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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Gebbia, V. Articles by Valdesi, M. Search for Related Content PubMed PubMed Citation Articles by Gebbia, V. Articles by Valdesi, M. Social Bookmarking                            What's this?

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

University of Palermo, La Maddalena Clinic for Cancer, Palermo, Italy
National Institute of Oncology, Bari, Italy
Ospedali Riuniti, Sciacca, Italy
La Maddalena Clinic for Cancer, Palermo, Italy
Centro Catanese de Oncologia, Catania, Italy
Casa di Cura Torina, Palermo, Italy
Ospedale Buccheri La Ferla, Palermo, Italy

To the Editor:Biliary tract carcinomas (BTC) are often diagnosed at an advanced/metastatic stage amenable only to palliative surgery, percutaneous/endoscopic procedures, and palliative chemotherapy (CT). Published data on palliative CT for BTC are quite scarce and rather disappointing: uracil/tegafur, paclitaxel, and cisplatin are poorly active, whereas mitomycin and fluorouracil (5-FU) have shown response rates ranging from 10% to 20%.^1,2 Median overall survival (OS) varies from 5 to 12 months (mean, 8 months), but OS data are very difficult to interpret because of the relatively small number of moderate-size trials published to date and the considerable variability of clinical characteristics of enrolled patients. To date there is no agreement on the best CT regimen for advanced BTC. Folinic acid (FA) plus 5-FU has been reported to be tolerated and active against BTC.⁴ In three trials including a total of 78 patients, FA/5FU, given both as a weekly bolus or weekly high-dose continuous venous infusion (CVI) or a standard bolus regimen for 5 days, has yielded an overall response rate (RR) of 30% to 34%.

Recently the new nucleoside analog gemcitabine (GEM) has been reported to be active against pancreatic adenocarcinoma, at least in terms of clinical benefit, being able to induce a 10% to 20% objective RR. To date, scientific reports concerning the clinical efficacy of GEM in BTC have been only occasional.^3-5 Therefore, FA/5FU may be empirically combined with GEM with the aim of identifying a new active and tolerated combination regimen for BTC. We therefore carried out a multicenter phase II trial that aimed to evaluate the tolerability and clinical activity of GEM both as a single agent and in combination with FA/5FU. Between 1997 and 2000, 40 consecutive patients (22 with gallbladder carcinoma and 18 with bile duct carcinoma) who satisfied standard eligibility criteria⁶ were included in the trial. The first cohort of 18 patients received single-agent GEM 1000 mg/m²/wk as 30-minute intravenous (IV) infusion for 3 consecutive weeks followed by a 15-day rest period. There were six male (33%) and 12 female patients (67%), with a median age of 62 years and a median Eastern Cooperative Oncology Group performance status of 1. The site of primary tumor was gallbladder in 12 patients (67%) and bile ducts in six (33%); histologically, there were 16 carcinomas (89%) and two cholangiocarcinomas (11%). Eight patients had received surgery (four palliative and four radical procedures), and nine patients had previous stent placement or percutaneous transepatic catheterism. Sites of disease included locoregional disease (44%), liver (61%), nodes (39%), intrahepatic tumor (11%), and peritoneum (6%). A 15% RR was required to proceed to the combination CT trial.

The second cohort included 22 patients who were treated with GEM 1,000 mg/m² on days 1 and 8 and FA 100 mg/m² over a 2-hour infusion, plus 5-FU 400 mg/m² IV bolus followed by a 22-hour CVI of 5-FU at the dose of 600 mg/m². This regimen was re-cycled every 21 days, and disease status was assessed after three cycles according to the World Health Organization criteria. In this cohort there were seven male (32%) and 15 female patients (68%), with a median age of 60 years (range, 45 to 75 years) and a median Eastern Cooperative Oncology Group performance status of 1. Sites of disease included locoregional disease (54%), liver (50%), nodes (27%), intrahepatic tumor (18%), lung (9%), and bone (9%). Previous treatments included palliative surgery in six cases (27%), radical intervention in three cases (14%), and stent placement or percutaneous transepatic catheterism in 10 patients (45%). In both groups, no patient had previously received radiotherapy and/or CT. No statistically significant imbalance in clinical characteristic was seen between the two groups. GEM was regularly delivered if the WBC count was 2,500/mm³, the absolute neutrophil count was 1,000/mm³, and platelets were 100,000/mm³. If the WBC, absolute neutrophil, or platelet counts were below reported values, CT was delayed by 1 week and subsequent doses of GEM were reduced to 800 mg/m². In case of hepatic toxicity grade 2, GEM dosage was reduced to 500 to 800 mg/m², depending on the severity of side effects. The occurrence of any grade 4 toxicity, with the exception of hematologic side effects, caused patients to be removed from study. If on the day of planned therapy, hematologic or hepatic recovery was not sufficient, then CT was delayed by 1 week. Duration of CT was dependent on clinical response. In case of a complete response (CR) or partial objective response (PR) or stabilization of disease (SD), after the first three cycles patients were given an additional three cycles of CT and were then re-staged. In the case of PR or SD, therapy was continued for three additional cycles in the absence of unacceptable toxicity. In case of progressive disease (PD), CT was withheld. Assessment of objective response was carried out according to an intent-to-treat fashion. Two patients in the single-agent GEM group and two in the combination group did not complete the first three cycles of CT because of clinically evidenced PD and were therefore considered to have experienced treatment failure.

