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Advances in Chemotherapy for Primary Liver Cancers: HCC and Biliary Adenocarcinomas

This presentation by Dr. Jennifer J. Knox from Princess Margaret Hospital addresses the complexities of treating primary liver cancers, specifically hepatocellular carcinoma (HCC) and biliary adenocarcinomas. It emphasizes the challenges posed by existing trial data and outlines a nuanced approach to patient selection for potential therapies. Participants will learn about the latest advancements in systemic therapy for these cancers and the importance of individualized treatment plans based on tumor and liver function assessments.

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Advances in Chemotherapy for Primary Liver Cancers: HCC and Biliary Adenocarcinomas

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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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