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Gallbladder Cancer, a Different Disease that Needs Individual Trials

Oncología Hospital Clínico Universidad de Chile; Facultad de Ciencias Químicas y Farmacéuticas Universidad de Chile; Instituto Terapias Oncológicas Providencia, Santiago, Chile

To the Editor:

In a recent study, Knox et al¹ reported interesting results in a phase II study that included patients with gallbladder cancer. Certainly in Canada, the United States, and many European countries, gallbladder cancer, which comprises 4% of the cancers of the gastrointestinal tract, is considered a rare disease,² but in other countries this is not so. Gallbladder cancer is the leading cause of cancer-related deaths for Chilean women (18 per 100,000). Thus it is not a strange epidemiologic case. 99% of the cases of gallbladder cancers are related to gallbladder stones; in cholangiocarcinoma this etiology does not play a role. Gallbladder cancer is a rapidly progressive disease; frequently cholangiocarcinoma is accompanied by displasia, a phenomenon that does not happen in gallbladder cancer. The metastasis pattern, tumor localization, and other clinical parameters differ sufficiently to warrant further investigation into the molecular biology of these two different diseases, and to warrant different clinical trials.

We agree with the statement that gallbladder carcinoma is a more aggressive disease than cholangiocarcinoma. Median survival for stage IV gallbladder patients without treatment is only 12 weeks. Reported median survival for patients with advanced cholangiocarcinoma, without treatment, is approximately 24 to 44 weeks. Therefore, if in a trial of gallbladder carcinoma some patients with cholangiocarcinoma are included even though the investigated therapy was not useful, the median survival will be better than expected. Conversely, in a cholangiocarcinoma trial, a contamination with some cases of gallbladder cancer will decrease the median survival. It seems to us that it is important and practical to separate clinical trials for these two different diseases or at least to consider the tumor type in the stratification strategy. Otherwise, results from phase II trials are not useful for patients with these diseases. In most trials mentioned in Table 4 of the Knox et al article, the observed median survival for gallbladder cancer cannot deducted, nor median survival for cholangiocarcinoma, nor the benefit of using chemotherapy in these patients.

Our study using gemcitabine for patients with advanced gallbladder cancer was the first and largest study in which patients with gallbladder cancer were treated with a uniform chemotherapy regimen. Results were promising, including a 35% response rate and a median survival of 30.3 weeks. Treatment-related toxicity was mild.³ A retrospective analysis of patients treated with gemcitabine suggests that this therapy not only prolongs survival for advanced gallbladder cancer as established in the previous trial, but also produces the so-called clinical benefit.⁴

As Knox et al suggest, in older trials based on fluoruracil, the response rate was low: 0% to 10%, without impact on survival. Until now, it was unclear if capecitabine is a useful drug in gallbladder cancer; probably it is, but the use of half doses makes its indication questionable.

Two drugs are not necessarily better than one. Large trials comparing gemcitabine versus gemcitabine-cisplatin or gemcitabine-fluorouracil in pancreas carcinoma did not show an advantage for the combination. In an indirect, certainly no less valid comparison, the response rate for gallbladder cancer of 28% and a median survival of 6.6 months in the Knox et al trial (using the combination), does not look better than using gemcitabine alone. As mentioned above, the response rate that we observed was 35%, and median survival was 7.3 months. In our second phase II, multicenter study of gemcitabine and cisplatin, which included 44 patients,⁵ the response rate was 46%, with some complete responses. The combination was associated with a tolerable toxicity profile, and median survival was 7 months. We have retrospectively reviewed our results comparing gemcitabine versus gemcitabine-cisplatin. Complete response and response rates are better with the combination, but unfortunately median survival was the same as in Table 4.¹

Until now, the only other published article that included only patients with gallbladder cancer is that of Doval et al.⁶ This study used a combination of gemcitabine-cisplatin. Response rate was 36% and median survival was only 6 months. Interestingly these results are similar to the others,^3,5 giving consistency to the smaller reports.

Even though gallbladder cancer is a rare disease, it is estimated that close to 7,000 new cases occur annually in the United States.⁷ More than half of those patients will die. Many patients do not receive palliative chemotherapy or adequate therapy. The question of whether a combined chemotherapy is better than a single drug—like gemcitabin—could be answered easily. In addition, a cooperative study could possibly provide definitive answers to questions such as which groups of patients benefit from adjuvant chemoradiotherapy. The role of adjuvant chemotherapy must also be investigated. International collaboration is more than a nice topic of discourse; in this case it is a necessity.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Knox JJ, Hedley D, 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. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51:15-36, 2001[Abstract/Free Full Text]

3. Gallardo J, 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]

4. Gallardo J, Rubio B, Fodor M, et al: Gemcitabine in gallbladder cancer: Clinical benefit assessment. Proc Am Soc Clin Oncol 21, 2002 (abstr 2305)

5. Reyes-Vidal J, Gallardo J, Yáñez 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 22:273, 2003 (abstr 1095)

6. Doval DC, Sekhon JS, Gupta SK, et al: A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer. Proc Am Soc Clin Oncol 20, 2001 (abstr 622)

7. American Cancer Society: Cancer Facts & Figures 2004, pp 4

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  Jennifer J. Knox
  JCO 2005 23: 7754-7755 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gallardo, J. Articles by Barajas, O. Search for Related Content PubMed PubMed Citation Articles by Gallardo, J. Articles by Barajas, O. Related Articles Related Reply Social Bookmarking                            What's this?