In the single-group agent, PR was recorded in four cases (22%; 95% confidence interval, 6% to 48%), with a duration of 3.4, 4, 5, and 7 months (median, 4.5 months). SD was seen in five cases (28%), whereas the remaining nine patients showed PD (50%). In the series of patients treated with GEM, FA, and 5-FU, PR was achieved in eight cases (36%; 95% confidence interval, 17% to 59%), with a median duration of 6 months (range, 4 to 9 months). SD was seen in five cases (23%) and PD in eight (36%). In the whole series, PR was seen in one of six cases of cholangiocarcinoma. Time to progression was 3.4 months (range, 2 to 7 months) in patients treated with GEM alone and 4.1 months (range, 2 to 9 months) in the FA/5-FU/GEM group. Median OS was 8 months in the single-agent group (range, 2 to 15 months), with 22% of patients alive at 1 year, and 11 months in the combination CT group (range, 2 to 22 months), with 36% of patients alive at 1 year. Side effects, reported according to the National Cancer Institute common toxicity criteria, were rather mild, with no cases of grade 4 toxicity. In no case was CT withheld because of toxicity. Hematologic and mucosal toxicities were the most frequently reported side effects, and both types were higher in the series treated with GEM plus FA/5-FU than in patients treated with a single-agent GEM. Grade 3 stomatitis and diarrhea were virtually absent in patients treated with GEM alone, whereas they were recorded in, respectively, 9% and 14% of patients treated with the combination regimen. Grade 1/2 liver toxicity was seen in 17% of patients treated with the combination CT. Grade 3 neutropenia was seen in 11% of patients who received single-agent GEM and 18% of patients who received GEM/FA/5-FU. Hand-foot syndrome was observed in one patient treated with the combination regimen. Flu-like syndrome was recorded in 28% and 23% of patients, respectively, in the single-agent group and in the combination CT group.

These results are comparable to data reported for other combination regimens, with the RR being close to the highest results and toxicity usually being mild, acceptable, and easily manageable. In fact, a phase II trial⁷ of high-dose FA plus 5-FU bolus and mitomycin in a small series of 13 patients reported a 23% overall RR (ORR) with a median OS of 5.3 months. A 24% ORR has been reported in a series of 25 patients, with a 10-month median OS, using cisplatin 100 mg/m² on day 2 and 5-FU 1 g/m²/d as a 5-day CVI.⁸ Carboplatin 300 mg/m² on day 1 substituted for cisplatin in a phase II study carried out on a series of 14 patients who also received 5-FU 400 mg/m² as an IV bolus on days 1 through 4 modulated by low-dose FA.⁹ The reported ORR was 21%, with a median OS of only 5 months. Both trials confirmed at least in part data previously reported by Ellis et al¹⁰ in a series of 20 patients treated with epirubicin, cisplatin, and prolonged-infusion 5-FU regimen as first-line treatment, which yielded a 40% ORR with a 10-month median OS.

In conclusion, data reported in this phase II trial demonstrate that single-agent GEM is active against advanced, unresectable recurrent and/or metastatic BTC with a good tolerability. The low toxicity profile of GEM should be considered when a treatment choice is to be made for a patient with advanced BTC. GEM may also be safely combined with a FA/5-FU infusional regimen, resulting in an improved RR with a slightly increased frequency and severity of side effects. Because of the noncomparative nature of this study, no conclusion on survival or activity may be inferred from the above-reported data. However, GEM deserves further study, with the aim of identifying new active combinations for the management of advanced and/or metastatic BTC.

REFERENCES

1. Pitt HA, Grotto LB, Abrams RA: Cancer of the biliary tree, in De Vita VT, Helena S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, ed 5. Philadelphia, PA, Lippincott-Raven, 1997, pp 1114-1128

2. van Riel JMGH, van Greningen CJ, Pinedo HM, et al: Current chemotherapeutic possibilities in pancreaticobiliary cancer. Ann Oncol 10: S157-S161, 1999 (suppl)[Abstract]

3. Castro MP: Efficacy of gemcitabine in the treatment of patients with gall bladder carcinoma. Cancer 15: 639-912, 2000

4. Teufel A, Lehnert T, Stemmel W, et al: Chemotherapy with gemcitabine in patients with advanced carcinoma. Z Gastroenterol 38: 909-912, 2000[Medline]

5. Verderame F, Mandina P, Abbruzzo F, et al: Biliary tract cancer: Our experience with gemcitabine treatment. Anticancer Drugs 11: 707-708, 2000[Medline]

