|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 19 (July 1), 2007: pp. 24e-25 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.6285
Questions About the Role of Palifermin in Fluorouracil-Based Therapy for Metastatic Colorectal CancerMelbourne Oncology Group, Cabrini Health; and the Department of Medicine, Monash University, Melbourne, Australia To the Editor: The study by Rosen et al1 entitled "Palifermin Reduces the Incidence of Oral Mucositis in Patients With Metastatic Colorectal Cancer With Fluorouracil-Based Chemotherapy" raised a number of questions that require a response. The title of the article and its conclusion imply that palifermin reduces the incidence of oral mucositis in all patients with metastic colorectal cancer on fluorouracil (FU)-based chemotherapy. Isn't this misleading? The study only showed the dose of paliferman used is better than nothing in patients receiving the very specific Mayo regimen of FU and folinic acid. One of the reasons that the Mayo regimen is outdated and now considered an inappropriate treatment for patients with metastatic colorectal cancer is that it has a very high incidence of oral mucositis, a very debilitating adverse effect.2,3 In a randomized comparison with the weekly Roswell Park regimen of FU and folinic acid, the outcomes were equivocal and the authors recommended the Roswell Park regimen because of markedly reduced toxicity, particularly mucositis and diarrhea.3 Why was the Mayo regimen chosen when it had been proven to be inferior to the de Gramont infusion regimen published in 1997?4 This randomized study also showed substantially reduced toxicity for the de Gramont regimen, particularly with mucositis (7.3% grade 3 to 4 mucositis with Mayo regimen v 1.9% with the de Gramont regimen). By 2000, FU and folinic acid regimens were shown to be inferior to irinotecan-containing chemotherapy regimens.5,6 Although the introduction mentions that the study was done in the 1990s, before the publication on data about irinotecan, the public presentation of the data for part A of this study at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 20 to 23, 2000,7 and part B of the study at 37th Annual Meeting of ASCO, May 12 to 15, 2001,8 suggests that some patients may have been entered onto the study as late as 2001. When exactly were the first and last patients entered onto this study? Why was a potentially inferior regimen chosen when it had a very high incidence of associated mucositis? Very importantly, why was a proven and very cheap preventative like oral cryotherapy not included in both arms of the study? Two studies in 1991 and 1994 showed significant reduction of mucositis in patients receiving FU-based chemotherapy by using oral cryotherapy.9,10 The authors acknowledged these studies in their introduction and conceded that cryotherapy is the standard care for patients receiving FU-based therapy who are at significant risk of oral mucositis.11 Was cryotherapy not used to increase the chance of showing a benefit for palifermin? Is it reasonable to leave oral cryotherapy out of both arms of such a study? Why did the authors expose their patients to such a high risk of mucositis without incorporating a proven treatment, such as oral cryotherapy, to reduce the incidence of mucositis? The protocol study design was said to allow for a 20% reduction in dose of FU during cycle 2 if moderately severe chemotherapy related toxicity occurred in cycle 1. Why was it that only 50% of those patients with grade 2 or higher mucositis in cycle 1 had their dose of FU reduced for the second cycle and according to a statement in the Results section? Why was this dose reduction only by 10% or greater? Why was there such a discrepancy between the incidence of skin adverse effects in the placebo patients between the abstract (where the incidence of skin adverse effects was reported as 22%)8 and the final full report of the study where the incidence was reported as 52%?1 Why are the levels of sponsorship provided for each author not included in the disclosure statement as used to be the case with Journal of Clinical Oncology authors? Precisely how much involvement did the sponsoring company, Amgen, have with the design, conduct, and reporting of this study? This study seems to demonstrate the serious doubts that can arise when pharmaceutical companies with vested interests in the outcome of studies are allowed to be too closely involved in the design, conduct, and reporting of clinical studies. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Rosen LS, Abdi E, Davis ID, et al: Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil based chemotherapy. J Clin Oncol 24:5194-5200, 2006[CrossRef][Medline] 2. Buroker TR, O'Connell MJ, Wieand HS, et al: Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 12:14-20, 1994[Abstract] 3. Wang WS, Lin JK, Chiou TJ, et al: Randomized trial comparing weekly bolus 5-fluorouracil plus leucovorin versus monthly 5-day 5-fluorouracil plus leucovorin in metastatic colorectal cancer. Hepatogastroenterology 47:1599-1603, 2000[Medline] 4. de Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815, 1997 5. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:1041-1047, 2000[CrossRef][Medline] 6. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343:905-914, 2000 7. Meropol NJ, Gutheil J, Pelley R, et al: Keratinocyte growth factor (KGF) as a mucositis protectant: A randomized phase I trial. Proc Am Soc Clin Oncol 19:603A, 2000 (abstr 2374) 8. Clarke SJ, Abdi E, Davis ID, et al: Recombinant human keratinocyte growth factor (rHuKGF) prevents chemotherapy-induced mucositis in patients with advanced colorectal cancer: A randomized phase II trial. Proc Am Soc Clin Oncol 19:383A, 2000 (abstr 1529) 9. Mahood DJ, Dose AM, Loprinzi CL, et al: Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol 9:449-452, 1991[Abstract] 10. Cascinu S, Fedeli A, Fedeli SL, et al: Oral cooling (cryotherapy), an effective treatment for the prevention of 5-fluorouracil-induced stomatitis. Eur J Cancer B Oral Oncol 30B:234-236, 1994[CrossRef] 11. Rubenstein EB, Peterson DE, Schubert M, et al: Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 100:2026-2046, 2004 (suppl 9)[CrossRef][Medline] Related Correspondence
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
