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In Reply

The Princess Margaret Hospital, University Health Network, Toronto, ON, Canada

We thank Dr Gallardo and his colleagues for their interest in our study and their comments regarding gallbladder cancer. We all share a commitment to advancing treatment options for patients with biliary cancer. Our study¹ reported that the combination of gemcitabine and capecitabine (GemCap) appeared active and well tolerated in patients with advanced adenocarcinoma of the biliary tract. The objective response rate, including some complete responses, was 31%, with an additional 42% of patients experiencing stable disease or minor responses on treatment. This disease control rate of 73% appears to translate into a median survival of 14 months, which compares favorably to all other trials or reports in this disease site. 22, or one half, of the patients had gallbladder cancer in our study. While response rates were similar between the patients with gallbladder cancer and the patients with bile duct cancer with this combination (28% versus 34%, respectively), the median survival times differed considerably (6.6 months versus 19 months, respectively, HR 3.61, P = .011). We argued that this reflects the more aggressive natural history of gallbladder cancer. Median survival for both tumor types in our trial, despite being quite disparate, do compare consistently and favorably to other reports where either tumor type dominated. This suggests that the GemCap combination has activity in both tumor types.

Dr Gallardo argues that gallbladder cancer is sufficiently different to be studied separately and perhaps with a different strategy than bile duct cancers. While we do not disagree that the two cancers appear to have different clinical behavior and geographical distributions, there appears to be enough similarity with respect to response to chemotherapy to warrant currently an overlap in development. Table 4 from our publication lists 14 of the larger, more recent trials in biliary cancer.^1-14 The relative numbers of bile duct or gallbladder cancers included are listed where available.

There is a tendency for the phase II trials of gallbladder cancer to have worse survival outcomes than phase II trials of largely bile duct cancer (eg, Table 4¹ or references 2, 3, and 4). However, comparisons between phase II trials can be problematic. For instance, the Chilean patient population in Dr Gallardo's phase II trial evaluating gemcitabine alone consisted of 65% women with a median age of 55.5 years.² Similarly, the study by Doval et al of the combination gemcitabine-cisplatin, was conducted in India, and consisted of 73% women and median age was 53 years.⁴ Our own patients with gallbladder cancer treated with GemCap were 58% female with an older median age of 62 years.¹ Race, sex, or age might impact outcome differences in these phase II trials. Regardless, the main purpose of referencing Table 4 from our paper is to draw attention to how similar response rates and median survivals are with the various newer chemotherapies, suggesting that biliary cancer is relatively chemotherapy sensitive, especially compared to pancreas cancer, for example. This sensitivity argues for further clinical development to establish a reference standard for chemotherapy treatment.

As both gallbladder and bile duct cancers are relatively rare, neither have been studied enough to have an established chemotherapy standard of care. I would argue that with the current level of knowledge, advancement of both sites would proceed more quickly from large, adequately powered, randomized trials that include both sites. Of course, biliary tumor type would need to be part of the planned stratification. We are planning to take the promising GemCap combination forward to a phase III trial with single agent gemcitabine as the comparator arm and overall survival as the primary end point. This trial led by the National Cancer Institute of Canada's Clinical Trials Group will stratify for gallbladder versus bile duct cancer as well as performance status and extent of disease. We will also bank tumor and plasma samples for further studies aimed at correlating tumor factors to clinical outcome. Both clinical benefit and quality of life data will be collected using validated tools. To be successful, this ambitious proposal will require international investigator collaboration to accrue sufficient numbers of patients, continued support from cooperative groups, and last, but not least, ongoing commitment from industry to help develop treatments for this orphan site. As Dr Gallardo has pointed out, there are geographic regions around the world where biliary cancer is a common cancer, and even in areas where it is less common, the annual case burden is fairly significant due its poor prognosis. The time has come to establish a standard of care from which further studies can build and fine-tune biliary cancer treatments.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Knox JJ, Hedley H, Oza A, et al: Combining gemcitabine and capecitabine in patients with advanced biliary cancer: A phase II trial. J Clin Oncol 23:2332-2338, 2005[Abstract/Free Full Text]

2. Gallardo JO, Rubio B, Fodor M, et al: A phase II study of gemcitabine in gallbladder carcinoma. Ann Oncol 12:1403-1406, 2001[Abstract/Free Full Text]

3. Reyes-Vidal J, Gallardo J, Yanez E et al: Gemcitabine and cisplatin in the treatment of patients with unresectable or metastatic gallbladder cancer: Results of the phase II Gocchi study 2000-13. Proc Am Soc Clin Oncol 22:2003 (abstr 1095)

4. Dorval DC, Sekhon JS, Gupta SK, et al: A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer. Br J Cancer 90:1516-1520, 2004[CrossRef][Medline]

5. Lozano RD, Patt YZ, Hassan MM, et al: Oral capecitabine (Xeloda) for the treatment of hepatobiliary cancers (hepatocellular carcinoma, cholangiocarcinoma and gallbladder cancer). Proc Am Soc Clin Oncol 19:264a, 2000 (abstr 1025)

6. Kubicka S, Rudolph KL, Tietze MK, et al: A phase II study of gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastrenterology 48:783-789, 2001

7. Gebbia V, Giuliani F, Maiello E, et al: Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: Results of a multicenter phase II study. Amer Soc Clin Oncol 10:4089-4091, 2001

8. Taïeb J, Mitry E, Boige V, et al: Optimization of 5-fluorouracil (5-FU)/ cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. Ann Oncol 13:1192-1196, 2002[Abstract/Free Full Text]

9. Hsu C, Shen Y-C, Yang C-H, et al: Weekly gemcitabine plus 24-h infusion of high-dose 5-fluorouracil/leucovorin for locally advanced or metastatic carcinoma of the biliary tract. Br J Cancer 90:1715-1719, 2004

10. Kuhn R, Hribaschek A, Eichelmann K, et al: Outpatient therapy with gemcitabine and docetaxel for gallbladder, biliary, and cholangio-carcinomas. Invest New Drugs 20:351-356, 2002[CrossRef][Medline]

11. Rao S, Cunningham D, Hawkins R, et al: Phase III trial of 5-FU etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5-FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer 92:1650-1654, 2005[CrossRef][Medline]

12. Nehls O, Oettle H, Hartmann J-T, et al: Multicenter phase II trial of oxaliplatin plus capecitabine (XELOX) in advanced biliary system adenocarcinomas (study CCC/GBC-01). Proc Am Soc Clin Oncol 22:2003 (abstr 1126)

13. Kornek GV, Schuell B, Laengle F, et al: Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: A randomized phase II trial. Ann Oncol 15:478-483, 2004[Abstract/Free Full Text]

14. André T, Tournigand C, Rosmorduc O, et al: Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: A GERCOR study. Ann Oncol 15:1339-1343, 2004[Abstract/Free Full Text]

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Related Correspondence

• Gallbladder Cancer, a Different Disease that Needs Individual Trials
  Jorge Gallardo, Betzabé Rubio, Luis Villanueva, and Olga Barajas
  JCO 2005 23: 7753-7754 [Full Text]

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