6. Gebbia V, Maiello E, Testa A, et al: Treatment of advanced adenocarcinomas of the exocrine pancreas and the gallbladder with 5-fluorouracil, high dose folinic acid and oral hydroxyurea on a weekly schedule. Cancer 78: 1300-1307, 1996[Medline]

7. Polyzos A, Nikou G, Giannopoulos A, et al: Chemotherapy of biliary tract cancer with mitomycin C and 5-fluorouracil biochemically modulated by folinic acid: A phase II study. Ann Oncol 7: 644-645, 1996[Free Full Text]

8. Rougier P, Zarba JJ, Ducreaux M, et al: Phase II study of cisplatin and 120 hour infusion 5-fluorouracil in patients with advanced pancreatic adenocarcinoma. Ann Oncol 4: 333-336, 2000[Abstract/Free Full Text]

9. Sanz-Altamira PM, Ferrante K, Jenkins RL, et al: A phase II trial of 5-fluorouracil, leucovorin, and carboplatin with unresectable biliary tree carcinoma. Cancer 15: 2321-2325, 1998

10. Ellis PA, Norman A, Hill A, et al: Epirubicin, cisplatin and infusional 5-fluorouracil (5-FU) (ECF) in hepatobiliary tumours. Eur J Cancer 31: 1594-1598, 1995

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. Kanai, S. Morita, S. Matsumoto, T. Nishimura, E. Hatano, S. Yazumi, T. Sasaki, H. Yasuda, T. Kitano, A. Misawa, et al. A history of smoking is inversely correlated with the incidence of gemcitabine-induced neutropenia Ann. Onc., August 1, 2009; 20(8): 1397 - 1401. [Abstract] [Full Text] [PDF]

				D. Koeberle, P. Saletti, M. Borner, D. Gerber, D. Dietrich, C. B. Caspar, W. Mingrone, K. Beretta, F. Strasser, T. Ruhstaller, et al. Patient-Reported Outcomes of Patients With Advanced Biliary Tract Cancers Receiving Gemcitabine Plus Capecitabine: A Multicenter, Phase II Trial of the Swiss Group for Clinical Cancer Research J. Clin. Oncol., August 1, 2008; 26(22): 3702 - 3708. [Abstract] [Full Text] [PDF]

				A. F. Hezel and A. X. Zhu Systemic Therapy for Biliary Tract Cancers Oncologist, April 1, 2008; 13(4): 415 - 423. [Abstract] [Full Text] [PDF]

				E. Ben-Josef, D. Normolle, W. D. Ensminger, S. Walker, D. Tatro, R. K. Ten Haken, J. Knol, L. A. Dawson, C. Pan, and T. S. Lawrence Phase II Trial of High-Dose Conformal Radiation Therapy With Concurrent Hepatic Artery Floxuridine for Unresectable Intrahepatic Malignancies J. Clin. Oncol., December 1, 2005; 23(34): 8739 - 8747. [Abstract] [Full Text] [PDF]

				J. J. Knox, D. Hedley, A. Oza, R. Feld, L. L. Siu, E. Chen, M. Nematollahi, G. R. Pond, J. Zhang, and M. J. Moore Combining Gemcitabine and Capecitabine in Patients With Advanced Biliary Cancer: A Phase II Trial J. Clin. Oncol., April 1, 2005; 23(10): 2332 - 2338. [Abstract] [Full Text] [PDF]

				J.-S. Park, S.-Y. Oh, S.-H. Kim, H.-C. Kwon, J.-S. Kim, H. Jin-Kim, and Y.-H. Kim Single-agent Gemcitabine in the Treatment of Advanced Biliary Tract Cancers: a Phase II Study Jpn. J. Clin. Oncol., February 1, 2005; 35(2): 68 - 73. [Abstract] [Full Text] [PDF]

				S. Thongprasert, S. Napapan, C. Charoentum, and S. Moonprakan Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma Ann. Onc., February 1, 2005; 16(2): 279 - 281. [Abstract] [Full Text] [PDF]

				T. Andre, C. Tournigand, O. Rosmorduc, S. Provent, F. Maindrault-Goebel, D. Avenin, F. Selle, F. Paye, L. Hannoun, S. Houry, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study Ann. Onc., September 1, 2004; 15(9): 1339 - 1343. [Abstract] [Full Text] [PDF]

				G. V. Kornek, B. Schuell, F. Laengle, T. Gruenberger, M. Penz, K. Karall, D. Depisch, F. Lang, and W. Scheithauer Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial Ann. Onc., March 1, 2004; 15(3): 478 - 483. [Abstract] [Full Text] [PDF]

				C. D. Anderson, C. Wright Pinson, J. Berlin, and R. S. Chari Diagnosis and Treatment of Cholangiocarcinoma Oncologist, February 1, 2004; 9(1): 43 - 57. [Abstract] [Full Text] [PDF]

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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Gebbia, V. Articles by Valdesi, M. Search for Related Content PubMed PubMed Citation Articles by Gebbia, V. Articles by Valdesi, M. Social Bookmarking                            What's this?