Abstract

Background: Carcinoma gallbladder is mostly diagnosed in locally advanced, inoperable, or metastatic stage. Best supportive care with or without palliative chemotherapy is the only feasible treatment option. Gemcitabine and platinum agents' combination is the most effective first option with no well-established second-line regimen. Objectives: We planned to study the response rate, safety, the progression-free survival (PFS), and overall survival (OS) on the second-line FOLFOX-4 chemotherapy. Methods: This is a prospective single-arm observational study of 29 eligible patients. Patients were studies for response to the second-line FOLFOX-4 chemotherapy. Positron emission tomography/computed tomography scans were done for response assessment; chemotherapy toxicity was graded using National Cancer Institute clinical toxicity criteria; and survival rates (PFS and OS) were studied. Results: Among the 39 patients with gemcitabine-based chemotherapy (CT-1), the median PFS-1 was 6.5 months. Twenty-nine patients received second-line chemotherapy (CT-2). Responses observed complete response in 2/29, partial response in 7/29, stable disease in 1/29 patients, and progressive disease in 19/29. The overall response rate was 9/29 (31.0%). Grades 2–4 toxicities were anemia (17.95%), thrombocytopenia (12.82%), neutropenia (12.82%), and peripheral neuropathy (7.69%). The median OS was 9.13 months. Late PFS-1 (>median PFS-1) patients had significantly lower mortality as compared to early PFS-1, odds ratio of 0.251 (P = 0.002), and median PFS-2 was 2.53 months. Conclusion: After the failure of gemcitabine and platinum-based chemotherapy, FOLFOX-4 is modestly effective, fairly well tolerated and this needs to be proven in a larger randomized phase 3 study. Further research into the pathogenesis of biliary tract cancer with the aim to identify new targets for treatments is required.

Introduction

Carcinoma gallbladder is a dreaded disease with dismal prognosis. Most of the patients are diagnosed in advanced inoperable stage, and best supportive care (BSC) with or without palliative chemotherapy is the only feasible treatment option.

At present, cytotoxic chemotherapy comprising a combination of gemcitabine and cisplatin is held as the most effective first-line regimen,[1] providing a tumor control rate of 81.4%, median progression-free survival (PFS) of 11.7 months versus gemcitabine alone (71.8%, 8.1 months), as reported by the phase 3 ABC-02 study.

GEM-OX is another well-accepted first-line regimen with nearly similar efficacy and less toxicity, as evidenced in the phase 2 study by Sharma et al.[2] After disease progression on the first-line chemotherapy, the efficacy of the second-line chemotherapy is less well established with no definitive recommendations.

We planned to study the tumor response rate, safety, the PFS, and overall survival (OS) on the second-line FOLFOX-4 chemotherapy.

Methods

This was a prospective single-arm, single-center, observational study. The study was conducted over a period of 2 years from July 2014 to June 2016.

Inclusion criteria are as follows:

• Histologically/cytologically confirmed, nonresectable or recurrent/metastatic adenocarcinoma of the gallbladder

• Who had failed one prior course of gemcitabine-based chemotherapy

• Eastern Cooperative Oncology Group performance status (ECOG-PS) 0–2

• Adequate bone marrow reserves and acceptable renal and liver functions (serum creatinine <1>

Thirty eligible patients were planned to be enrolled for the second-line chemotherapy in this study. Eligible patients who progressed on gemcitabine and platinum-based chemotherapy (CT-1) were treated using the FOLFOX regimen (CT-2). This regimen consisted of:

• Oxaliplatin (85 mg/m2) and leucovorin (200 mg/m2) on day 1, followed by a 5-FU bolus (400 mg/m2/day) and 22-h infusion of 5-FU (600 mg/m2/day) for 2 consecutive days.

Each cycle consisted of two doses of chemotherapy, 2 weeks apart. Tumor response was radiologically assessed with positron emission tomography and/or Computed tomography scan after 3 and 6 cycles of chemotherapy using the PERCIST and RECIST criteria version 1.1. Toxicity of chemotherapy was graded using standard CTC criteria on clinical examination and blood investigation reports. The overall response rate (ORR) was calculated as the sum of rates of partial response (PR) and complete response (CR).

PFS was defined as the time from start of treatment to the first radiologic confirmation of disease progression, or death from any cause within 60 days after the last assessment, whichever came first. PFS on the first-line gemcitabine and platinum-based chemotherapy (CT-1) was designated as “PFS-1,” and PFS on the second-line FOLFOX regimen (CT-2) was designated as “PFS-2.” OS was defined as the time period from the first administration of study treatment (CT-1) to death from any cause.

