FOLFOX-4 as second-line therapy after failure of gemcitabine and platinum combination in advanced gall bladder cancer patients

Transcription

1 Japanese Journal of Clinical Oncology, 2016, 46(1) doi: /jjco/hyv148 Advance Access Publication Date: 24 November 2015 Original Article Original Article FOLFOX-4 as second-line therapy after failure of gemcitabine and platinum combination in advanced gall bladder cancer patients Chandragouda Dodagoudar 1, Dinesh Chandra Doval 1, *, Anupam Mahanta 2, Varun Goel 1, Amitabh Upadhyay 2, Pankaj Goyal 2, Vineet Talwar 1, Sajjan Singh 1, Mithun Chacko John 2, Srikant Tiwari 2, and Nivedita Patnaik 3 1 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, 2 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, and 3 Senior Resident, Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Dilshad Garden, New Delhi, India *For reprints and all correspondence: Dinesh Chandra Doval, Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi , India. doval.dc@rgcirc.org Received 16 January 2015; Accepted 3 September 2015 Abstract Objective: There is no standard second-line chemotherapy after progression on first-line therapy including gemcitabine and platinum combination in advanced gall bladder cancer patients. So this study was undertaken to assess the efficacy and safety of FOLFOX-4 regimen in this setting. Methods: In this observational study, patients with performance status 2, who progressed on firstline therapy, were enrolled from May 2010 to June FOLFOX-4 based treatment was administered until progression, unacceptable toxicity or up to 12 cycles. Results: A total of 66 patients were enrolled in this study. The median age of patients was 52.5 years (32 66 years),of which 24 (36.36%) were males and 42 (63.63%) were females. The median number of cycles could be given were 9.5 (2 12). Only 43.93% patients in this study completed full 12 cycles of chemotherapy. Sixteen patients (24.24%) in this study required the dose reduction at least in one cycle of chemotherapy due to toxicities. Disease control rate was seen in 39 (59.09%) patients, with complete response in none, partial response in 16 (24.24%), stable disease in 23 (34.84%) and progressive disease in 27 (40.90%) patients. The median progression free survival was 3.9 months; median overall survival was 7.6 months. The main Grade 3/4 side effects seen were hematological in 31.81% (n = 21) and gastrointestinal in 25.75% (n = 17) patients. Majority of patients (46%) had Grade 1/2 peripheral neuropathy. Conclusions: FOLFOX-4 is an effective and well-tolerated regimen as a second-line treatment in advanced gall bladder cancer patients. Further studies are required, especially in the Indian subcontinent. Key words: carcinoma gall bladder, FOLFOX-4, gemcitabine, platinum, second line Introduction Gall bladder cancer (GBC) is the most common biliary tract malignancy (1) and carries a worse prognosis than any other gastrointestinal (GI) or hepatobiliary neoplasm. Median survival for patients presenting with unresectable disease is 2 4 months, with fewer than 5% patients surviving 1 year (2). Surgical resection offers the only potentially The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com 57

2 58 FOLFOX-4 in advanced gall bladder cancer curative option, but <35% of patients are candidates for radical surgical resection at presentation, and even among those patients, recurrence rates are high. In rest of the patients with advanced GBC, a survival benefit has been shown with the use of chemotherapy in firstline setting (3). Several Phase II studies of gemcitabine and platinum combination therapy showed a good antitumor effect (4) and later in 2010, two randomized trials provided evidence that the regimen with gemcitabine + cisplatin is an effective therapy for advanced biliary cancer (5,6). There are very few data available in the literature regarding second-line chemotherapy for advanced GBC. Moreover, no clinical study comparing chemotherapy with best supportive care (BSC) exists (7). There is lack of standard second-line therapy following gemcitabine refractoriness (8). The studies conducted so far are primarily Phase II studies comprising small number of patients. Moreover, these studies involved heterogeneous group of patients suffering from GBC, cholangiocarcinoma and periampullary carcinoma. So it was decided to conduct a prospective observational study where FOLFOX-4 regimen was studied in locally advanced unresectable and metastatic gall bladder adenocarcinomas in whom the disease progressed after first-line therapy with gemcitabine and a platinum. Primary aim of this study is to determine the overall survival (OS) of oxaliplatin, 5FU, leucovorin-based combination chemotherapy (FOLFOX) in unresectable or metastatic GBC as second-line therapy after failure of therapy with gemcitabine and a platinum agent. Secondary aim of this study is to evaluate the toxicity profile, response rate and progression free survival (PFS). Patients and methods This is a single-center, a prospective observational study Conducted in the department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India. Patient eligibility criteria Patients with histologically or cytologically diagnosed advanced or metastatic carcinoma gall bladder patients and documented progressive disease after first-line gemcitabine/platinum chemotherapy were considered eligible. Additional eligibility criteria included age years; measurable and/or evaluable disease; an Eastern Cooperation Oncology Group (ECOG) performance status (PS) score of 0 2; adequate bone marrow reserve with white blood cells count 3500/mm 3, absolute neutrophil counts 1500/mm 3 and platelet count /mm 3,adequate hepatic function with serum bilirubin <1.5 mg/dl, serum transaminases <2 times upper limit of normal and in the case of liver metastasis transaminases and bilirubin up to four times upper limit of normal, adequate renal function with serum creatinine >1.5 mg/dl, absence of pregnancy, lactation (pregnancy test by enzyme-linked immunosorbent assay was performed and should be negative) and no evidence of symptomatic neuropathy due to comorbid conditions. Patients were excluded if they had not received gemcitabine/ cisplatin as first-line therapy or had already received fluoropyrimidinebased regimens, or they had central nervous system metastases, mental disease, active infections, massive ascites and pleural effusion, unstable cardiovascular disease, ECOG PS 3 and 4, coexistent/synchronous malignancies and baseline sensitive peripheral neuropathy and were pregnant or lactating. Written informed consent was obtained from each patient before entering the study (Thumb Impression if the patient is illiterate), which was approved by the local ethics committee. Treatment FOLFOX-4 consisted of oxaliplatin 85 mg/m 2 on Day 1 only, given as a 2 h infusion in 250 ml of 5% dextrose, LV 200 mg/m 2 /day as a 2 h infusion followed by bolus 5-FU 400 mg/m 2 /day and a 22 h infusion of 5-FU 600 mg/m 2 /day, repeated for two consecutive days every 2 weeks. Routine antiemetic prophylaxis was used for FOLFOX-4. In the event of Grade 3 4 neutropenia, Grade 4 thrombocytopenia, the chemotherapeutic dosage of 5FU was reduced by 25% in all subsequent cycles. In the event of Grade 3 diarrhea, the doses of 5FU was reduced by 25% in all subsequent cycles. Growth factor support, filgrastim will be administered only as secondary prophylaxis if required. Treatment was biweekly administered until PD or unacceptable toxicities, patient refusal and physician decision or treatment interruption for 2 weeks. Toxicity profiles were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Statistical analysis All analyses were performed with the statistical software SPSS version 22 (SPSS, Inc., Chicago, Ill., USA). For response and progression data, two-sided 95% confidence intervals (CIs) were calculated based on an exact binomial probability at an α level of 0.05.The OS and time to tumor progression was estimated using the Kaplan Meier method. Data were analyzed using χ 2 test and Fisher s exact test, wherever appropriate. Statistical significance was defined as P Response duration was measured from the onset of response until disease progression. Time to progression was calculated from the date of entry into the study until the date of progression. Overall survival was defined as the period between the date of the start of the first cycle of chemotherapy and the date of death or last follow-up. All analyses were made on an intention-to-treat basis. Patients, who did not finish two treatment cycles, whatever the reason, were considered to have treatment failures and listed as disease progressions. Patients were planned for 12 cycles of FOLFOX chemotherapy. An interim evaluation was done after six cycles of chemotherapy. If there was a progression, the FOLFOX chemotherapy was discontinued and patients were followed up. If there was complete response or partial response after six cycles, the chemotherapy was continued for six more cycles. Re-evaluation was done again 4 weeks after 12 cycles. The patients showing complete or partial response were followed up. Results There were 360 patients of GBC registered at RGCI & RC from May 2010 to June Of them, 46 patients came for second opinion and 65 patients underwent curative surgery with or without adjuvant therapy. Twenty-five patients underwent surgery after neoadjuvant chemotherapy. The remaining 224 patients were found to be inoperable (locally advanced) or metastatic at presentation. Among them, 88 patients received BSC only and 136 patients were considered for palliative chemotherapy. Ten patients were not willing for chemotherapy and hence advised BSC. One hundred twenty-six patients received gemcitabine + platinum (cisplatin/carboplatin)-based combination therapy as a first-line treatment. On progression, they were considered for second-line therapy. Seventy patients were randomly selected for second-line therapy with FOLFOX regimen based on inclusion criteria mentioned earlier. Four patients had voluntarily withdrawn from the study. At the end of the study, 66 patients were available for final analysis.

3 Jpn J Clin Oncol, 2016, Vol. 46, No Demographic profile In this present study, majority of the cases were in middle age group, i.e. 52% was in the years age group. The mean age was years (range, years) (Table 1). The study was carried out in 66 patients comprising 24 males and 42 females. The percentage of female (63.63%) patients was more than male patients (36.36%) in the present study. In most cases either one or two organs were involved and common sites of metastasis were liver, lymph nodes, omentum and peritoneum. Only 43.93% patients in this study completed full 12 cycles of chemotherapy (Table 2). The reasons for discontinuation of chemotherapy were progression of disease, intolerance to chemotherapy and Grade 3 and 4 toxicities. Sixteen patients (24.24%) in this study required the dose reduction at least in one cycle of chemotherapy due to toxicities (Table 3). Thirteen (19.69%) patients in this study required delay in at least one cycle chemotherapy due to Grade 3 and 4 hematologic toxicities and febrile Table 1. Patients characteristics Patient characteristics Number of patients (%) Age ± 6.56 a ; median 52.5 years (32 66 years), Sex Male 24 (36.36) Female 42 (63.63) ECOG PS 0 13 (19.69) 1 37 (56) 2 16 (24.24) Stage at entry Locally advanced 16 (24.24) Metastatic 50 (75.75) (Metastasis) no. of sites 1 28 (42.4) 2 31 (47) >2 7 (10.60) Smokers 21 (31.81) Non-smokers 45 (68.18) ECOG, Eastern Cooperative Oncology Group; PS, performance status. a Mean ± SD wherever applicable. Table 2. Distribution of patients according to number of chemotherapy cycles received No. of cycles of chemotherapy Frequency Percentage Total neutropenia. The median duration of delay was 4 days (range 2 7 days). The toxicities of patients in this study were mainly hematologic (Table 4). The majority of these Grade 3 and 4 complications were seen at the mean duration of Day 9 (range 7 14)ofchemotherapy and mainly comprise of neutropenia, leucopenia and thrombocytopenia. Febrile neutropenia was seen in 4 (6.06%) patients. The GI toxicities of patients mainly consist of stomatitis, nausea, vomiting and diarrhea. However, these complications did not result in delay or discontinuation of chemotherapy. The cardiac complications of patients mainly consist of edema, angina and ST-T changes. These were attributable to 5 fluorouracil (FU). In this present study, majority of patients (46%, n = 30) had Grade 1 or Grade 2 peripheral neuropathy which did not lead to treatment delay or discontinuation of therapy (Table 5). Distribution of patients according to response evaluation (n = 66) The evaluation of response to chemotherapy was done by computed tomography/magnetic resonance imaging abdomen or positron emission tomography-ct if it was done as a staging procedure. In a total of 66 patients in this study, 16 (24.24%) patients had a partial response and 0% had complete response. A total of 27 (40.90%) patients progressed on chemotherapy and 23 (34.84%) had stable disease. The disease control rate (responses and stable disease) was 59%. The median duration of follow up of these patients was 9.5 months. The median OS was 7.5 ± months (range 1 18, 95% CI months) (Fig. 1) (Table 6). The median PFS was 3.9 ± 0.4 months (range months, 95% CI: months) (Fig. 2). Table 4. Grade 3 and 4 toxicities Complications Frequency Percentage Neutropenia Leukopenia Thrombocytopenia Febrile neutropenia Stomatitis/mucositis Nausea Vomiting Diarrhea Edema Angina ST-T changes 2 3 LV dysfunction 0 0 Anorexia 9 36 Weakness 9 36 Nail disorders/skin changes Hand foot syndrome 4 16 Table 3. Distribution of patients requiring dose reduction Table 5. Grades of peripheral neuropathy Frequency Percentage Grades Frequency Percentage Dose reduction: at least in one cycle No dose reduction Delay at least in one cycle No delay of chemotherapy I II III IV 0 0

4 60 FOLFOX-4 in advanced gall bladder cancer Figure 1. Kaplan Meier distribution of overall survival (months). Table 6. Response evaluation Response Frequency Percentage Complete response 0 0 Partial response Stable disease Progressive disease Total Discussion Gall bladder adenocarcinomas present in an advanced stage in a majority of cases. Chemotherapy has been reported to have a significant benefit as compared with BSC (3,9). Since the study reported by Vally et al. (10), the combination of gemcitabine and cisplatin has been considered as a standard first-line therapy, with median PFS and OS of 8.0 and 11.7 months, respectively. There is no standard second-line chemotherapy after progression with gemcitabine and platinum-based palliative therapy as there are no randomized Phase III trials of chemotherapy conducted in this setting. Reports suggest second-line chemotherapy (CT2) is utilized in 18 35% of patients (10,11) The benefits of CT2, even in a wellselected population, are unclear. Indeed, due to the relatively poor outcomes from first-line treatment and the rarity of this disease, limited studies on CT2 after gemcitabine-based chemotherapy failure have been performed (12,13). The studies conducted so far are primarily Phase II studies comprising small number of patients. Moreover, these studies involved a heterogeneous group of patients suffering from GBC, cholangiocarcinoma and periampullary carcinoma. There is no study done internationally that involve GBC exclusively. The various chemotherapeutic combination agents used in Phase II trials were 5FU, platinum derivatives (e.g. cisplatin, oxaliplatin), capecitabine, gemcitabine and modifications of these regimens. So it was decided to conduct a prospective observational study where FOLFOX-4 regimen was studied in locally advanced unresectable and metastatic gall bladder adenocarcinomas for OS, response rates, time to tumor progression and toxicity profile. The primary endpoint was the OS. In this study, median OS was 7.6 months (range 1 11, 95% CI, months) which is comparable with other studies done by Jen-Shi et al. (FOLFOX) (14) and Nehls et al. (CAPOX) (15) (7.0 and 8.2 months, respectively). The secondary aim of the study was to evaluate the toxicity profile, response rate and PFS. Toxicity profile of FOLFOX chemotherapy was recorded as per common terminology criteria version 4. A total of 66 patients were enrolled. The median age of patients was 52.5 years (32 66 years), out of which 24 (36.36%) were males and 42 (63.63%) were females. The median number of cycles could be given were 9.5 (2 12). Only 43.93% patients in this study completed full 12 cycles of chemotherapy. Sixteen patients (24.24%) in this study required the dose reduction at least in one cycle of chemotherapy due to toxicities. Disease control rate was seen in 39 (59.09%) patients, with CR in none, PR in 16 (24.24%), SD in 23 (34.84%) and PD in 27 (40.90%) patients. The median PFS was 3.9 months, median OS was 7.5 months. The main Grade 3/4 side effects seen were Table 7. Comparison of efficacy results in percentage Response (%) Jen-Shi et al. (14) (FOLFOX) N =32 Nehls et al. (15) (CAPOX) N =27 Present study N =66 ORR CR PR PD SD PFS (months) Median OS (months) Figure 2. Kaplan Meier distribution of progression-free survival (months). ORR, overall response rate, CR, complete response, PR, partial response; PD, progressive disease; SD, stable disease; PFS, progression-free survival.

5 Jpn J Clin Oncol, 2016, Vol. 46, No Table 8. Comparison of toxicity profile (in percentage) Authors Jen-Shi et al. (14) (FOLFOX) N =32 Nehls et al. (15) (CAPOX) N =27 Present study (FOLFOX) N =66 All (%) Grade 3 (%) Grade 4 (%) All (%) Grade 3 (%) Grade 4 (%) All (%) Grade 3 (%) Grade 4 (%) Hematologic Neutropenia Leucopenia NR NR NR Thrombocytopenia Anemia Febrile neutropenia NR NR NR Gastrointestinal Mucositis Nausea Vomiting Diarrhea Liver transaminases NR NR NR Other Anorexia NR NR NR NR NR NR Weakness NR NR NR Nail disorders/skin changes NR NR NR NR NR NR 44 0 NA Hand foot syndrome NA 14 4 NA 16 0 NA NR, not reported. hematological in 31.81% (n = 21) and GI in 25.75% (n = 17) patients. Majority of patients (46%) had Grade 1/2 peripheral neuropathy. The response and outcome data were compared with other studies by Jen-Shi et al. (FOLFOX) (14) and Nehls et al. (CAPOX) (15). These studies have shown overall response rate (ORR) of 18.8% and 11.0%, respectively. The median PFS in these studies were 3.7 and 4.7 months, respectively. The response and the outcome (PFS) data of the present study were comparable with these international studies and tabulated in Table 7. In the present study, Grade III and IV hematologic, GI and neurologic complications were noted in a majority of patients and other toxicities like cardiac, skin and nail disorders were noted only in a minority of the patients. The Grade III and IV hematologic complications were noted in 31.81% (n = 21) of patients and they are the most common toxicities that lead to treatment delay. These toxicities were neutropenia, leucopenia, thrombocytopenia, anemia and febrile neutropenia and were noted in 40, 36, 12, 32 and 4% of patients, respectively. FOL- FOX chemotherapy toxicity data were comparable with the other study by Jen-Shi et al. (14). However, the study by Nehls et al. (15) who used CAPOX chemotherapy noted thrombocytopenia more than neutropenia and anemia (29, 14 and 18%, respectively). These hematologic toxicities were compared with the present study in Table 8. The GI complications were second most common toxicities noted in the present study. They comprise of stomatitis/mucositis (44%), nausea (28%), vomiting(8%) and diarrhea(16%), respectively. When compared with other studies by Jen-Shi et al. (14) and Nehls et al. (15), these GI complications were comparable. However, increased liver transaminases were noted in 48% of patients in the current study, but were not reported in studies by Nehls et al. in which CAPOX regimen was used. Neurologic complication in the form of sensory neuropathy was the most common toxicity seen in the present study. Forty-eight percent of patients developed peripheral neuropathy of which one patient had Grade III toxicity. When compared with other studies by Jen-Shi et al. (14) and Nehls et al. (15), these complications were comparable Table 9. Comparison of toxicity profile peripheral neuropathy Grade III and IV (in percentage) Study All (%) Grade 3 (%) Grade 4 (%) Jen-Shi et al. (14) (FOLFOX) N = Nehls et al. (15) (CAPOX) N = Present study N = Table 10. Comparison of toxicity profile cardiac (in percentage) Cardiac toxicity (%) Jen-Shi et al. (14) (FOLFOX) N =32 Nehls et al. (15) (CAPOX) N =27 Present study (FOLFOX) N =66 Edema Angina ST-T changes Thromboembolic events (Table 9). However, Grade III toxicity was more commonly observed (15%) in the study Nehls et al. where CAPOX regimen was used. In the current study, the cardiac complications were minimal with FOLFOX chemotherapy. These were angina, ST-T changes on electrocardiogram and were observed in 4% of patients. This study also noted edema in 12% of patients. However, cardiac toxicities were not noted in other international studies. The cardiac complications are tabulated in Table 10. In Indian context, study done by Sharma et al. (3) to evaluate efficacy of modified gemcitabine and oxaliplatin (mgemox) over BSC or FU and folinic acid (FA) in unresectable GBC. Two patients in the mgemox arm and one patient in the FUFA arm underwent curative resection after chemotherapy. One patient in the mgemox arm had complete pathologic response. Median OS was 4.5, 4.6 and 9.5 months for the BSC, FUFA and mgemox arms (P = 0.039), respectively. PFS was 2.8, 3.5 and 8.5 months for the three groups (P <0.001). The authors concluded that the efficacy of chemotherapy (mgemox)

