Key Points
Question
Does combination chemotherapy with capecitabine plus irinotecan (CAPIRI) improve overall survival (OS) compared with irinotecan monotherapy in patients with advanced gallbladder cancer who have received prior treatment with a gemcitabine-platinum regimen?
Findings
Use of a CAPIRI regimen did not improve OS compared with irinotecan; more patients in the CAPIRI arm required dose modification compared with those in the irinotecan arm.
Meaning
Combination chemotherapy did not improve OS compared with single-agent chemotherapy in previously treated patients with advanced gallbladder cancer.
This randomized clinical trial compares the efficacy of capecitabine plus irinotecan vs irinotecan alone in patients with advanced gallbladder cancer who had disease progression after gemcitabine-based first-line treatment.
Abstract
Importance
There is therapeutic uncertainty regarding use of combination or single-agent chemotherapy in the treatment of patients with gallbladder cancer who experience disease progression after first-line chemotherapy.
Objective
To compare the efficacy of capecitabine plus irinotecan (CAPIRI) vs irinotecan (IRI) alone in patients with advanced gallbladder cancer (GBC) who have disease progression after gemcitabine-based first-line treatment.
Design, Setting, and Participants
The GB-SELECT trial was a multicenter, open-label, phase 2, randomized clinical trial of CAPIRI vs IRI alone for treatment of gallbladder cancer in patients who had disease progression after prior gemcitabine-based chemotherapy.The study was carried out in 2 tertiary care institutions in India. Patients aged between 18 and 70 years with histopathologic diagnosis of adenocarcinoma gallbladder, advanced or metastatic disease, previous treatment with gemcitabine-based chemotherapy, adequate hematologic, liver, and renal functions, and ECOG performance status of 1 or less were included in the study between August 2018 and January 2020. The data were analyzed for this report with cutoff on May 19, 2020.
Interventions
Patients were randomized 1:1 to receive capecitabine, 1700 mg/m2 per day, on days 1 to 14 plus intravenous irinotecan, 200 mg/m2, on day 1 or intravenous irinotecan, 240 mg/m2, on day 1, in 21-day cycles until disease progression or unacceptable toxic effects.
Main Outcomes and Measures
The primary end point was overall survival (OS) at 6 months. The secondary end points were progression-free survival and quality of life.
Results
A total of 98 patients were randomized, 49 in each arm, with median (range) age of 51 (29-70) years, with 60 (61%) being women. In the CAPIRI vs IRI arms, the number of deaths at 6 months, 6-month OS, and median OS were 35, 34, 38.4% (95% CI, 24.2%-52.6%) and 5.16 (95% CI, 4.26-6.06) months vs 34, 29, 54.2% (95% CI, 39.4%-69.0%) and 6.28 (95% CI, 4.25-8.30) months, respectively, with a hazard ratio of 1.02 (95% CI, 0.64-1.49, P = .93). There were no chemotherapy-related deaths but more patients required dose modification in CAPIRI compared with the IRI arm (13 [27%] vs 4 [9%], respectively, P = .03).
Conclusions and Relevance
There was no significant difference in OS between treatment with capecitabine plus irinotecan or irinotecan alone among previously treated patients with gallbladder cancer. Single-agent irinotecan should be the preferred treatment option for such patients.
Trial Registration
Introduction
Patients with gallbladder cancer commonly present in an advanced stage where the current standard treatment is chemotherapy with a gemcitabine-platinum doublet regimen.1,2,3 Most patients experience disease progression within 4 to 8 months of initiating treatment, and 20% to 30% of them retain good performance status after disease progression.2,4 Such patients are offered chemotherapy regimens commonly used in gastrointestinal cancers. There is currently insufficient evidence in this setting on the comparative efficacy and toxic effects of combination vs single-agent chemotherapy, especially in patients with gallbladder cancer. Commonly used regimens include mFOLFOX, capecitabine plus irinotecan, or single-agent irinotecan.5,6,7,8
Methods
The trial protocol is available in Supplement 1. This study was designed as a multicenter, open-label, phase 2, randomized clinical trial to evaluate the superiority of capecitabine plus irinotecan (CAPIRI) compared with single-agent irinotecan (IRI) in patients with advanced or metastatic gallbladder cancer who had disease progression after treatment with a first-line gemcitabine-based chemotherapy regimen. Patients had to be aged between 18 and 70 years, with adenocarcinoma histologic analysis results, with adequate hematologic, liver, and renal functions, and Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less, to be eligible for study inclusion. Written informed consent was obtained from all study participants. The study was reviewed and approved by the respective institutional ethics committees at Tata Memorial Centre, Mumbai (IEC/0520/1849 ) and All India Institute of Medical Sciences, New Delhi, India (IEC-51/02.02.2018, RP-12/2018).
Quality-of-life (QOL) assessments were performed at baseline and every 6 to 8 weeks using the Functional Assessment of Cancer Therapy-Hepatobiliary Cancer (FACT-Hep) version 4 questionnaire.
Patients were centrally randomized in a 1:1 ratio, with block size of 4, to the CAPIRI or IRI arms, using a concealed list. Patients in the CAPIRI arm received oral capecitabine, 1700 mg/m2 per day, on days 1 to 14 plus intravenous irinotecan, 200 mg/m2, on day 1 while those in the IRI arm received intravenous irinotecan 240 mg/m2 on day 1, every 3 weeks until documented disease progression or unacceptable toxic effects.
The primary end point of the study was percentage overall survival (OS) at 6 months, with OS defined as time period from randomization to death due to any cause. The secondary end points were progression-free survival (PFS), objective tumor response rate, and QOL.
A sample size of 98 was considered adequate to detect an increase in 6-month OS from 55% in the IRI arm to 70% in the CAPIRI arm with an alpha error of 0.1 and power of 80%, using a 2-sided log-rank test, and accounting for 10% attrition. The primary analysis was planned when at least 68 events (deaths) had occurred. Overall OS and PFS were assessed in the intention-to-treat population.
Further details of eligibility criteria, study procedures, study treatments, randomization, end point definition, and statistical analysis are included the eAppendix in Supplement 2.
Results
Between August 2018 and January 2020, 147 patients were evaluated for enrolment, of whom 98 were randomly assigned in the study, 49 in each arm (Figure 1), with a median follow-up in surviving patients of 7.33 (4.17-20.27) months at data cutoff on May 19, 2020. All included patients were available for efficacy and safety analyses and the study arms were balanced with respect to baseline characteristics (eTable 1 in Supplement 2).
Figure 1. CONSORT Diagram.
CAPIRI indicates capecitabine plus irinotecan.
In the CAPIRI vs IRI arms, the number of deaths at 6 months, 6-month OS, and median OS were 35, 34, 38.4% (95% CI, 24.2%-52.6%) and 5.16 (95% CI, 4.26-6.06) months vs 34, 29 54.2% (95% CI, 39.4%-69.0%) and 6.28 (95% CI, 4.25-8.3) months, respectively, with an unadjusted hazard ratio of 1.02 (95% CI, 0.64-1.49; P = .93) (Figure 2A). Forty-two (85.7%) patients each, in the CAPIRI and IRI arms, had documented PFS events with median PFS of 2.27 (95% CI, 1.37-3.17) months and 3.12 (95% CI, 1.04-5.20) months, respectively, and an unadjusted hazard ratio of 1.11 (95% CI, 0.72-1.72; P = .63) (Figure 2B).
Figure 2. Kaplan-Meyer Curves for Overall and Progression-Free Survival.
A, Overall survival for capecitabine plus irinotecan (CAPIRI) vs irinotecan alone. B, Progression-free survival for CAPIRI vs irinotecan alone. HR indicates hazard ratio.
At the time of analysis, 43 patients in the CAPIRI arm and 42 patients in the IRI arm had discontinued treatment. In the CAPIRI and IRI arms, the mean (range) number of chemotherapy cycles were 3 (1-17) and 4 (1-14), respectively, whereas dose modifications due to toxic effects were required in 13 (27%) patients and 4 (9%) patients, respectively, which was statistically significant (P = .02). Numerically, the CAPIRI arm had an increased incidence of any grade toxic effects (92% vs 82%; P = .31), grade 3/4 toxic effects (42% vs 30%; P = .21), grade 3/4 febrile neutropenia (12% vs 6%; P = .29), grade 3/4 fever (16% vs 8%; P = .22), and any grade fatigue (84% vs 69%; P = .21), whereas the incidence of any grade nausea and/or vomiting (28% vs 45%; P = .27) was numerically higher in the IRI arm. None of these differences were statistically significant (Table).
