|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 5 (February 10), 2007: pp. 602-603 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.2171
Addition of Weekly Oxaliplatin to Standard Preoperative Chemoradiation for Locally Advanced Rectal CancerDepartment of Medical Oncology, E.O. Ospedali Galliera, Genova, Italy
Department of Medical Oncology, Istituto Oncologico Veneto, Padova, Italy To the Editor: We read with great interest the article published in the Journal of Clinical Oncology by Ryan et al,1 which reports on a phase I-II study of weekly oxaliplatin (OXA), infused fluorouracil (FU), and pelvic radiotherapy (RT) in locally advanced rectal cancer. This study duplicates the original phase I-II trial assessing the incorporation of weekly OXA into a standard program of pelvic RT and continuous infusion FU that we presented in abstract format at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002,2 and then published in the official ESMO journal on May 2005.3 The two studies have striking similarities in terms of sample size (46 v 44 patients), trial design (phase I-II), patient characteristics (median age, 59 v 55 years; males:females, 59%:41% v 64%:36%; T4, 35 v 25%), RT doses and fields, and the same range of OXA doses were tested. In addition, and at variance with other OXA-containing chemoradiotherapy regimens, a weekly OXA schedule with six administrations concomitant to RT was used. This may optimize the inhibition of sublethal, radiation-induced DNA damage repair and allow a higher OXA dose and dose-intensity with a potential enhancement of local and systemic activity. The feasibility of this regimen and the recommended dose of weekly OXA previously established in our study (60 mg/m2/wk) were confirmed in Cancer and Leukemia Group B (CALGB) trial 89901. The total dose of OXA delivered concomitant to radiation with this regimen is substantially higher compared with other recently developed OXA-based chemoradiotherapy programs.4,5 In addition, this OXA dose is potentially active also systemically with a dose-intensity approximately 50% higher compared with the regimens commonly used in the treatment of metastatic colorectal cancer.6 The ability to deliver this high dose of OXA is also more relevant considering that in both of these studies OXA and FU were combined with a 50.4 Gy RT course, while in previous studies of this combination, the RT dose was generally limited to 45 Gy.4,7 A fixed dose of 200 mg/ m2/d of FU was used in the US study. Why further escalation was not pursued is unclear. This is in fact a (slightly) reduced dose compared with the standard 225 mg/ m2/d commonly used in combined modality programs for locally advanced rectal cancer. In our original trial, FU could be escalated to 225 mg/ m2/d, in combination with OXA at 60 mg/ m2/wk, without additional toxicity. Of interest, the slightly reduced FU dose of CALGB 89901 does not appear to affect clinical activity with a pathologic complete response rate that is in the same range of our trial, possibly underlining the role of the incorporation of OXA in determining tumor response. Gastrointestinal toxicity among the patients treated with the recommended OXA dose appeared to be higher in the US study with 38% compared with 16% of patients experiencing grade 3-4 events. This might depend on differences in drug and RT scheduling. The interval between OXA administration and delivery of RT prescribed in CALGB 89901 might have resulted in more effective RT sensitization and, therefore, toxicity. However, the similar antitumor activity observed between the two studies argues against this explanation. Similarly, although the shortened duration of OXA infusion in the US study (1 hour) might theoretically affect toxicity, a selective effect on gastrointestinal toxicity is unlikely. Neurotoxicity rates were in fact slightly higher in our study (grade 1-2, 80% v 66%). This difference may have other explanations. While patients in our study were accrued and treated at a single institution, patients in the US study were recruited at several centers. Different toxicity grading systems may have also been used. While in our study toxicity was scored according to the Nation Cancer Institute Common Toxicity Criteria version 2, the scoring system used in the US trial was not specified. Despite the higher incidence of grade 3-4 diarrhea observed in the US study, the frequency of dehydration and electrolytes unbalances was in fact lower and comparable with that observed in our study. A further potential explanation for the higher toxicity rates observed in CALGB 89901 is the inclusion of patients up to age 79 years while the upper limit of the age range in our study was 73 years with only two patients older than 70 years accrued. Finally, this difference may be ascribed to the low number of patients analyzed in the two studies with large confidence limits for toxicity rates. A more real estimate of the toxicity associated with this regimen should thus be provided by the ongoing larger and controlled trials. Promising pathologic complete response rates are consistently reported in the two studies (28% and 25%). Assessment of the activity of this chemoradiotherapy regimen in randomized trials is thus deserved. Of note, comparative studies will also allow to investigate the potential activity of this chemoradiotherapy program that incorporates fully active doses of FU and OXA on micrometastases at distant sites. The currently ongoing US (National Surgical Adjuvant Breast and Bowel Project R-04) and Italian (Studio Terapia Adiuvante Retto [STAR]) randomized trials are thus particularly important for the world-wide development of this regimen of weekly OXA, infused FU, and pelvic RT originally generated in Italy. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES
1. Ryan DF, Niedzwiecki D, Hollis D, et al: Phase I/II study of preoperative oxaliplatin, fluorouracil, and external-beam radiation therapy in patients with locally advanced rectal cancer: Cancer and Leukemia Group B 89901. J Clin Oncol 24:2557-2562, 2006 2. Aschele C, Friso ML, Pucciarelli S, et al: A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer. Proc Am Soc Clin Oncol 21:132a, 2002 (abstr 527) 3. Aschele C, Friso ML, Pucciarelli S, et al: A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer. Ann Oncol 16:1140-1146, 2005 4. Freyer G, Bossard N, Romestaing P, et al: Addition of oxaliplatin to continuous fluorouracil l-folinic acid and concomitant radiotherapy in rectal cancer: The Lyon R97-03 phase I trial. J Clin Oncol 19:2433-2438, 2001 5. Carraro S, Roca EL, Cartelli C, et al: Radiochemotherapy with short daily infusion of low-dose oxaliplatin, leucovorin, and 5-FU in T3–T4 unresectable rectal cancer: A phase II IATTGI study. Int J Radiat Oncol Biol Phys 54:397-402, 2002[CrossRef][Medline] 6. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 7. Sebag-Montefiore D, Glynne-Jones R, Falk S, et al: A phase I/II study of oxaliplatin when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: A Colorectal Clinical Oncology Group (CCOG) study. Br J Cancer 93:993-998, 2005[CrossRef][Medline]
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