6 62 FOLFOX-4 in advanced gall bladder cancer is comparable with BSC and FUFA in improving OS and PFS in unresectable GBC. Overall, the FOLFOX-4 regimen was very well tolerated in the present study. The findings of the study have significant implications for clinical practice. The clinical outcome toxicity profile of patients receiving chemotherapy for advanced GBC has been observed to be similar to that reported from the west. However, this must be tested in a randomized controlled trial. Conclusion FOLFOX-4 chemotherapy is an effective and well-tolerated chemotherapy regimen as a second-line treatment in patients with advanced GBC who progressed after gemcitabine- and cisplatin-based therapy, especially in patients with good PS. FOLFOX-4 chemotherapy has an acceptable toxicity profile and mainly comprises hematologic, GI and peripheral neuropathy. They are mostly Grade 1 3 and do not lead to discontinuation of therapy. There is no treatment-related death. More research is required, especially in the Indian subcontinent, to assess the efficacy and tolerability of this regime for confirmation and deserves further study. Conflict of interest statement None declared. References 1. Greenle RT, Murray T, Bolden S, Wingo PA. Cancer Statistics, CA Cancer J Clin 2000;50: Perpetuo MO, Valdivieso M, Heilbrun LK, Nelson RS, Connor T, Bodey GP. Natural history study of gallbladder cancer: A review of 36 years experience at M.D. Anderson Hospital and Tumor Institute. Cancer 1978;42: Sharma A, Dwary AD, Mohanti BK, et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol 2010;28: Doval DC, Sekhon JS, Gupta SK, et al. A phase II study of gemcitabine and cisplatin in chemotherapy naive, unresectable gall bladder cancer. Br J Cancer 2004;90: Weigt J, Malfertheiner P. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. Expert Rev Gastroenterol Hepatol 2010;4: Okusaka T, Nakachi K, Fukutomi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. Br J Cancer 2010;103: Sasaki T, Isayama H, Nakai Y, Koike K. Current status of chemotherapy for the treatment of advanced biliary tract cancer. Korean J Intern Med 2013;28: Yi JH, Thongprasert S, Lee J, et al. A phase II study of sunitinib as a secondline treatment in advanced biliary tract carcinoma: a multicentre, multinational study. Eur J Cancer 2012;48: Glimelius B, Hoffman K, Sjoden PO, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996;7: Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362: Cassier PA, Thevenet C, Walter T, et al. Outcome of patients receiving chemotherapy for advanced biliary tract or gall bladder carcinoma. Eur J Gastroenterol Hepatol 2010;22: Sasaki T, Isayama H, Nakai Y, et al. Feasibility study of gemcitabine and cisplatin combination chemotherapy for patients with refractory biliary tract cancer. Invest New Drugs 2011;29: Oh SY, Jeong CY, Hong SC, et al. Phase II study of second line gemcitabine single chemotherapy for biliary tract cancer patients with 5-fluorouracil refractoriness. Invest New Drugs 2011;29: Chen JS, Chao Y, Yang TS, et al. A phase II trial of biweekly oxaliplatin with simplified schedule of 48-h infusion of high-dose 5-fluorouracil and leucorvin for advanced biliary tract carcinoma. Cancer Chemother Pharmacol 2009;65: Nehls O, Oettle H, Hartmann JT, et al. Capecitabine plus oxaliplatin as firstline treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial. Br J Cancer 2008;98: