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ORIGINAL ARTICLE
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A comparative study of gemcitabine and cisplatin versus oral capecitabine alone in metastatic gallbladder cancer


1 Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh; Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Radiotherapy and Radiation Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Date of Submission20-Oct-2019
Date of Decision11-Feb-2020
Date of Acceptance22-Apr-2020
Date of Web Publication23-Oct-2021

Correspondence Address:
Deepak Kumar,
H19/95, Rohini, Sector -7, New Delhi
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_896_19

 > Abstract 


Aims: There is no consensus for palliative chemotherapy regimen in metastatic gallbladder cancer. We did a retrospective study to compare the treatment outcome in patients of metastatic gallbladder cancer treated with either gemcitabine + cisplatin (regimen A) or oral capecitabine (regimen B) alone.
Subjects and Methods: A total of 67 patients between January 2015 and September 15 treated with either regimen A or regimen B were retrospectively evaluated. Statistical analysis was done in June 2019. Kaplan–Meir and Log rank test were used to compare survival between two arms.
Results: Out of 67 patients, 31/67 (46%) received regimen A, and 36/67 (54%) received regimen B. Male to female ratio was 1:3. About 42% patients in regimen A and 20% in regimen B required palliative stenting. Median number of chemotherapy cycles was 4 in both regimen A (range 1->6) and regimen B (range 1->6). Patients receiving 3 cycles and 6 cycles of chemotherapy in regimen A and regimen B was 68% and 31% versus 70% and 63%, respectively (P = 0.86). Response assessment as any response (complete response + partial response + disease was stable) after 3 cycles and 6 cycles was 71% and 57% (P = 0.20), 44% and 39% (P = 0.29), in regimen A and B, respectively. Median survival was 23 weeks (range 2–106 weeks) in regimen A and 15 weeks (range 4–83 weeks) in regimen B (P = 0.40).
Conclusions: The present study shows gemcitabine and cisplatin has nonsignificant better survival compared to oral capecitabine. However, oral capecitabine is more convenient and easy to administer. Studies with larger sample size are needed to further establish the standard chemotherapy guidelines.

Keywords: Capecitabine, gallbladder cancer, gemcitabine, metastasis, palliative chemotherapy



How to cite this URL:
Kumar D, Rastogi N, Agarwal S, Mishra S, Kumar S, Lal P, Singh S, Choudhary S. A comparative study of gemcitabine and cisplatin versus oral capecitabine alone in metastatic gallbladder cancer. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 6]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=329058




 > Introduction Top


Worldwide gallbladder cancer has its highest incidences in Japan, Korea, Latin America, few part of Eastern Europe and India.[1] Globally, the total incidence is about 219,420 as 1.2% of all cancer site, and with total mortality of 165,087 consisting of 1.7% of all site as per the GLOBOCAN 2018 data.[2] In India, there is wide geographical variation in incidences with higher incidences in Northern (Gangetic belt) and Northeast part compared to Southern part of the country.[3],[4]

Metastatic gallbladder cancer is defined as disease presentation with any T with N2 or M1 (Stage IVB) as per AJCC 8th edition TNM staging system.[5] Data from few studies reported, 60%–70% patients in India present with Stage IV disease and approximately one-third of the patient has metastatic disease (Stage IVB) at presentation.[6],[7] Patients at this stage of disease mostly present with severe abdominal pain, jaundice, loss of appetite, or with cancer cachexia and prognosis at this stage is dismal.

There is no definitive consensus to manage patients of metastatic gallbladder cancer. However, effective strategy for management can be either palliative chemotherapy, with or without palliative radiotherapy or best supportive care depending on age, performance status, comorbidity, disease burden, and outcome of disease.

Palliative chemotherapy regimen exclusively in metastatic gallbladder cancer is not well established. Phase II/III studies in advance biliary tract cancer has supported gemcitabine and cisplatin as most effective chemotherapy compared to other regimens.[8],[9]

However, majority of the studies which had addressed this issue has included patients mostly with advance biliary tract cancer. These includes malignancy arising from gall bladder, bile duct, and advance pancreatic cancer and among them prognosis are not equivalent. As compared among different sites of origin of biliary tract cancer, it is well known fact that gallbladder cancer is most aggressive with poor clinical outcome.

Hence, we did a retrospective review of patients which were chemotherapy naïve metastatic gallbladder cancer. The aim was to study whether patients receiving gemcitabine and cisplatin or oral capecitabine alone, shows a difference in terms of survival, response and compliance to the treatment.


