HEPATOCELLULAR CARCINOMA N. A.OTHIENO ABINYA

HEPATOCELLULAR CARCINOMA N. A.OTHIENO ABINYA

- 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.

- 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.

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.

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

- 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

Response Rates to Older Single Chemotheraeutic Agents by HCC Drug Number of Objective Reference Patients Response Rate% Doxorubicin 41 17 Vogel-1977 Etoposide 24 18 Melia-1983 Cis-platin 35 17 Folkson-1987 Mitoxantrone 35 0 Folkson-1987 Vinblastine 25 8 Damrongak- IFN-alpha 2b - 7 Anonymous-1990 - Newer generation chemotherapeutic agents have not shown better responses and at times they have shown less activity.

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 37 13 Lazano-2000 Capecitabine 37 13 Patt-2000 Gemcitabine 28 18 Yang-2000 Gemcitabine 37 5 Kubicka-2001 Irinotecan 14 7 O Reilly-2001

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.

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.

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

(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)

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

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

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).

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.

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

- 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).

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.

- Multikinase inhibitor with antiangiogenic properties (Sorafenib) - Multicentre randomized placebo controlled phase III trial Sorafenib Placebo Patients-602: 299 303 Deaths-321: 143 178 Median o/s (months):10.7 7.9 Median TTP: 5.5 2.8 ORR 2.5%? (Not stated) Llovet J, et at. Proc. Am soc Clin Oncol 2007.

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