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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 2  |  Page : 42-45

An investigator-initiated study of gemcitabine and capecitabine in Indian patients with unresectable or metastatic gallbladder cancer


1 Department of Medical Oncology, Shalby Hospital, Jaipur, Rajasthan, India
2 Department of Surgical Oncology, Bhagwan Mahaveer Cancer Hospital and Research Centre, Jaipur, Rajasthan, India
3 Department of Medical Oncology, Bhagwan Mahaveer Cancer Hospital and Research Centre, Jaipur, Rajasthan, India

Date of Submission17-Feb-2022
Date of Decision30-May-2022
Date of Acceptance08-Aug-2022
Date of Web Publication29-Aug-2022

Correspondence Address:
Sudhir Palsaniya
Department of Medical Oncology, Shalby Hospital, Jaipur - 302 021, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/oji.oji_8_22

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  Abstract 


Background: Gallbladder cancer (GBC) has a high incidence rate in the Indo-Gangetic belt and is usually presented in the unresectable advanced or metastatic stage. In this study, we evaluated the response rate and toxicities of the gemcitabine plus capecitabine (GEM-CAP)-based combination chemotherapy in unresectable or metastatic GBC patients. Subjects and Methods: This was an investigator-initiated, single-arm, prospective study conducted on unresectable or metastatic GBC patients at Jaipur, India, for 1 year. All the patients received a GEM-CAP combination chemotherapy regimen which consisted of gemcitabine 1000 mg/m2 intravenously over 30 min on days 1 and 8 and capecitabine at 800 mg/m2 orally twice a day for 14 days, administered every 21 days. The response was evaluated in terms of overall response rate (ORR), tumor control rate (TCR), and progression-free survival (PFS). Both quantitative and qualitative toxicities were assessed. Results: A total of 35 patients were enrolled, of which 3 patients were excluded due to treatment interruption. The mean age of patients was 55 (32–80) years, with the majority being female (77.14%), having an ECOG score of 1 (71.43%), and with Stage IVB disease (77.14%). The ORR was 25%, TCR was 50%, and median PFS was 4 months. Major toxicities noted were Grade I and II hematological and nonhematological toxicities, which were managed adequately. Conclusion: The combination therapy of gemcitabine and capecitabine is reasonable, feasible, and well-tolerated approach for the treatment of unresectable advanced and metastatic GBC patients, a disease that had limited treatment options.

Keywords: Capecitabine, gemcitabine, metastatic gallbladder cancer, overall response rate


How to cite this article:
Palsaniya S, Saini S K, Samar A, Patni S, Bapna A. An investigator-initiated study of gemcitabine and capecitabine in Indian patients with unresectable or metastatic gallbladder cancer. Oncol J India 2022;6:42-5

How to cite this URL:
Palsaniya S, Saini S K, Samar A, Patni S, Bapna A. An investigator-initiated study of gemcitabine and capecitabine in Indian patients with unresectable or metastatic gallbladder cancer. Oncol J India [serial online] 2022 [cited 2022 Sep 30];6:42-5. Available from: https://www.ojionline.org/text.asp?2022/6/2/42/354903




  Introduction Top


Gallbladder cancers (GBCs) are the most common cancer among the biliary tract malignancies.[1],[2] Unique features of GBC such as strong gender, ethnic, and geographical propensity suggest the influence of genetic and environmental factors.[3],[4],[5] With an age-standardized rate of 1.4/100,000 population, about 19,500 new cases are seen each year. This incidence is expected to increase by 64.3% by the year 2040.[6] It is among the most common digestive cancers in North Indian women, with the Indo-Gangetic belt being the highest affected region with an incidence of about 21/100,000 population.[7],[8]

Most of GBC patients present at advanced stages with limited treatment options and poor survival. The standard treatment regimen for GBC patients is not clear due to the availability of less randomized studies. In the past, biliary cancer was considered a chemo-resistant disease because 5-fluorouracil-based regimens led to tumor responses in <10% of patients.[9],[10] At present, the standard treatment for advanced GBC patients is gemcitabine-based doublet palliative chemotherapy, in which cisplatin or oxaliplatin being the accompanying drug. Only few studies evaluated the role of gemcitabine-based doublet chemotherapy using capecitabine as the accompanying drug.

Based on the results of previous studies conducted, including the investigator-initiated study of gemcitabine and capecitabine in patients with unresectable or metastatic GBC or cholangiocarcinoma: Southwest Oncology Group Study S0202 by Iqbal et al.,[11] we conducted a prospective/longitudinal study to analyze response and toxicity of this combination chemotherapy in Indian patients with unresectable advanced or metastatic GBC.


  Subjects and Methods Top


This was an investigator-initiated single-arm prospective study conducted for 1 year from July 2017 to June 2018. The unresectable or metastatic GBC patients who attained the department of medical oncology of a tertiary cancer hospital in Jaipur, Rajasthan, were enrolled in the study.

Patients between the ages of >18 and ≤80 years, with cytologically or histopathologically diagnosed advanced or metastatic adenocarcinoma of the gallbladder and untreatable with surgery or radiation, were included. Prior attempted surgery was allowed more than 14 days before registration. Patients with adequate organ function, an ECOG performance status ≤2, the ability to swallow or/and receive enteral medications through gastrostomy feeding tube, and gave their signed consent were included in the study.

Patients with clinically significant cardiac disease not well controlled by medication; pregnant and lactating female patients and patients previously treated for metastatic disease were excluded from the study. Patients may have received prior chemotherapy, hormonal therapy, immunotherapy, radiation therapy (≤25% of bone marrow), or chemoradiotherapy as neoadjuvant or adjuvant treatment. This must have been completed at least 12 months before documented recurrence or metastatic disease.

The patients were treated with gemcitabine plus capecitabine (GEM-CAP)-based combination chemotherapy regimen over a 21-day cycle which consisted of gemcitabine at a fixed dose of 1000 mg/m2 intravenously over 30 min on days 1 and 8 plus tablet capecitabine at 800 mg/m2 orally twice a day for 14 days. The primary objective of this study was to assess the objective response rate in terms of overall response rate (ORR), tumor control rate (TCR), and progression-free survival (PFS). The secondary objective included the evaluation of the quantitative and qualitative toxicities of this chemotherapy regimen. Tumor response to treatment was assessed after completion of each two cycles of chemotherapy (6 weeks), and the response was coded according to Response Evaluation Criteria in Solid Tumors Criteria 1.1. The response parameters are complete response (CR), partial response (PR), stable disease (SD), and progressive disease. The criteria are based on the visual assessment of tumor size in morphological images provided by computed tomography. ORR is defined by the combination of CR and PR. TCR is defined by the combination of CR, PR, and SD. Patients were monitored for toxicity, weekly at the treating physician's discretion and were graded according to the Common Terminology Criteria for Adverse Events Version 5.0.

Patients were recruited for 6 months or till desired sample size was attained and was followed up for the next 6 months. The protocol of the study was reviewed and approved by Institutional Ethics Committee (ECR19/Inst/RJ/2013/RR-16).

Statistical analysis

Continuous variables were summarized as mean and standard deviation, whereas nominal/categorical variables as proportions (%). Paired t-test, repeated measure ANOVA test, and Pearson correlation coefficient were used for the analysis of continuous variables. While the Chi-square test and Fisher's exact test were used for nominal/categorical variables. P < 0.05 is considered statistically significant and Medcalc 16.4 version by Medcalc software ltd. (Belgium) software was used for all statistical analyses.


  Results Top


A total of 35 patients were enrolled in the study. Three patients were excluded from the analysis due to treatment interruption. Hence, the sample size for the study analysis was 32. The basic characteristics of the patients are depicted in [Table 1]. The mean age of patients was 55 (32–80) years, with the majority being female (77.14%), having an ECOG score of 1 (71.43%), and with Stage IV disease (77.14%).
Table 1: Patient and tumor characteristics (n=35)

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Treatment efficacy

Of the 32 patients evaluated, the best response was observed at week 6. The primary intent of the study, which was objective responses to the combination of gemcitabine and capecitabine, is summarized in [Table 2]. The ORR that includes CR and PR was 25%. The TCR that includes CR, PR, and SD was 50%. Median PFS was 4 months [Figure 1].
Figure 1: PFS Kaplan–Meier Plot. PFS: Progression-free survival

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Table 2: Response assessment at week 6 (best response)

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Toxicity

Out of 32 patients, 10 (31.25%) patients had hematological toxicities, and 22 patients (68.75%) had nonhematological toxicities, Two patients (6.25%) had both the toxicities. [Table 3] shows adverse events encountered with grading. Apart from this, one patient (3.13%) developed melena, one patient (3.13%) developed weakness and fatigue, three patients (9.38%) developed hepatic dysfunction (hepatitis), and one patient (3.13%) developed pulmonary symptoms (dry cough).
Table 3: Adverse events

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The most frequent toxicities reported were Grade I and Grade II which included hand–foot syndrome, nausea, vomiting, mucositis, and hematologic toxicity. The Grade III toxicities included nausea (three patients), vomiting (three patients), and neutropenia (one patient). The only Grade IV toxicity reported for two patients was vomiting. The patients who developed Grade III and IV toxicities were hospitalized for supportive care.

Among all, three patients (9.37%) completed 6-month treatment. Twenty-four patients (75%) had progression of disease. Four patients (12.5%) showed poor tolerability, out of which one patient also had progression of disease. One patient (3.13%) had recurrent ascites.


  Discussion Top


The majority of GBC cases (70%–90%) are present at the unresectable advanced or metastatic stage; hence, curative radical surgery cannot be employed in these patients. The standard of care in such patients is palliative chemotherapy using a gemcitabine doublet, with platinum-based chemotherapy commonly being the accompanying drug.[12] ABC-02 trial evaluated cisplatin plus gemcitabine in locally advanced or metastatic biliary cancer. The overall median PFS was 8 months, and in gallbladder tumors (n = 56), the ORR was 32.1%, and tumor control rate of 81.4%.[13] BT-22 trial also analyzed cisplatin plus gemcitabine in biliary tract tumors, with an ORR of 19.5%, tumor control rate of 68.3%, median PFS of 5.8 months, and median OS of 11.2 months. GBC-specific median survival was 9.1 months.[14] From India, Sharma et al. evaluated gemcitabine plus oxaliplatin in unresectable GBC. These patients showed an ORR of 30.7%, tumor control rate of 69.2%, median PFS of 8.5 months, and median OS of 9.5 months.[15] However, Sud et al. reported limited response of gemcitabine and cisplatin in advanced GBC in Indian patients.[16] However, only few studies have evaluated the role of GEM-CAP-based combination chemotherapy in advanced unresectable biliary tract cancers. In this prospective study, we evaluated the role of GEM-CAP-based chemotherapy in advanced unresectable or metastatic GBC patients in an Indian context. The ORR, tumor control rate, and PFS along with toxicities were evaluated.

In our study, the combination of gemcitabine and capecitabine was used and well tolerated with one CR and seven PR, giving an ORR of 25%. The majority of the toxicities were Grade I/II and manageable. Other clinical studies have also evaluated the combination of gemcitabine and capecitabine in unresectable advanced or metastatic GBC or cholangiocarcinoma in different parts of the world. SWOG S0202 study reported an overall response probability of 25%, median OS of 7 months, and 6-month survival rate of 55%.[11] In Canada, Riechelmann et al. observed a response rate of 29% and overall survival of 12.7 months.[17] In South Korea, Cho et al. reported a response rate of 32% and median overall survival of 14 months.[18] Iyer et al. noted a response rate of 16.7% and median overall survival of 14 months.[19]

Limitations of the study

This study addresses important concerns in the treatment of metastatic gallbladder cancer. However, there are certain limitations that can be addressed in future, more elaborate studies. The sample size used in the study is limited. Moreover, this is a single-arm study and future clinical trials with multiple arms can help in refining the data. The study design here allowed up to 6-month follow-up after treatment, and therefore, OS could not be evaluated. In recent years, a number of clinical trials have represented a potential approach for immunotherapy in biliary tract cancers which needs further investigation.


  Conclusion Top


In this study, the response rate toward GEM-CAP combination treatment was consistent with previously published studies. While the combination of gemcitabine with platinum-based chemotherapy remains the standard of care in these patients, gemcitabine and capecitabine are reasonable alternatives. Further research is warranted involving novel targeted therapy in biliary cancer to improve patient outcomes. Chemotherapy regimens, including GEM-CAP, remain a reasonable treatment option for now.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Iqbal S, Rankin C, Lenz HJ, Gold PJ, Ahmad SA, El-Khoueiry AB, et al. A phase II trial of gemcitabine and capecitabine in patients with unresectable or metastatic gallbladder cancer or cholangiocarcinoma: Southwest Oncology Group study S0202. Cancer Chemother Pharmacol 2011;68:1595-602.  Back to cited text no. 11
    
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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.  Back to cited text no. 13
    
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Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi 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;103:469-74.  Back to cited text no. 14
    
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Iyer RV, Gibbs J, Kuvshinoff B, Fakih M, Kepner J, Soehnlein N, et al. A phase II study of gemcitabine and capecitabine in advanced cholangiocarcinoma and carcinoma of the gallbladder: A single-institution prospective study. Ann Surg Oncol 2007;14:3202-9.  Back to cited text no. 19
    


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