Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :566
Small font sizeDefault font sizeIncrease font size
Navigate here
  Search
 
  
Resource links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (400 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)  

 
  In this article
 »  Abstract
 » Introduction
 » Patients and Methods
 » Results
 » Discussion
 » Conclusion
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed129    
    Printed2    
    Emailed0    
    PDF Downloaded45    
    Comments [Add]    

Recommend this journal

 


 
  Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 55  |  Issue : 3  |  Page : 222-225
 

Gemcitabine with carboplatin for advanced intrahepatic cholangiocarcinoma: A study from North India Cancer Centre


1 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
2 Department of Anaesthesia, Dr. Baba Saheb Ambedkar Medical College and Hospital, Rohini, New Delhi, India
3 Department of Surgical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
4 Medical Research Officer, CSIR - Institute of Genomics and Integrative Biology, New Delhi, India

Date of Web Publication28-Jan-2019

Correspondence Address:
Dr. Venkata Pradeep K Babu
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_622_17

Rights and Permissions

 » Abstract 


BACKGROUND: Gemcitabine plus cisplatin has been established as a standard chemotherapy regimen for advanced biliary tract cancers (BTCs) based on the phase III UK ABC-02 study, which included all types of biliary cancers. There is very limited data regarding the effectiveness of known chemotherapeutic regimens especially in IHCC. METHODS: Records of 63 patients diagnosis of IHCC who received Gemcitabine and Carboplatin (G-C Regimen) chemotherapy as a first line were retrospectively reviewed. The primary aim of this study was to assess the response rate of gemcitabine carboplatin-based chemotherapy as a first line therapy in advanced intrahepatic cholangiocarcinoma (IHCC). The secondary objectives were to assess toxicity, progression free survival and overall survival. RESULTS: There were 38 men and 25 women in our study with a median age of 56.75 years (range 31–78 years). Of the 38+25= 63 patients, 21 patients (33.8%) progressed, 5 patients (8.06%) had complete response, 25 patients (40.3%) had partial response, 12 patients (19.3%) had stable disease. Overall response rate was 48.36% and tumor control rate was 67.6%. Progression free survival was 5.3 months and overall survival of 10.3 months was seen. The most common grade 3–4 toxicities were anemia, neutropenia, and thrombocytopenia. Most common nonhematological toxicity was fatigue. CONCLUSION: Gemcitabine in combination with carboplatin has activity against advanced IHCC. Our results are comparable with other gemcitabine carboplatin studies as well as gemcitabine cisplatin-based studies.


Keywords: Biliary cancer, chemotherapy, gemcitabine carboplatin, intrahepatic cholangiocarcinoma


How to cite this article:
Babu VP, Talwar V, Raina S, Goel V, Dash PK, Bajaj R, Sharma M, Medisetty P, Ram D, Agrawal C, Desiraju K, Doval DC. Gemcitabine with carboplatin for advanced intrahepatic cholangiocarcinoma: A study from North India Cancer Centre. Indian J Cancer 2018;55:222-5

How to cite this URL:
Babu VP, Talwar V, Raina S, Goel V, Dash PK, Bajaj R, Sharma M, Medisetty P, Ram D, Agrawal C, Desiraju K, Doval DC. Gemcitabine with carboplatin for advanced intrahepatic cholangiocarcinoma: A study from North India Cancer Centre. Indian J Cancer [serial online] 2018 [cited 2019 Feb 15];55:222-5. Available from: http://www.indianjcancer.com/text.asp?2018/55/3/222/250896





 » Introduction Top


Biliary tract cancers (BTCs) include a heterogenous group of rare malignancies like gall bladder, ampullary intrahepatic, extrahepatic, hilar cholangiocarcinomas. These account for 4% of all gastrointestinal malignancies.[1] The reported incidence of cholangiocarcinomas in the United States are 1–2 cases for 10,000 population.[2] The exact incidence of IHCC in India is not known. Due to rarity of these malignancies, trials often combine these heterogenous cancers, making it difficult to make an individual therapeutic decision in cholangiocarcinoma.

Although early IHCCs are approached with curative intent, systemic chemotherapy is the mainstay of treatment for unresectable and advanced IHCC. Because of lack of specific symptoms, most of the IHCCs are diagnosed at an advanced stage and prognosis is extremely poor with median survival less than a year.[3] A randomized study showed that palliative chemotherapy improves quality of life compared to best supportive care in patients with BTCs.[4] The response rates with doublets agents, both gemcitabine based and fluoropyrimidine based, proved to be better than single agents. Gemcitabine plus cisplatin is commonly used first line chemotherapy regimen based on the results of ABC-02 phase III trial, in which single agent gemcitabine was compared to gemcitabine platinum doublet, with median PFS of 8 months and median OS of 11.7 months for gemcitabine platinum doublet.[5]

Regarding the choice of platinum, carboplatin is well-tolerated drug and has a better nonhematological toxicity profile with less risk for nephrotoxicity and cumulative neurotoxicity and lesser requirement of pre- and posttreatment hydration. Carboplatin has been shown to be equally efficacious and tolerable as cisplatin in several other malignancies.[6],[7],[8]


 » Patients and Methods Top


The primary objective of this study was to assess the response rate of gemcitabine carboplatin-based chemotherapy as a first line therapy in advanced intrahepatic cholangiocarcinoma (IHCC). The secondary objectives were to assess toxicity, progression free survival, and overall survival.

A retrospective chart review was conducted of patients with advanced IHCC who were treated with gemcitabine carboplatin chemotherapy from January 2012 to January 2017. Patients were required to have bi-dimensionally measurable disease with age greater than 18 years. None of the patients received any prior radiotherapy or any other type of chemotherapy. All patients received first line chemotherapy and restaging at our institute. Complete blood counts and clinical assessment of nonhematological toxicities was carried at at baseline and Day one of every cycle. Adenocarcinomas, which were immunohistochemistry (CK 7+, CK 20±) and radiologically proven cases of IHCC were included. Patients with dual malignancies were excluded. The study was conducted according to the ethical principles stated in the latest version of Helsinki Declaration,[9] and the applicable guidelines for good clinical practice.

The following baseline characteristics were assessed: age at diagnosis, sex, baseline CA19-9 levels, stage of disease. Data collected (including the dates of diagnosis, response, progression, last follow-up, and death) were used to determine overall response rate, duration of response, and overall survival. Response evaluation was done according to RECIST criteria and responses included partial response (PR), complete response (CR), progressive disease (PD), and stable disease (SD). Overall response rate was defined as CR + PR.

Treatment schedule

Gemcitabine at a dose of 1,000 mg/m2 was administered as a 30-min intravenous (i.v.) infusion on days 1 and 8 of a 21-day cycle. Carboplatin, at an area-under-the-curve (AUC) of 5, was administered as a 1-h i.v. infusion on day 1 of a 21-day cycle. Gemcitabine was administered prior to carboplatin on day 1 of each cycle. Patients in this study received a median of 4.4 cycles and a maximum of 11 cycles of therapy. Treatments after the prescribed six cycles were administered as per the treating physician's discretion.

Statistical analysis

The primary endpoint of this study was response rate. The width of the resultant confidence intervals (CIs) for parameters to be estimated was constructed with a significance level of 0.05, that is, a 95% CI. Overall survival and PFS were analyzed with the use of Kaplan–Meier survival analysis and estimates were provided with 95% CIs. Statistical analysis was performed using SAS 8.02 (SAS Institute Inc.).


 » Results Top


Sixty-three patients met inclusion criteria and were eligible for analysis. Patient characteristics were depicted in [Table 1]. Of the 63 patients, 21 patients (33.8%) progressed, 5 patients (8.06%) had CR, 25 patients (40.3%) had PR, 12 patients (19.3%) had SD. Overall response rate was 48.36% and tumor control rate was 67.6%. Progression free survival was 5.3 months and overall survival of 10.3 months was seen. A total of 278 chemotherapy cycles were administered among the 63 eligible patients. The median number of treatment cycles given was 4.4 cycles per patient (range, 1–11).
Table 1: Characteristics of patients enrolled in the study

Click here to view


Twenty-eight patients (45.1%) completed the maximum of six cycles. Reasons for discontinuing the therapy included progression (29.4%) and toxicity (26%). Toxicities are depicted in [Table 2]. During the entire chemotherapy, 65% patients required dose modifications (52% required one dose reduction in gemcitabine to 750 mg/m2, and carboplatin to AUC 4, 13% patients required 2 and more dose reductions). Common toxicity criteria grade 3 or 4 anemia were seen in 16% and grade 3 or 4 thrombocytopenia was seen in 25% of patients. All grades of neutropenia seen in 66% of patients and grade 3 or 4 neutropenia in 33%. The most common nonhematological toxicity observed was fatigue (72%). PFS and OS of all evaluable patients are depicted in the Kaplan Meier curves [Figure 1] and [Figure 2].
Table 2: Grade 3 or 4 toxicities observed in the study

Click here to view
Figure 1: Progression-free survival

Click here to view
Figure 2: Overall survival

Click here to view



 » Discussion Top


BTCs are relatively uncommon, usually diagnosed in advanced stage and portend a very poor prognosis. Because of the rarity of these cancers, multiple small uncontrolled trials were done with single agents and various combinations of chemotherapeutic agents. 5-fluorouracil has been the most studied agent in these cancers with single agent activity reported between 0% and 21% in several studies.[10],[11],[12],[13] There is no standard established first line chemotherapy for advanced BTCs. However recent studies have established the potential regimens.

Till date, the highest response rates were shown with gemcitabine and platinum combination regimen, from pooled analysis comprising 2,810 patients from 104 trials.[14] The pooled response rate with gemcitabine and cisplatin was 22.6% and tumor control rate was 57.3% that correlated with survival. The ABC-02 trial compared gemcitabine platinum doublet with single agent gemcitabine in locally advanced and metastatic BTCs, and showed improved survival with the combination regimen (11.7 vs 8.1 months). In this trial, 59% had bile duct cancers, but site of bile duct disease was not specified. Although gemcitabine cisplatin combination has now become the standard first line regimen for cholangiocarcinoma, alternatives needed to be explored for those patients in which this regimen cannot be used. Now that the ABC-02 trial has established a preferred regimen in advanced BTCs, the logical next step would be to analyze each subtype of these cancers to determine if these regimens work effectively in each type of disease.

In a single institution phase II study of gemcitabine and carboplatin for advanced BTCs by Williams et al.,[15] 35 cases accounting for 71% cases are histologically cholangiocarcinomas. This study has reported a response rate of 23.5% and tumor control rate of 73.5%. Our study comprised 63 patients of exclusively IHCC. In our study, response rate was 47.6%, that is, much higher than the above study, but in our study was 66.6%, lower than the above study. This is also comparable to the response rates seen in gemcitabine cisplatin arms of ABC-02 (37.7%) and BT22 (19.5%) trials. The limitation being a retrospective nonrandomized study. If prospective trials can establish a similar response rates, a new alternative regimen will get established for populations who are not suitable for cisplatin-based combination.

The median PFS reported in ABC-02 was 8 months (15) and in BT22 trial (16), it was 5.4 months. In Williams et al., study PFS was 7.9 months and OS was 10.6 months in cholangiocarcinoma group. In our study the median PFS among 58 evaluable patients was 5.3 months (95% CI 3.97–6.13 months), which was comparable to above study. The median overall survival was 10.3 months (95% CI 7.8–10.8 months), which is also comparable to above phase II study.

The gemcitabine cisplatin arm of ABC-02 trial reported grade 3 or 4 toxicities in 70.7% patients, 56% in BT22 trial. The gemcitabine carboplatin combination in Williams et al., study reported grade 3 or 4 hematological toxicities in 69% of patients accounting for anemia, thrombocytopenia, and neutropenia. In our study, grade 3 or 4 hematological toxicities were reported in 74% of patients. These hematological toxicities were substantially higher than cisplatin containing regimens of ABC-02 and BT22 trials.[16],[17]


 » Conclusion Top


Gemcitabine in combination with carboplatin has activity against advanced IHCC. The activity is comparable with gemcitabine cisplatin and gemcitabine fluoropyrimidine-based regimens. This forms a potential alternative for patients who are not suitable or intolerant to cisplatin. In our study grade 3 or 4 hematological toxicities were reported in 74% of patients. These hematological toxicities were substantially higher than cisplatin containing regimens of ABC-02 and BT22 trials. Further large multicenter randomized biliary duct site specific trials are necessary to establish the efficacy of this regimen in this rare malignancy.

Acknowledgment

This work was supported by Rajiv Gandhi Cancer Institute and Research Centre, New Delhi.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Ahlgren J. Neoplasms of the Hepatobiliary System. New York: McGraw-Hill; 1993.  Back to cited text no. 1
    
2.
Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. Oncologist 2016;21:594-9.  Back to cited text no. 2
    
3.
Shani M, Hart J, Modan B. Cancer of the biliary system: A study of 445 cases. Br J Surg 1974;61:98-100.  Back to cited text no. 3
    
4.
Glimelius B, Hoffman K, Sjoden PO, Jacobsson G, Sellstrom H, Enander LK, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996;7:593-600.  Back to cited text no. 4
    
5.
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. 5
    
6.
Dogliotti L, Carteni G, Siena S, Bertetto O, Martoni A, Bono A, et al. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: Results of a randomized phase 2 trial. Eur Urol 2007;52:134-41.  Back to cited text no. 6
    
7.
Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: An intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 2006;24:4699-707.  Back to cited text no. 7
    
8.
Yardley DA, Burris HA, 3rd, Simons L, Spigel DR, Greco FA, Barton JH et al. A phase II trial of gemcitabine/carboplatin with or without trastuzumab in the first-line treatment of patients with metastatic breast cancer. Clin Breast Cancer 2008;8:425-31.  Back to cited text no. 8
    
9.
World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013;310:2191-4.  Back to cited text no. 9
    
10.
Ueno H, Okusaka T, Ikeda M, Takezako Y, Morizane C. Phase II study of S-1 in patients with advanced biliary tract cancer. Br J Cancer 2004;91:1769-74  Back to cited text no. 10
    
11.
Falkson G, MacIntyre JM, Moertel CG. Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer 1984;54:965-9.  Back to cited text no. 11
    
12.
Ghadyalpatil NS, Supriya C, Prachi P, Ashwin D, Avanish S. Gastrointestinal cancers in India: Treatment perspective. South Asian J Cancer 2016;5:126-36.  Back to cited text no. 12
[PUBMED]  [Full text]  
13.
Shani M, Hart J, Modan B. Cancer of the biliary system: A study of 445 cases. Br J Surg 1974;61:98-100.  Back to cited text no. 13
    
14.
Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: A pooled analysis of clinical trials. Br J Cancer 2007;96:896-902.  Back to cited text no. 14
    
15.
Williams KJ, Picus J, Trinkhaus K, Fournier CC, Suresh R, James JS, et al. Gemcitabine with carboplatin for advanced biliary tract cancers: A phase II single institution study. HPB (Oxford) 2010;12:418-26.  Back to cited text no. 15
    
16.
Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-81.  Back to cited text no. 16
    
17.
Valle JW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H, et al. Cisplatin and gemcitabine for advanced biliary tract cancer: A meta-analysis of two randomised trials. Ann Oncol 2014;25:391-8.  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
Print this article  Email this article
 

    

  Site Map | What's new | Copyright and Disclaimer
  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow