HEPATOCELLULAR CARCINOMA N. A.OTHIENO ABINYA

Transcription

1 HEPATOCELLULAR CARCINOMA N. A.OTHIENO ABINYA

2 - One of the most common solid organ tumours worldwide. - A public health problem in parts of Asia and subsaharan Africa, with incidence upto 50/100,000 population/year. - Incidence mirrors that of chronic liver injury, due principally to hepatitis (B & C) viral infection.

3 - Incidence and mortality increasing even in Western countries. - Other causes of cirrhosis include alcohol, metabolic diseases, and environmental exposure (Toxins, especially aflatoxin B1). - Liver cirrhosis a very common feature in relation to HCC.

4 Treatment: - Surgery can offer cure, but over 90% are unresectable in Western countries. - Intraarterial local ablative therapies feasible for unresectable disease. - However, majority of patients have too extensive disease for this kind of therapy.

5 Systemic therapy: - The only treatment option for the majority. - Indications for systemic therapy: 1. Extra hepatic extension 2. Localized disease not suitable for surgery, local ablation, or intra arterial therapy 3. Main portal vein thrombosis 4. Good performance status (KPS >70%; ECOG 1

6 - HCC generally considered chemoresistant - Initially,most commonly used agents were doxorubicin and epirubicin, with response rates of 10-15% - Reported response rates to doxorubicin extremely variable, and its has never been conclusively demonstrated to impact positively on survival - Complete remission described, but very brief. (Leung TWT et al. Semin Oncol 2001; Johnson PJ et al. Lancet 1978) - Reviews have not demonstrated survival effects of doxorubicin (Mathurin P. et al. Alignment Pharmacol Ther 1998) - Many older reports used poorly defined criteria and are difficult to compare with current trial reports

7 Response Rates to Older Single Chemotheraeutic Agents by HCC Drug Number of Objective Reference Patients Response Rate% Doxorubicin Vogel-1977 Etoposide Melia-1983 Cis-platin Folkson-1987 Mitoxantrone 35 0 Folkson-1987 Vinblastine 25 8 Damrongak- IFN-alpha 2b - 7 Anonymous Newer generation chemotherapeutic agents have not shown better responses and at times they have shown less activity.

8 Objective Response Rates for Newer Chemotherapeutic Agents in HCC Drug Number of Objective Reference Patients Response Rate% Paclitaxel 20 0 Chao-1998 Nolatrexed 37 0 Mok-1999 Liposomal DNR 14 0 Yeo-1999 Leposomal Doxo 16 0 Halm-2000 Capecitabine Lazano-2000 Capecitabine Patt-2000 Gemcitabine Yang-2000 Gemcitabine 37 5 Kubicka-2001 Irinotecan 14 7 O Reilly-2001

9 Difficulties in Consistency of trials also lies in the fact that HCC s are often infiltrative, numerous lesions, irregular, difficult to measure objectively by conventional radiologic methods.

10 Combination Chemotherapy: - Improved response rates, but only modestly, and with no clear impact on survival. - Doxorubicin/cis-platin included in most combination regimens. - Most studies were single arm phase II trials, so no good comparison and different response criteria used.

11 PIAF 1999 Two studies four drugs systemic CDDP 80mg/m 2 i.v. day 1 Doxorubicin 40 mg/m 2 i.v. day 1 5-FU 400 mg/m 2 i.v. days 1-5 IFN- -2b 5mu subcut days 1, 3, 5 OR CDDP 20mg/m 2 i.v. days 1-4 Doxorubicin 40mg/m 2 i.v. day 1 5-FU400 mg/m 2 i.v. days 1-4 IFN- -2b 5mu/m 2 i.v. days 1-4 Q3-4 weeks

12 (Leung TWT et al. Hong Kong Study; Clin Cancer Res 1999; Patt YZ, et al, Am J Clin Oncol 1999). - Disease was rendered operable in 9/13-4/13 had pathologic CRs Update of PIAF by same Hong Kong group. - PIAF surgical resection - 8/15 complete pathologic remission - 7/15 95% necrosis (Lau WY, et al. Am J Surg 2001)

13 BUT - 2/50 deaths from toxicity (febrile neutropenia) - G3/4 leukopenia in 34% - G3/4 thrombocytopenia in 22% same Hong Kong group trial PIAF vs Doxorubicin SA PIAF Doxo Objective RR 20% 10% Median survival 40.8 weeks 29.3 weeks The differences were not statistically significant. G3/4 myelotoxicity higher with PIAF

14 Some Newer Combination Therapies Combination Number of Objective Reference Patients Response Rate % IFN- + Doxo -?0 Kardianal-1993 IFN- + 5-FU - 31 Patt-1993 IFN- + 5-FU -?0 Stuart-1996 IFN- + CDDP - 13 Ji-1996 PIAF - 26 Platt-2000

15 What is the problem with hepatoma? - Progenitor cell of highly resistant clones (De Vita VT, Jr et al. Cancer J 2000) - There is a high genetic mutational load that makes hepatoma cells less amenable to chemotherapy. - HCC cells relatively well differentiated and carry several mechanisms of drug resistance. - HCC cells carry high levels of dihydropyrimidine dehydrogenase (DPD), conferring resistance to 5-FU (Jiang et al. Cancer Res 1998) - HCC cells overexpress MDR 1 gene, and the gene product PGP. - (Chinuvesse X, et al. J. Jepatol 1993; soini Y et al. J Clin Pathol 1996).

16 BUT: - In a phase III trial, overcoming MDR did not show marked improvement in response rates compared with historical controls. - (Leung TW et al. Profc Am Soc Clin Oncolo 2003) - Association with liver cirrhosis and attendant drug toxicities make it a problem for proper dosing. - Patients in score C Child s-pugh should not be given chemotherapy.

17 Evaluated New Therapeutic Strageties - EGFR inhibitors including C225- no role. - Her-2/neu Rarely expressed. - Hepatocyte growth factor and its receptor c-met expressed in 33% and 20% of human hepatoma cells respectively no role - (Kiss A et al. Cancer Re 1997). Inhibitors of Ras activity: - Raf kinase inhibition no role - Erlotinib (tarceva) 10% PR (Phillip PA et al. Proc Am Soc Clin Oncol 2004) - Sorafenib

18 - Because it is highly vascular VEGF inhibition bevacizumab (Avastin) in a phase II trial PR in 1/12 patients (Schwartz JD, et al. Proc Am Soc Clin Oncol 2004) - Thalidomide 5% objective responses (Patt YZ, et al. Am J Clin Oncol 200).

19 Others: Imatinib Cyclin dependent kinase inhibition flavopiridol monotherapy no use Flavopiridol + irinotecan -?some response. Other issues - Reactivation of hepatitis:c - interferon B-?Routine incorporation of lamivudine.

20 - Multikinase inhibitor with antiangiogenic properties (Sorafenib) - Multicentre randomized placebo controlled phase III trial Sorafenib Placebo Patients-602: Deaths-321: Median o/s (months): Median TTP: ORR 2.5%? (Not stated) Llovet J, et at. Proc. Am soc Clin Oncol 2007.

21 The decision is yours But do no harm.