, post transplant)

  39. Erlotinib (Tarceva) in HCC • Targeting EGFR in HCC • Phase II, n=38…Philip et al, JCO 2005 • 88% EGFR+ • 32% progression-free at 6 months • 10% PR • Med OS 13 months (encouraging)

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