|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.03.8315 on December 12 2005 © 2006 American Society of Clinical Oncology.
Gemcitabine Doublets in Advanced Pancreatic Cancer: Should We Move On?University of Miami and Sylvester Cancer Center, Miami, FL The last drug to receive regulatory approval in pancreatic cancer, based on a randomized trial, was gemcitabine in the mid 1990s.1 The strategy to improve the treatment of advanced and metastatic pancreatic cancer since then has been focused on adding a second agent to gemcitabine. Unfortunately, this strategy has not been overtly successful.
Drug development in pancreatic cancer, like in many other gastrointestinal malignancies, was initially centered on fluorouracil (FU)-based chemotherapy. Despite many clinical trials with fluoropyrimidines in pancreatic cancer, little information is available on the survival and quality-of-life (QOL) benefits of FU-based chemotherapy in this disease. A small randomized trial evaluated the benefits of FU-based chemotherapy in survival and QOL in pancreatic and biliary cancers.2 This prospective randomized trial compared FU combined with leucovorin (in patients older than 60 years old or Karnofsky Performance Status [KPS]
Gemcitabine has shown modest response rates in phase II trials in advanced and metastatic pancreatic cancer, with improvement in disease-related symptoms observed in patients with a response or stable disease.3 In the pivotal phase III trial, comparing gemcitabine to single agent bolus FU, patients with advanced and metastatic pancreatic cancer receiving gemcitabine had improved clinical benefit response (CBR; improvement sustained for Gemcitabine is a prodrug that is converted to its active triphosphate form before incorporation into DNA. When the ratio of the cellular concentrations of gemcitabine triphosphate to deoxycytidine triphosphate increases, incorporation into DNA of the triphosphate form of gemcitabine is favored.4 Fixed-dose rate infusion (FDR) gemcitabine at 10 mg/m2/min resulted in the best generation of the triphosphate form in mononuclear cells and leukemic cells based on phase I pharmacokinetic studies.5,6 The hypothesis supporting the study of FDR gemcitabine is that the higher intracellular concentrations of gemcitabine active metabolite will result in improved efficacy. Provocative results from a randomized phase II trial in which gemcitabine at 2,200 mg/m2 infused at standard rate and at a dose of 1,500 mg/m2 FDR infusion on days 1, 8, and 15 of a 4-week cycle suggested that FDR gemcitabine is superior in regard to efficacy but associated with more hematologic toxicity, despite the higher doses of gemcitabine infused at standard rate.7 Caution should be emphasized in regards to these results since this was a small randomized trial not powered for comparative analyses. Gemcitabine may be safely combined with several other cytotoxic drugs. Results from phase II studies of gemcitabine combined with cisplatin, FU, irinotecan, and oxaliplatin, in advanced and metastatic pancreatic cancer have suggested that efficacy could be improved.8-13 However, phase III trials of these combinations have not confirmed their superiority to single agent gemcitabine.14-17 On the other hand, randomized phase III trials adding a platinum to gemcitabine compared to gemcitabine alone showed a survival trend favoring the experimental arm.18-20 Additionally, CBR results—the primary end point of the pivotal trial of gemcitabine compared to bolus FU in advanced pancreatic cancer—favored the experimental arm of FDR gemcitabine and oxaliplatin (GEMOX) compared to gemcitabine alone at standard infusion rate gemcitabine.20 Whether this improvement was a result of the addition of oxaliplatin to gemcitabine or the contribution of FDR gemcitabine to the GEMOX arm is not defined at this time. The recent Eastern Cooperative Oncology Group 6201 trial may be able to answer that question (ongoing trial; http://danafarber.org/can/clinical/default.asp?audience_id=&doc=CDR287015.xml&is_active=True). The optimum sequence and interval between gemcitabine and a platinum analog has not been clearly established. In vitro and in vivo studies suggest that the interaction between gemcitabine and cisplatin is complex and in vitro synergism was found to be schedule dependent.22-24 Antitumor activity with simultaneous exposure of gemcitabine and cisplatin for 72 hours was synergistic in eight different cell lines (head/neck, colon, ovarian, and lung cancer). The sequences gemcitabine-cisplatin or cisplatin-gemcitabine were equally synergistic with this exposure time, as well as at shorter periods of exposure. An interval of four hours or more was required for these two sequences to be synergistic.21,22 In vivo sequential administration—with cisplatin administered first followed four hours later by gemcitabine—showed additive antitumor activity in head and neck cancer mouse xenograft models.23 However, in colorectal and human leukemic cell lines exposed to the combination of gemcitabine and oxaliplatin there was a supra-additive effect when gemcitabine exposure was first followed 24 hours later by oxaliplatin.24 The relevance of these observations at the bedside has not been established. The optimal dosing sequence regimen for gemcitabine/platinum doublets remains to be determined. The present study of Dr Ko et al25 combined FDR gemcitabine at 1,000 mg/m2 given first at a rate of 10 mg/m2/min immediately followed by cisplatin 20 mg/m2 on days 1 and 8 of a 21-day cycle. The authors comment that a preceding, unreported phase I trial from the same group with this two-drug combination determined the doses and schedule of this regimen. The toxicity encountered with the combination of FDR gemcitabine and weekly cisplatin on day 1 and 8 every 21-day cycle led to a change in the schedule where this two-drug combination was administered on day 1 and 15. Indeed, higher dose-intensity was achieved with the schedule change, with less toxicity.25 The better dose-intensity of an every other week schedule of gemcitabine combinations is expected since phase I experience with this antimetabolite as a single agent given on an every other week schedule defined the maximum-tolerated dose of 5.7 g every other week.26 The efficacy results reported by Ko et al are interesting.25 The interpretation of the results are more straightforward since unlike other phase II experiences with gemcitabine combinations in pancreatic cancer, the efficacy results were not "inflated" by the enrollment of patients with locally advanced disease. The analyses of phase II trials based on historical controls are subject to incorrect and misleading conclusions. However, it is an exercise investigators often do in order to position the results of their clinical trials outcomes with others similar reported experiences. The response rate of 19.1%, median survival time of 7.1 months, and one-year survival rate of 29% are comparable to other gemcitabine and platinum combinations in metastatic disease.11-13,18,19 However, the short median time to progression of 3.9 months was felt to be disappointing, which the authors discuss appropriately.25 Most importantly, the authors also discuss the similar efficacy results, particularly the median survivals, between the current FDR-gemcitabine and cisplatin experience and the previous experience with single agent FDR-gemcitabine in the subset of metastatic disease patients as authored by Dr Tempero, the senior author of this article.7,25 Whether the addition of low-dose cisplatin to FDR gemcitabine can improve the efficacy results of FDR gemcitabine alone would require a randomized phase III trial. The plateau of efficacy results with gemcitabine combinations with standard cytotoxic drugs suggest that this strategy should be superseded by the study of novel therapeutic approaches in order to improve the prognosis of patients with pancreatic cancer. Among these strategies, drugs that target molecular abnormalities hold the greatest promise for the near future. Despite the lack of exciting results in the early development of targeted therapy in pancreatic cancer with the farnesyl transferase inhibitors and matrix metalloproteinase inhibitors, the investigation of targeting agents should continue.27,28 Recent data with the angiogenesis inhibitor bevacizumab and the EGFR-1 inhibitors cetuximab and erlotinib hold hopes that a paradigm shift in the management of advanced pancreatic cancer is forthcoming.29-31 Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Author Contributions
Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
REFERENCES
1. Burris HA, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first- line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403-2413, 1997 2. Glimelius B, Hoffman K, Sjoden PO, et al: Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 7:593-600, 1996 3. Casper ES, Green MR, Kelsen DP, et al: Phase II trial of gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 12:29-34, 1994[CrossRef][Medline] 4. Plunkett W, Huang P, Searcy CE, et al: Gemcitabine: Preclinical pharmacology and mechanisms of action. Semin Oncol 23:3-15, 1996 (suppl 10)[Medline] 5. Grunewald R, Kantarjian H, Keating MJ, et al: Pharmacologically directed design of the dose rate and schedule of 2',2'-difluorodeoxycytidine (Gemcitabine) administration in leukemia. Cancer Res 50:6823-6826, 1990 6. Abbruzzese JL, Grunewald R, Weeks EA, et al: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491-498, 1991[Abstract] 7. Tempero M, Plunkett W, Ruiz Van Haperen V, et al: Randomized phase II comparison of dose-intense