Data analysis

The median OS and PFS were estimated using the Kaplan–Meier method, Kaplan–Meier with log rank test. Univariate cox proportional hazard regression analysis of the link between each variable and OS was performed, and univariate logistic regression analysis was performed to find the risk factors of early recurrence. A value of P < 0>

Results

A total of 58 patients of CA GB were enrolled for the management during study period. Ninety-five percent patients (56 out of 58) had adenocarcinoma histology. One patient had adenosquamous histology and one had neuroendocrine carcinoma and both were not eligible for this study. Of this cohort, another 19 patients could not receive any chemotherapy due to their poor general condition or no patient consent. Thus, a total of 39 patients could receive the first-line chemotherapy (CT-1). The population included 28 females and 11 males (ratio, 2.6:1), with a median age of 54 years (range, 34–72 years). About 87.1% of eligible patients had an ECOG PS of 0–1. [Figure 1a], [b], [c] depicts the study population characteristics.

| Figure 1 Age distribution of population. (b) Disease status of patients. (c) Histopathology grade of carcinoma gallbladder

A total of 39 patients who received CT-1 (gemcitabine plus cisplatin or carboplatin) the PFS-1 ranged from 1.43 to 16.57 months with a median PFS-1 of 6.5 months [Figure 2]. All of these patients progressed on or after completion of gemcitabine-based first-line chemotherapy. Twenty-nine of these 39 patients fulfilled the eligibility criteria for the second-line chemotherapy and the rest were either in poor general condition or refused further chemotherapy. The best tumor response observed was CR in 2/29 patients, PR in 7/29 patients, SD in 1/29 patients, and 19/29 patients had PD with no radiological response at all. Thus, the ORR (rate of PR + SD) was 9/29, i.e., 31.0% only. Patients were followed at regular intervals until progression or death till the study cutoff date. The PFS-2 ranged from 1.27 to 9.33 months [Figure 3], with a median PFS-2 of 2.53 months. Forty-one percent of the patients developed Grades 2–4 toxicities.

| Figure 2 Kaplan–Meier curve depicting progression-free survival-1, which ranged from 1.4 to 14.9 months with a median progression-free survival-1 of 6.5 months

| Figure 3 Kaplan–Meier curve depicting progression-free survival-2, which ranged from 1.27 to 9.33 months, with a median progression-free survival-2 of 2.53 months

The most common Grade 3 or 4 toxicities observed were anemia (17.95%), thrombocytopenia (12.82%), neutropenia (12.82%), peripheral neuropathy (7.69%), hand-foot syndrome (2.56%), and electrolyte imbalance (2.56%). Dose reduction by 25% was needed in one-third of our study patients [Figure 4].    

| Figure 4 Toxicity profile of the second-line FOFOX-4 in carcinoma gallbladder patients

At the end of study period, six patients were alive (OS not reached). The median OS among the rest was 9.13 months. On univariate analysis, it was observed that late PFS-1 patients have significantly lower chances of death as compared to early PFS-1 with an odds ratio (OR) of 0.251 (P = 0.002) [Figure 5].

| Figure 5 Kaplan–Meier curve depicting overall survival. The median overall survival among the rest was 9.13 months

Discussion

There are limited clinical data to suggest a clinical benefit of the second-line chemotherapy in advanced biliary tract cancer, and there is no regimen considered as standard in this setting. In our study, the ORR was 31.0%. He et al. have reported an ORR of 21.6% to FOLFOX chemotherapy [3] whereas Ramaswamy et al.[4] from Mumbai have reported an ORR of 21.8% to CAPIRI chemotherapy. The multicenter French study by Brieau et al.,[5] which used multiple CT-2 regimens, reported ORR ranging from 10% to 13.5% with no statistically significant difference between the various CT-2 regimens. This numerically large difference in ORR between our study and the French study, however, did not translate into much difference in survival data (PFS and OS). The median PFS for the second-line chemotherapy was 2.53 months in our study. The median PFS reported by Brieau et al.[5] and Fiteni et al.[6] are 3.40 and 4.0 months, respectively, to various second-line chemotherapy regimens. This is quite similar to our observation, suggesting that probably there is not much difference in efficacy among the various 5FU, capecitabine, oxaliplatin, and irinotecan-based mono- or polychemotherapy regimens. Ramaswamy et al.[4] from Mumbai have reported a median PFS of 6.0 months with CAPIRI regimen. However, the superior PFS reported by them did not translate into superior OS. The median OS was 9.1 months in our study. The median survival reported by Brieau et al.[5] and Ramaswamy et al.[4] were 6.7 and 8.0 months, respectively.

In Mane et al.[7] phase-2 study, capecitabine with oxaliplatin regimen was studied in 17 cases of unresectable biliary tract cancer in the second-line setting. They have reported a disease control rate of 22%, PFS of 15 weeks (95% CI: 6.6–23.3), and OS of 19 weeks (95% CI: 10.4–27.5). These survival data are similarly dismal and emphasize the unmet need for effective second-line chemotherapy regimens.

Grade 3 or 4 toxicity was observed in 31% of patients in the current study, necessitating dose reduction by 20% in these cases. Only one patient could not be continued on chemotherapy due to Grade 4 myelo-Univariate analysis-patients having late PFS-1 (more than 6.5 months) have significantly lower chances of death as compared to early PFS-1 with an OR of 0.251 (P = 0.002). Logrank test also inferred that mortality is significantly higher in patients who progressed earlier on the first-line chemotherapy (with PFS-1 less than the median PFS-1 of 6.5 months, P < 0>

Brieau et al.[5] observed CA 19.9 level >400 IU/ml, ECOG-PS 2 or higher and median PFS <6>

1.  Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A. et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273-81
2.  Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V. et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: A randomized controlled study. J Clin Oncol 2010; 28: 4581-6
3.  He S, Shen J, Sun X, Liu L, Dong J. A phase II FOLFOX-4 regimen as second-line treatment in advanced biliary tract cancer refractory to gemcitabine/cisplatin. J Chemother 2014; 26: 243-7
4.  Ramaswamy A, Ostwal V, Pande N, Sahu A, Jandyal S, Ramadwar M. et al. Second-line palliative chemotherapy in advanced gall bladder cancer, CAP-IRI: Safe and effective option. J Gastrointest Cancer 2016; 47: 305-12
5.  Brieau B, Dahan L, De Rycke Y, Boussaha T, Vasseur P, Tougeron D. et al. Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum combination: A large multicenter study by the Association des Gastro-Entérologues Oncologues. Cancer 2015; 121: 3290-7
6.  Fiteni F, Jary M, Monnien F, Nguyen T, Beohou E, Demarchi M. et al. Advanced biliary tract carcinomas: A retrospective multicenter analysis of first and second-line chemotherapy. BMC Gastroenterol 2014; 14: 143
7.  Mane J, Iruarrizaga E, Rubio I, Fonseca E, Iza R, Casas I. et al. Second-line chemotherapy with capecitabine (CAP) and oxaliplatin (OX) in patients with pancreatic or biliary tree adenocarcinoma (ADC). 2011 Gastrointestinal Cancers Symposium. J Clin Oncol 2011;29 Suppl 4:Abstract 308

| Figure 1 Age distribution of population. (b) Disease status of patients. (c) Histopathology grade of carcinoma gallbladder

| Figure 2 Kaplan–Meier curve depicting progression-free survival-1, which ranged from 1.4 to 14.9 months with a median progression-free survival-1 of 6.5 months

| Figure 3 Kaplan–Meier curve depicting progression-free survival-2, which ranged from 1.27 to 9.33 months, with a median progression-free survival-2 of 2.53 months

| Figure 4 Toxicity profile of the second-line FOFOX-4 in carcinoma gallbladder patients

| Figure 5 Kaplan–Meier curve depicting overall survival. The median overall survival among the rest was 9.13 months

1.  Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A. et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273-81
2.  Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V. et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: A randomized controlled study. J Clin Oncol 2010; 28: 4581-6
3.  He S, Shen J, Sun X, Liu L, Dong J. A phase II FOLFOX-4 regimen as second-line treatment in advanced biliary tract cancer refractory to gemcitabine/cisplatin. J Chemother 2014; 26: 243-7
4.  Ramaswamy A, Ostwal V, Pande N, Sahu A, Jandyal S, Ramadwar M. et al. Second-line palliative chemotherapy in advanced gall bladder cancer, CAP-IRI: Safe and effective option. J Gastrointest Cancer 2016; 47: 305-12
5.  Brieau B, Dahan L, De Rycke Y, Boussaha T, Vasseur P, Tougeron D. et al. Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum combination: A large multicenter study by the Association des Gastro-Entérologues Oncologues. Cancer 2015; 121: 3290-7
6.  Fiteni F, Jary M, Monnien F, Nguyen T, Beohou E, Demarchi M. et al. Advanced biliary tract carcinomas: A retrospective multicenter analysis of first and second-line chemotherapy. BMC Gastroenterol 2014; 14: 143
7.  Mane J, Iruarrizaga E, Rubio I, Fonseca E, Iza R, Casas I. et al. Second-line chemotherapy with capecitabine (CAP) and oxaliplatin (OX) in patients with pancreatic or biliary tree adenocarcinoma (ADC). 2011 Gastrointestinal Cancers Symposium. J Clin Oncol 2011;29 Suppl 4:Abstract 308