Clinical Trials for Liver and Pancreatic Cancer in Taiwan

Japan - Taiwan Joint Symposium on Medical Oncology Session 6 Hepatobiliary and pancreatic cancers Clinical Trials for Liver and Pancreatic Cancer in Taiwan Li-Tzong Chen 1,2 *, Jacqueline Whang-Peng 1,3 journal homepage:www.cos.org.tw/web/index.asp 1 National Institute of Cancer Research, National Health Research Institutes 2 Department of Internal Medicine, National Cheng-Kung University Hospital, Tainan 3 Division of Cancer Center, Taipei Medical University Hospital, Taipei Abstract. Although with limited clinical activity, gemcitabine monotherapy is still the standard of care for patients with advanced pancreatic cancer. To improve the therapeutic results of gemcitabine for advanced pancreatic cancer, we firstly had a phase I/II study to determine the maximum tolerated dose of 24-hour infusion of high-dose 5-FU and leucovorin (HDFL) in combination with weekly 800 mg/m 2 of gemcitabine in advanced pancreatic cancer. With the recommended dose of 5-FU, which was determined to be 2000 mg/m 2, the gemcitabine-hdfl regimen could achieve 22% of response rate, 6.9 months of overall survival and acceptable toxicity profile in advanced pancreatic cancer. Then we further incorporated oxaliplatin into the gemcitabine-hdfl regimen. The three drug combination gemcitabine, oxaliplatin plus infusional 5-FU and leucovorin (GOFL regimen) has been shown to be feasible and moderate active in patients with advanced pancreatic cancer, not only as the primary therapy for patients with advanced diseases but also as an inductional chemotherapy for patients with unresectable, locally advanced diseases. Further randomization will be warranted to evaluate the true clinical benefit of the triplet regimen in patients with advanced pancreatic cancer. In recently years, molecular targeting agent either alone or in combination with chemotherapy or other targeting agents is the mainstream for hepatocellular carcinoma (HCC) studies in Taiwan, as well as the rest part of the world. However, the targeting therapy for advanced HCC in Taiwan was started with the thalidomide program in 1999. We firstly completed a phase I and pharmacokinetic study to show that severity of underlying cirrhosis does not affect the absorption and elimination of thalidomide in HCC patients, and the maximum tolerated dose and recommended dose of thalidomide for HCC patients was 300 and 200 mg/day, respectively. Further studies suggested that oral thalidomide has a potential to stabilizing the progression of advanced HCC (30-40% of disease stabilization rate with objective response in 5-10%) even in patients with severe underlying cirrhosis. Based on such observations, a placebo-controlled phase III trial has been taken to evaluate the true therapeutic effects of thalidomide in Child-Pugh s B/C HCC patients. In addition, to improve the surgical outcome of patients with curative resection of HCC, we had also conducted a randomized, phase III TCOG trial to evaluate whether the use of interferon-α, an anti-virus, anti-proliferative, and anti-angiogenic immunomodulator, could reduce or delay the recurrence and thus, to improve the survival in post-operative HCC patients or not. This is the largest adjuvant therapy trial for (target patients population: 268) post-operative HCC in the world. The preliminary results will be disclosed in the text. Keywords : Clinical trial, liver cancer, pancreatic cancer

L. T. Chen et al./ Proc JTJS (2007) 60-64 61 ADENOCARCINOMA OF EXOCRINE PANCREAS Gemcitabine is the standard therapy for advanced pancreatic adenocarcinoma with modest anti-tumor efficacy, 6-11% of overall response rate and 5-6 months of overall survival time. We have made effort to improve the therapeutic efficacy by series of combination chemotherapy trials in advanced diseases. In the past decade years, we have firstly conducted a phase I/II trial of weekly gemcitabine (800 mg/m 2 ) plus 24-hr infusion of high-dose 5-FU/LV in advanced pancreatic cancer [1]. The treatment was given at day 1, 8 and 15 every 28 days, which demonstrated the regimen could achieve an overall and clinical benefit response rate of 22% and 46%, respectively; with median progression-free and overall survival of 4.1 and 6.9 months, respectively. The recommended dose of 5-FU for the combination was 2,000 mg/m 2. However, with the disclosure of ECOG 2297 trial, the combination of gemcitabine and 5-FU±LV became an unappealing regimen for further phase III study. Therefore, the combination of additional potentially active, non-cross resistant, and low-toxic cytotoxic agent seems to be a reasonable approach to further improve the therapeutic index of systemic chemotherapy for advanced pancreatic cancer. We had described an extremely excellent response of a metastatic pancreatic cancer to the combination of oxaliplatin to our gemcitabine-5-fu/lv regimen [2]. With such an observation, we started a phase I/II trial of biweekly gemcitabine (fixed rate infusion of 800 mg/m 2 ) followed by oxaliplatin and 48-hr infusion of 5-FU/LV (3000 and 300 mg/m 2, respectively), the GOFL regimen. The phase I study demonstrated that GOFL is a well-tolerated and moderate active (overall response rate of *Corresponding author: Li-Tzong Chen M.D., Ph.D. Tel: +886-6-2083422 ext.65110 Fax: +886-6-2083427 E-mail: leochen@nhri.org.tw 33.3%), regimen for advanced pancreatic cancer. The recommended dose of oxaliplatin for phase II trial was 85 mg/m 2 [3]. In phase II study, 45 patients (median age: 57 years-old) were enrolled, 36 (80.0%) of them had metastatic diseases. A total of 342 cycles were delivered, with a median of 7 cycles (95% CI, 6.4-8.8 cycles) per patient. Objective tumor response was achieved in 15, stable disease in 16, and progressive disease or unevaluable in 14. On intent-to-treat analysis, the overall response rate and disease-control rate was 33.3% (95% CI, 19.0-47.7%) and 68.9% (95% CI, 54.8-83.0%), respectively. Major grade 3/4 toxicities were neutropenia (33.3%, with 4.4% complicated with fever), nausea (15.6%), peripheral sensory neuropathy (15.6%), vomiting (8.9%) and diarrhea (8.9%). There was two treatment-related mortality. The median progression-free survival and overall survival was 4.7 months (95% CI, 3.3-6.0 months) and 9.8 months (95% CI, 7.0-12.6 months), respectively. The medial survivals of patients with metastatic and locally advanced disease were 7.8 months (95% CI, 7.2-11.7 months) and 15.9 months (95% CI, 11.5-21.0 months) respectively. The results showed that triplet regimen is not only feasible but also exhibits promising activity against advanced pancreatic cancer that deserves further exploration [4]. Management of unresectable, locally advanced pancreatic cancer patients remains controversial. Concurrent chemo-radiotherapy (CRT) is one of the most commonly used modality to treat locally advanced pancreatic cancer. However, systemic dissemination is the major cause of treatment failure, which may present even during or immediately after CRT. To treat undetectable metastases and to select patients who may potentially benefit from CRT, induction chemotherapy followed by CRT has recently become a favorable strategy for treating locally advanced pancreatic cancer. However, the efficacy of induction chemotherapy has been one of the major concerns for this multimodality approach. With the exciting results of GOFL regimen for patients with

62 L. T. Chen et al./ Proc JTJS (2007) 60-64 Table 1. Okuda s stage-stratified overall survival in HCC patients who received thalidomide treatment Overall survival, months Okuda s Okuda et al.* Chen et al. 10 Stage Score Chemotherapy Untreated Thalidomide I 4 4.3 (n=23) 8.3 (n=62) 7.6 (n=16) II 5-6 2.5 (n=82) 2.0 (n=134) 2.6 (n=21) III 7-8 1.4 (n=17) 0.7 (n=33) 3.9 (n=5) *, Okuda K, et al. Cancer 1985;56:918-28 locally advanced or metastatic pancreatic cancer, we have also initiated a phase II study of induction GOFL followed by CRT for locally advanced pancreatic cancer since 2004. In this study, patients who had responsive or stable diseases after 6 cycles (3 months) of induction GOFL would receive concurrent chemoradiotherapy (CRT) 3-4 weeks after the last dose of induction GOFL. Radiation was consisting of 5,040 cgy in 25 fractions along with weekly gemcitabine at dose of 400mg/m 2. Four weeks after completion of CRT, patients would be re-evaluated for surgical intervention. Inoperable patients would have further GOFL treatment until disease progression, the presence of unacceptable toxicity or patient's refusal. Among the 27 pts (13 F / 14 M, median age 61 years, range 29-80) who were enrolled into the first stage of the study, 24 (88%) and 9 (33%) of them had T3-4 and N2 disease, respectively. All 27 patients received induction chemotherapy and were evaluable for GO- FL-related toxicity. Thirteen patients off-studied after induction chemotherapy, due to disease progression in 10 and GOFL-related toxicity in 3. Among the 14 pts feasible for subsequent CRT, four refused CRT, thus only 10 pts received CRT and were evaluable for its toxicity. The most common grade 3/4 toxicities during induction GOFL were neutropenia (25.9%), nausea (33.3%), vomiting (25.9%), anorexia (18.5%) and anemia (11.1%). Grade 2 neuropathy occurred in 8 (29.7%). CRT was well-tolerated, and only one developed febrile neutropenia and 3 had grade 3/4 anemia. The results suggest GOFL followed by gemcitabine-based CRT is feasible in LAPC. Further patient accrual is still ongoing [5]. HEPATOCELLULAR CARCINOMA Therapy for Advanced Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and also the leading cause of cancer death of man in Taiwan. The median survival of symptomatic patients was less than 6 months. In recently years, molecular targeting agent either alone or in combination with chemotherapy or other targeting agents is the mainstream for hepatocellular carcinoma (HCC) studies in Taiwan, as well as the rest part of the world. However, the targeting therapy for advanced HCC in Taiwan was started with the thalidomide program in 1999. In a phase I study, we firstly determined the maximum tolerated dose and recommended dose of thalidomide in patients with HCC was 300 and 200 mg per day, respectively [6]. Further phase II study shown that thalidomide could have a tumor response rate of 7% and a disease control rate of 40% in advanced HCC [7]. Hemodynamic study with either dynamic contrast-enhanced MRI (DCE-MRI) or power Doppler sonography (PDS), both suggested thalidomide therapy was associated with significant reduction of tumor perfusion (measurement of the maximal enhancement, and the en-

L. T. Chen et al./ Proc JTJS (2007) 60-64 63 hancement slope percentage in the first-pass study by DCE-MRI and tumor vascularity index by PDS) in responsive HCC, but not un-responsive ones [8,9]. Based on these findings, a concurrent chemoradiotherapy (CCRT) with thalidomide as radio-enhancer, with DCE-MRI assessment of perfusion changes before and 1 week after CCRT, is currently ongoing. In addition, we have recently demonstrated that tumor marker (alpha- fetoprotein, AFP) response can more accurately reflect the biological response of advanced HCC to thalidomide therapy than radiographic response [10]. Despite the low tumor response rate in earlier studies, thalidomide therapy may sometimes provide effective palliation for patients with far advanced HCC with symptomatic IVC/RA tumor thrombi and who are not candidates for alternative treatment options [11]. Subgroup analysis of our prior study showed that the survival of our HCC patients receiving thalidomide therapy was 7.6, 2.6 and 3.9 months for patients of Okuda stage I, II and III, respectively. The survival of corresponding group of patients who had not received any therapy in the original report of Okuda et al. was 8.3, 2.0 and 0.7 months, respectively (Table 1). Based on the results, we initiated a placebo-controlled, phase III study to evaluate the effects of thalidomide on the survival of patients with advanced HCC and poor liver reserve (Child- Pugh s B and C). Currently, 74 patients have been enrolled, and an interim analysis will be carried out after the accrual of 82 patients (amended according to the suggestion of Data Monitoring and Safety Committee of TCOG). The VGH-Cooperative Ward trial of transcatheter arterial chemoembolization (TACE) alone versus thalidomide plus TACE for HCC (initiated by Dr. Chao Yee) was early terminated because of poor patient accrual. Adjuvant Therapy in Patients with Curative Resection Early detection of asymptomatic, small HCC plus curative resection provides the best chance of long- term survival. Recently, several large series of hepatic resection in HCC have been published. Despite of the improvement of surgical techniques and postoperative care which make the operation mortality to decline below 10%, the 5-year survival rate of patients who underwent curative resection still less than 30-50%. Most of the patients had and died of intrahepatic recurrence. The high incidence of recurrence, lack of effective therapy after recurrence and subsequently poor outcome indicate the need for adjuvant therapy in post-operative HCC. A Taiwan Cooperative Oncology Group study, the T1297 is a randomization, phase III trial testing whether adjuvant interferon alfa-2b (IFNα-2b) can prevent or delay intrahepatic recurrence in post-operative viral-related hepatocellular carcinoma (HCC) or not. The preliminary data was firstly disclosed at the December 2004 TCOG Annual Meeting (in Conjunction with Asian-Pacific Gastrointestinal Tract Malignancies Symposium) and then presented in the Presidential Symposium of the 2005 AASLD Annual Meeting [12]. In this randomization, controlled study, patients with hepatitis B or C virus-related HCC that had curative resection (no radiographic evidence of vascular involvement, gross resection margin > 1 cm and negative cutting end in histology) were eligible. Patients were stratified by their viral status (HBsAg+ versus HBsAg-/anti-HCV+) and randomly allocated to adjuvant IFN-α2b treatment (53 weeks) or observation alone. Among the 264 eligible patients, with median follow-up of 41.8 [95% CI: 39.3 44.4] months, 127 (48.1%) patients suffered disease recurrence (64 in IFN-α2b arm and 63 in observation arm), and 58 (22.0%) patients died (29 in IFN-α2b arm and 29 in observation arm). The 6-year overall survival (OS) rate was 68.4% in IFN-α2b arm and 72.1% in observation arm, (p=0.89, log-rank test); while the 6-year recurrence-free survival (RFS) rate was 42.3% and 45.6% (p=0.89, log-rank test), respectively. Among clinicopathological variables, only patients performance status, tumor size, and microvascular invasion were independent prognostic factors

64 L. T. Chen et al./ Proc JTJS (2007) 60-64 for OS. Stepwise Cox s proportional hazard model analysis showed adjuvant IFN-a2b was an independent prognostic factor for better RFS [HR: 0.477 (95% CI: 0.243 0.940), p=0.032] and OS [HR: 0.280 (95% CI: 0.125 0.630), p=0.002] in HBsAg+ patients whose tumor equal or greater than 5 cm (n=68), but neither for those with tumor smaller than 5 cm (n=144) nor for HBsAg-/anti-HCV+ patients (n=52). We conclude that 53-week adjuvant IFN-α2b therapy did not improve the RFS and OS of post-operative viral-related HCC patients in this endemic area of HBV infection. Further study using less toxic, anti-hbv nucleotide/nucleoside as adjuvant setting in patients with low-risk of recurrence after curative resection of HBV-related HCC is currently ongoing. REFERENCES 1. Shiah HS, Cheng AL, Hsu C, et al. Phase I-II trial of weekly gemcitabine plus high-dose 5-fluorouracil and leucovorin in advanced pancreatic cancer. J Gastroenterol Hepatol 21: 531-6, 2006. 2. Wu CW, Chen SC, Su YC, et al. Complete remission of metastatic pancreatic cancer with cardiac involvement after gemcitabine, oxaliplatin and 46-h infusion of 5-fluorouracil/leucovorin. J Gastroenterol Hepatol 19: 716-7, 2004. 3. Ch ang HJ, Wang CC, Cheng AL, et al. Phase I study of biweekly gemcitabine, oxaliplatin and simplified 48-hr infusion of fluorouracil / leucovorin (GOFL) for advanced pancreatic cancer. J Gastroenterol Hepatol 21: 874-9, 2006. 4. Chen LT, Ch'ang HJ, Huang CL, et al. Phase II study of biweekly gemcitabine followed by oxaliplatin and simplified 48-hr Infusion of 5- fluorouracil / leucovorin (GOFL) in advanced pancreatic cancer. Proceeding of ASCO GI Symposium, 2008. 5. Chen LT, Ch'ang HJ, Huang CL, et al. Feasibility of gemcitabine-based chemoradiotherapy (CRT) after triplet chemotherapy (CT) for locally-advanced (LA) pancreatic cancer patients: Preliminary data from Taiwan Cooperative Oncology Group (TCOG) T1204 Study. Proceeding of ASCO GI Symposium, 2008. 6. Shiah HS, Chao Y, Chen LT, et al. Phase I and pharmacokinetic study of oral thalidomide in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 58: 654-64, 2006. 7. Hsu C, Chen CN, Chen LT, et al. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology 65: 242-9, 2003. 8. Hsu C, Chen CN, Chen LT, et al. Use of power doppler sonography and circulating angiogenic factors to assess the anti-angiogenic effect of thalidomide in hepatocellular carcinoma. Radiology 235: 509-16, 2005. [SCI, 3/84, I.F.5.08]. 9. Wang J, Chen LT, Tsang YM, et al. Dynamic contrast-enhanced MRI analysis of perfusion changes in advanced hepatocellular carcinoma treated with an antiangiogenic agent: a preliminary study. Am J Roentgenol 183: 713-9, 2004. [SCI, 18/83, I.F. 2.47]. 10. Chen LT, Liu TW, Chao Y, et al. Alpha-fetoprotein response predicts survival benefits of thalidomide for advanced hepatocellular carcinom. Aliment Pharmacol Ther 22: 217-26, 2005. 11. Chang JY, Ka WS, Chao TY, et al. Hepatocellular carcinoma with intra-atrial tumor thrombi A report of three cases responsive to thalidomide treatment and literature review. Oncology 67: 320-6, 2004. 12. Chen LT, Chen MF, Li LA, et al. Randomized phase III study of adjuvant interferon alfa-2b in hepatocellular carcinoma with curative resection the Taiwan Cooperative Oncology Group (TCOG) T1297 study. Proceeding of 2005 AASLD Annual Meeting.