gemcitabine: Thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21:3402-3408, 2003 8. Hidalgo M, Castellano D, Paz-Ares L, et al: Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer. J Clin Oncol 17:585-592, 1999 9. Berlin JD, Adak S, Vaughn DJ, et al: A phase II study of gemcitabine and 5-fluorouracil in metastatic pancreatic cancer: An Eastern Cooperative Oncology Group Study (E3296). Oncology 58:215-218, 2000[CrossRef][Medline] 10. Rocha Lima CM, Savarese D, Bruckner H, et al: Irinotecan plus gemcitabine induces both radiographic and CA 19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer. J Clin Oncol 20:1182-1191, 2002 11. Brodowicz T, Wolfram RM, Kostler WJ, et al: Phase II study of gemcitabine in combination with cisplatin in patients with locally advanced and/or metastatic pancreatic cancer. Anticancer Drugs 11:623-628, 2000[CrossRef][Medline] 12. Philip PA, Zalupski MM, Vaitkevicius VK, et al: Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma. Cancer 92:569-577, 2001[CrossRef][Medline] 13. Louvet C, Andre T, Lledo G, et al: Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: Final results of a GERCOR multicenter phase II study. J Clin Oncol 20:1512-1518, 2002 14. Berlin JD, Catalano P, Thomas JP, et al: Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 20:3270-3275, 2002 15. Rocha Lima CM, Green MR, Rotche R, et al: Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22:776-3783, 2004 16. Oettle H, Richards D, Ramanathan RK, et al: A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 16:1639-1645, 2005 17. O'Reilly M, Abou-Alfa G, Letourneau R, et al: A randomized phase III trial of DX-8951f (exatecan mesylate; DX) and gemcitabine (GEM) vs. gemcitabine alone in advanced pancreatic cancer (APC). J Clin Oncol 22:314s, 2004 (suppl 14; abstr 4006) 18. Colucci G, Giuliani F, Gebbia V, et al: Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: A prospective, randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale. Cancer 94:902-910, 2002[CrossRef][Medline] 19. Heinemann V, Quietzsch D, Gieseler F, et al: A phase III trial comparing gemcitabine plus cisplatin vs. gemcitabine alone in advanced pancreatic carcinoma. Proc Am Soc Clin Oncol 22:250, 2003 (abstr 1003) 20. Louvet C, Labianca R, Hammel P, et al: Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:3509-3516, 2005 21. Peters GJ, Bergman AM, Ruiz van Haperen VWT, et al: Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 22:72-79, 1995 (suppl 11)[Medline] 22. Bergman AM, Ruiz van Haperen VWT, Veerman G, et al: Synergistic interaction between gemcitabine and cisplatin in vitro. Clin Cancer Res 2:521-530, 1996[Abstract] 23. Braakhuis BJ, Ruiz van Haperen VW, Welters MJ, et al: Schedule-dependent therapeutic efficacy of the combination of gemcitabine and cisplatin in head and neck cancer xenografts. Eur J Cancer 31A:2335-2340, 1995[CrossRef] 24. Faivre S, Raymond E, Woynarowski JM, et al: Supraadditive effect of 2',2'-difluorodeoxycytidine (gemcitabine) in combination with oxaliplatin in human cancer cell lines. Cancer Chemother Pharmacol 44:117-123, 1999[CrossRef][Medline] 25. Ko AH, Dito E, Shillinger B, et al: A phase II study of gemcitabine at fixed dose rate infusion in combination with low dose cisplatin for metastatic adenocarcinoma of the pancreas. J Clin Oncol 24:379-385, 2006 26. Vermorken JB, Guastalla JP, Hatty SR, et al: Phase I study of gemcitabine using a once every 2 weeks schedule. Br J Cancer 76:1489-1493, 1997[Medline] 27. Van Cutsem E, Van de Velde H, Karasek P, et al: Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22:1430-1438, 2004 28. Bramhall SR, Schulz J, Nemunaitis J, et al: A double blind placebo controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 87:161-167, 2002[CrossRef][Medline] 29. Kindler HL, Friberg G, Stadler WM, et al: Bevacizumab (B) plus gemcitabine (G) in patients with advanced pancreatic cancer: Updated results of a multi-center trial. J Clin Oncol 22:315s, 2004 (suppl 14; abstr 4009)[CrossRef] 30. Xiong HQ, Rosenberg A, LoBuglio A, et al: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: A multicenter phase II trial. J Clin Oncol 22:2610-2616, 2004 31. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib improves survival when added to gemcitabine in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trial Group (NCIC-CTG). Proc 2005 Gastrointestinal Cancers Symposium, Orlando, FL, January 27-29, 2005 (abstr 77)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
70%) or FU, leucovorin sequenced with etoposide (younger and better KPS patients) to best supportive care (BSC) for patients with pancreatic and biliary cancers. Median survival and QOL evaluated with the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 instrument favored the treatment arms. 
4 weeks in at least one of the following: 