 > Subjects and methods Top


We searched the patient database registered to our department from January 2015 to November 2015. We selected patients which had histological proof or radiological evidence of metastatic disease at presentation and had received palliative chemotherapy with or without palliative radiotherapy as treatment option. Patients who had surgical excision of gallbladder in past for either benign or malignant disease and were chemotherapy naïve were also included. Patients who had received either of two different chemotherapy regimen as gemcitabine and cisplatin (regimen A) or single-agent oral capecitabine (regimen B) alone were identified. Choice of chemotherapy regimen depends on physician preference and their practice and was not dependent on patient or tumor characteristics. Patients who had received at least 1 cycle of chemotherapy were included. Total sixty-seven (n = 67) cases were identified for this study.

Patients treated with curative intent in combination of surgery, radiotherapy, or with chemotherapy were excluded. The patient managed with best supportive care upfront and histology other than adenocarcinoma was also excluded.

Patterns of care of selected patients were studied with respect to tumor characteristics, site and number of metastasis, requirement of biliary stenting, type of treatment and compliance to treatment and overall survival (OS). The patient either lost to follow-up or dead is considered as an event.

Analysis was done in June 2019 using SPSS version 16 (SPSS Inc., Chicago, IL, USA 2007).

Ethical clearance is not required as the study was retrospective.

Treatment

The patient received palliative chemotherapy either as gemcitabine 1 g/m2 D1 and D8 and cisplatin 25 mg/m2 D1 and D8, repeated at 3 weekly cycle (regimen A) or oral capecitabine 1650 mg/m2 in two divided doses for 14 days repeat at 3 weekly cycle (regimen B). Patients were first assessed after 2–3 cycles of chemotherapy with their baseline investigation and chemotherapy were continued if there was symptomatic or objective response as complete response (CR), partial response (PR), or Stable disease (SD) along with the tolerance of drug to patient. Patients were re-assessed after completion of 6 cycles of chemotherapy and continuation of further cycles were done based on response, tolerance to drug and outcome of treatment. Patients having progression after first-line chemotherapy were either switched to second-line chemotherapy or were kept on best supportive care depending on disease burden and performance status. Radiation therapy (RT) as either palliative dose or curative dose was also given depending on response to treatment or symptoms of patients.

Response assessment

Tumor response was done as per the World Health Organization standard response criteria.[10] A CR was defined as complete absence of all measurable or evaluable disease and no appearance of new lesion for at least 4 weeks. A PR defined as 50% or more decrease in size of lesion and no appearance of new lesion for at least 4 weeks. A no change or stable disease (SD) defined when 50% decrease in size of measurable lesion cannot be established nor 25% increase in size of measurable lesion. Progressive disease (PD) as 25% or more increase in size of measurable lesion or appearance of new lesion.[10] The percentage of response rate determined as any response by the addition of CR, PR, and SD (CR + PR + SD). Response assessment was done after 3 cycles and again after completion of 6 cycles of chemotherapy. Patients receiving <3 cycles were evaluated for survival analysis only.

Statistical analysis

Primary endpoint was OS. Secondary endpoints were response rate and compliance to treatment. Survival was calculated from the date of registration to last follow-up. Survival curve is obtained from Kaplan–Meir methods and comparison of survival was done through log rank test. P ≤0.05 was considered statistically significant.


 > Results Top


A total of 67 patients were studied and out of which 31 patients received Gemcitabine and cisplatin (regimen A), and 36 patients received oral capecitabine (regimen B). Patient's characteristics are described in [Table 1]. Male to female ratio of 1:3 were noted. The median age of presentation was 55 years. About 22% (15/67) patients presented with jaundice alone, while 10% (7/67) presented with gastric outlet obstruction along with jaundice. Hence, 29% (20/67) required either biliary stenting or combined antroduodenal stenting with biliary stenting. There was no difference in patient characteristics between two regimen arms. Patient with de novo origin of metastatic tumor were the most common (70%) and among them, 40% (27/67) of patients presented with both N2 and M1. Liver was the most common site of metastasis [Table 2].
Table 1: Patient characteristics receiving two different chemotherapy regimen

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Table 2: Tumor characteristics in two different chemotherapy regimen

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Total 18% (12/67) patients received palliative radiotherapy as 20 Gy/5 fractions in 1 week to symptomatic site along with chemotherapy [Table 3]. One patients in regimen B had CR after 3 cycles of chemotherapy and so radical RT 50.4 Gy/28 fractions in 5½ weeks was given to primary disease site. Median number of chemotherapy cycles were 4 in both the arms (range 1->6). More than two third of patients received at least 3 cycles of chemotherapy.

Response assessment after 3 cycles defined as any response (CR + PR + SD) in regimen A and B, were 71% (15/21) and 57% (16/28), respectively [Table 4]. Further after 6 cycles, it was 44% (7/16) and 39% (9/23), in regimen A and B, respectively. No difference was seen with respect to response to two different chemotherapy regimens.

About 84% of patients were lost to follow-up. These all patients were considered dead as disease has poor prognosis. Median survival was 23 weeks in regimen A (range, 2–106), 15 weeks in regimen B (range, 4–83) (log rank P = 0.40) [Table 5] and [Figure 1].
Table 3: Treatment characteristics and compliance between two chemotherapy regimens

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Table 4: Response assessment

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Table 5: Survival and patient status at last follow-up

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Figure 1: Kaplan–Meir survival curve in weeks of patients receiving gemcitabine and cisplatin (regimen A) or oral capecitabine alone (regimen B)

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 > Discussion Top


Carcinoma gallbladder is considered a disease of elderly. Palliative chemotherapy is one of the treatment options for patients with metastatic gallbladder cancer. Majority of patients are symptomatic with poor performance status due to advance stage of presentation and administration of chemotherapy is becomes a challenge for a physician.

Our study found metastatic gallbladder cancer is more common in female than in males (M/F 1:3). Similar pattern of distribution was also noted by Valle et al., Doval et al., and André et al., where the reported ratio was found to be 1:3, 1:3, and 1:2.5, respectively.[9],[11],[12] Median age of presentation in our study is 55 years (range: 29–72 years). Sixth decade of life as the most common age of presentation were also recorded in other Indian studies.[13],[14]

Most of the patients of metastatic gallbladder cancer present with poor performance status, raised bilirubin level and multiple sign and symptoms as pain abdomen, loss of appetite, ascites, or hepatomegaly. Jaundice per se considered a poor prognostic factor. Patients presenting with obstructive jaundice or gastric outlet obstruction requires either biliary stenting or antro-duodenal stenting before administrating chemotherapy.[15] Approximately 29% of patients in our study needed either biliary stenting or antroduodenal stenting. Previous studies have also reported to about 7.2%–45% patients had required such procedure to alleviate their symptoms.[9],[16] Such procedure also precludes from life-threatening biliary sepsis.

Various phase II/III studies have suggested gemcitabine and cisplatin as standard chemotherapy option in locally advance unresectable and metastatic biliary tract cancer.

Management options for unresectable biliary tract cancer may differs compared to metastatic disease. Patients can be converted to definitive management after a good response to chemotherapy in case of unresectable disease. Hence, patients with unresectable disease show a better treatment outcome compared to metastatic one which seldom move for definitive management.

However, among these studies, the sample size of patients belonging exclusively to metastatic gallbladder cancer is very less. Therefore, exact outcome of combination chemotherapy as of locally advance cases for metastatic patients could be deceptive.

Appropriate selection of chemotherapy regimen depends upon patient performance status, toxicity profile, disease status, and patient choice. Occasionally, patients are intolerant to combination chemotherapy even though having good performance status. There is no head to head trial which recommends a particular regimen is advantage compared to other in patients of metastatic gallbladder cancer.

Hence, there is lack of sufficient data to establish a standard chemotherapy regimen for metastatic gallbladder cancer. We did a retrospective study to assess the response rate of gemcitabine and cisplatin versus oral capecitabine alone. Our purpose is to acknowledge whether different combination chemotherapy selection has a difference in clinical outcome among Indian patients.

Fluoropyrimidine-based chemotherapy

Various studies which used fluoropyrimidine-based chemotherapy has depicted response rate range between 25% and 60% with median survival of 6–11 months[17],[18],[19],[20],[21],[22],[23] [Table 6]. The studies had used combination of fluoropyrimidine with a platinum compound or with gemcitabine. Ducreux et al. had shown interesting survival advantage from combination of 5Flurouracil and cisplatin with median survival of 11 months as compared to studies involving similar chemotherapy regimens.[18] However, the study entered few numbers of patient (n = 11) with metastatic gallbladder cancer. Another study by Nehl et al. has demonstrated better response rate as 63% using Capecitabine and Oxaliplatin (CAPOX) as compared to their contemporary studies.[22] Similarly, a phase II study by Graham et al., consisting 18 patients with their site of origin from gallbladder, evaluated efficacy of CAPOX combination chemotherapy in unresectable biliary tract cancer. Overall response rate was 54.8% and 28.6% had PD. Median OS was 7.9 months (95% confidence interval [CI], 5.3–10.4 months).[23]
Table 6: Phase II/III studies representing clinical outcome in metastatic gallbladder cancer

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Patients who received regimen B as single-agent capecitabine has response rate of 57% after 3 cycles of chemotherapy and which later dropped to 39% after receiving 6 cycles of chemotherapy. Dose used as single agent was 1650 mg/m2 in two divided doses for 14 days is comparable to as used as single agent by Patt et al., but with some dose modification so as to make the drug more tolerable and compliant by majority of patients as observed clinically. Patt et al. in their retrospective study evaluated outcome of single-agent capecitabine 2000 mg/m2 in two divided doses daily for 14 days in 21 days cycle and included 8 out of 63 patients with locally advance gallbladder cancer. Response rate (CR + PR) was 50% and 2/8 (25%) patients had complete metabolic response. The study also observed efficacy of single agent capecitabine in gallbladder subsite among hepato-biliary cancer. Median OS was 9.9 months (95% CI, 4.4–15.4 months).[27]

Median OS in various phase I/II studies with fluropyramidine-based regimen range from 6.6 to 11.5 months as compared to patients of our study which shown median OS of 15 weeks (4 months). Decrease survival could be attributed because our study population exclusively included patients with metastatic gallbladder cases only, which has dismal prognosis compared to locally advance disease and also late reporting of patients to hospital which further affects prognosis.

Gemcitabine-based chemotherapy

Major phase II and phase III studies using gemcitabine based regimen has proved advantage of combination as compared to single-agent gemcitabine.[9],[24],[26] Osusaka et al. had earlier compared difference in treatment outcome between gemcitabine and cisplatin versus monotherapy as gemcitabine alone. However, results did not depicted a significant difference in outcome between two different regimen but combination arm had a better median survival as 11.2 months and 7.7 months, respectively.[26]

Majority of studies has used combination therapy as gemcitabine along with platinum agents either Cisplatin or Oxaliplatin. Response rates with gemcitabine-based combination agent varied between 60% and 70% as CR + PR + SD with median survival range between 5 and 11 months.[8],[9],[10],[11],[12],[24],[26] André et al. explored survival and tolerance with gemcitabine and oxaliplatin (GEMOX)-based chemotherapy in patients with good performance status and low serum bilirubin level in comparison to those with poor performance status and raised bilirubin level. Patients with good performance patient had better survival outcome compared to other group with median survival 15.4 months and 7.6 months, respectively. Furthermore, there was no significant difference in toxicity between both the groups.[12] A recent Korean randomized controlled phase III trial did a noninferiority comparison of GEMOX to combination of capecitabine and oxaliplatin (XELOX) in patients of advance biliary tract cancer. There were 61 cases of metastatic gallbladder cases divided equally into both arms. The estimated median PFS was 5.3 months (95% CI, 4.1–6.8 months) for the GEMOX group and 5.8 months (95% CI, 4.2–8.0 months) for the XELOX group. The subgroup analysis of gallbladder cases had hazard ratio of 0.63 (0.32–1.25) for GEMOX compared to XELOX regimen.[28]

Another study in context with Indian population has compared best supportive care versus combination chemotherapy as Gemcitabine and Cisplatin regimen. Combination chemotherapy was better tolerable and the response rate was 61% (n = 20) with 13% showing CR and had median survival of 5 months.[11] Our study population which received gemcitabine and cisplatin with n = 31, had median survival of 23 weeks (5.5 months) and is comparable to afore mentioned Indian study. Above comparison also shows variability in outcome of survival with similar chemotherapy regimen in Indian patients compared to western world. Paucity of data and less number of patients is limitations of these studies.

Limitations

The study is retrospective in nature. Toxicity assessment was not evaluated due to insufficient data.


 > Conclusions Top


Palliative chemotherapy is a treatment option in metastatic gallbladder cancer. Choice of chemotherapy should be optimized upon case to case basis. The study shows nonsignificant difference in survival and response rate between either of two regimen. However, gemcitabine and platinum should be the choice if seems feasible, otherwise capecitabine is very convenient to administer and can be a choice for patient with poor performance status. Further prospective studies with large sample size are needed to show the efficacy of one regimen over another in Indian patients of metastatic gallbladder cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Pandey M, Pathak AK, Gautam A, Aryya NC, Shukla VK. Carcinoma of the gallbladder: A retrospective review of 99 cases. Dig Dis Sci 2001;46:1145-51.  Back to cited text no. 14
    
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Regimbeau JM, Fuks D, Bachellier P, Le Treut YP, Pruvot FR, Navarro F, et al. Prognostic value of jaundice in patients with gallbladder cancer by the AFC-GBC-2009 study group. Eur J Surg Oncol 2011;37:505-12.  Back to cited text no. 15
    
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

 
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