Table. Adverse Events.
| Toxic Effect | No. (%) | |||
|---|---|---|---|---|
| CAPIRI | Irinotecan | |||
| All grades | Grade 3 or 4 | All grades | Grade 3 or 4 | |
| Hematologic | ||||
| Thrombocytopenia | 7 (14) | 2(4) | 10 (20) | 2 (4) |
| Neutropenia | 8 (16) | 3 (6) | 7 (14) | 3 (6) |
| Febrile neutropenia | 6 (12) | 3 (6) | ||
| Anemia | 23 (47) | 2 (4) | 23 (47) | 1 (2) |
| Nonhematologic | ||||
| Fever | 0 | 8 (16) | 0 | 4 (8) |
| Diarrhea | 17 (35) | 5 (10) | 12 (24) | 4 (8) |
| Nausea and vomiting | 14 (28) | 1 (2) | 22 (45) | 5 (10) |
| Fatigue | 41 (84) | 6 (12) | 34 (69) | 5 (10) |
| Cumulative toxicities | 45 (92) | 21 (42) | 40 (82) | 15 (30) |
Abbreviation: CAPIRI, capecitabine plus irinotecan.
The estimated mean value of delta FACT-HEP at 2 months in the CAPIRI and IRI arms were 19.44 (standard error = 5.72) and 12.65 (standard error = 4.81), respectively, with no significant difference (1, 21 = 0.80, P = .38) (eFigure 1 in Supplement 2).
Discussion
The results of this randomized clinical trial suggest that there was no difference in OS and progression-free survival between doublet chemotherapy, CAPIRI, and monotherapy, IRI, in patients with advanced gall bladder cancer who had disease progression on gemcitabine-based first-line chemotherapy. Irinotecan-based regimens were selected in the study to avoid potential cross-resistance with platinum-based regimens, which are commonly used as first-line treatment and because of their known safety and efficacy profile in gastrointestinal cancers.9,10
There could be multiple reasons for the lack of OS improvement with CAPIRI in this study. These include compromised ability to deliver full-dose treatment, with 13 (27%) patients in the CAPIRI arm requiring dose modification, and the low potential efficacy of 5–fluorouracil and its analogue capecitabine in biliary tract cancers because of high expression of thymidylate synthase.11,12
Previous second-line studies have aggregated various biliary tract cancers together despite their variable biological characteristics and natural histories,5,7 making it difficult to apply the results to any particular group of patients. The strength of our study is inclusion of only gallbladder cancer patients. ABC-06 trial of second-line chemotherapy in patients with advanced biliary tract cancers, including 21% patients with gallbladder cancer, showed that the modified FOLFOX regimen significantly improved overall survival compared with active symptom control (6-month OS, 50.6% and 35.5%, respectively; P = .031).5 The 6-month OS in the modified FOLFOX arm of ABC-06 trial and the irinotecan arm of our study are very similar (50.6% and 54.2%, respectively), suggesting, with the caveat of a cross-trial comparison, that combination chemotherapy may not be more efficacious than single agent treatment in these patients.
The smaller phase 2 study of second-line chemotherapy from China in patients with advanced biliary tract cancers suggested a survival benefit of CAPIRI compared with single agent irinotecan but predominantly included patients with cholangio carcinomas.7
With no substantial differences in either response or survival it is not surprising that there was also no difference in patient reported outcomes between the 2 arms in our study. Given these considerations it is important that the treatment regimen with lesser toxicity and better tolerability is chosen as the preferred treatment regimen in these advanced stage patients.
Limitations
Our study has some limitations. The sample size was small and based on a phase 2 design with higher type-1 error and larger planned effect size. However, this design was considered feasible because only a relatively small proportion of patients with advanced gallbladder cancer are able to receive second-line therapy.
Conclusions
In this randomized clinical trial, there was no significant difference in OS between CAPIRI and irinotecan in patients with advanced gallbladder cancer who have disease progression after prior gemcitabine-based treatment. Single-agent irinotecan should be the preferred treatment option for these patients and the control arm for future studies.
Trial protocol
eMethods. Search strategy for Medline (using PubMed)
eTable 1. Baseline characteristics
eTable 2. Efficacy
eTable 3. Longitudinal analysis of CA 19-9 levels and Chemotherapy related adverse events
eFigure 1. Patient-reported outcomes
eFigure 2. Longitudinal changes in CA 19-9 with chemotherapy
Data sharing statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
eMethods. Search strategy for Medline (using PubMed)
eTable 1. Baseline characteristics
eTable 2. Efficacy
eTable 3. Longitudinal analysis of CA 19-9 levels and Chemotherapy related adverse events
eFigure 1. Patient-reported outcomes
eFigure 2. Longitudinal changes in CA 19-9 with chemotherapy
Data sharing statement