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© 2002 American Society for Clinical Oncology
Chronomodulated Chemotherapy in Advanced Colorectal Carcinoma
Queen Elizabeth Hospital To the Editor:Chemotherapy for advanced colorectal carcinoma has progressed considerably in the last decade with new, non–cross-resistant drugs now available. Combinations of agents have resulted in time to progression1-3 and overall survival advantages.2,3 Alternatively, some investigators have explored the use of chronomodulated delivery systems, delivering both new and old drugs in a circadian rhythm seeking to maximize dose-intensity and subsequently outcomes, while also attempting to minimize toxicity. It is important to note, however, that despite the use of chronomodulation in combination schedules or as a single agent, there are to date no reported randomized trials comparing continuous infusion or bolus fluorouracil (5-FU) against chronomodulated 5-FU alone. Curé et al4 in the March 1, 2002 issue of the Journal of Clinical Oncology report their phase II trial of chronomodulated infusion of high-dose 5-FU and l-folinic acid in previously untreated patients with metastatic colorectal cancer. The outcome of this trial indicated that dose-intensification is possible and that overall response rate (RR) of single-agent 5-FU can be increased to 41%. Furthermore, median progression-free survival of 7 months and overall median survival of 17 months is reported. Grade 3 toxicity as reported consisted of mucositis, 26%; diarrhea, 21%; and hand-foot syndrome, 38%. Interestingly, no severe hematologic toxicity was seen. The authors suggest that this regimen is equivalent to current combination schedules in respect to RR and survival and allude to a toxicity advantage. However, although the toxicity is generally superior to oxaliplatin and CPT-11 combinations, there are alternate regimens using 5-FU that have resulted in significantly less toxicity and similar survival outcomes as those reported by Curé et al.4 For example, in a large randomized study, the combination of continuous-infusion 5-FU and mitomycin, as reported at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology in 1999, led to a RR of 43%, failure-free survival of 8.6 months, and overall median survival of 17 months. Moreover, grade 3 or 4 toxicity consisted of diarrhea, 6.5%; mucositis, 4%; and plantar palmar erythema, 5.9%. Hematologic toxicity was similarly very low.5 Moreover, this trial does go some way to answering the question as to the benefit of chronomodulated 5-FU. Both arms of this randomized trial contained mitomycin, with the only variable being the mode of 5-FU delivery. A circadian timed 5-FU regimen was compared with a protracted infusion 5-FU. Although it is acknowledged that the treatment design using a simplified circadian delivery system has drawbacks, dose-intensification was achieved. Despite this, failure-free and median survival was not altered. Levi et al6 have also reported results of a randomized trial comparing chronomodulation to flat-rate infusion; however, oxaliplatin was combined with 5-FU and also delivered in a chronomodulated fashion, complicating the interpretation of results. Median and 3-year survival did not differ between the chronomodulated and standard-infusion rate arms despite a higher RR and longer time to disease progression with chronomodulation. Superior response rates using chronomodulation have been reported previously. Response rates of 35% and 40% in chemotherapy-naïve patients were seen in two phase I/II studies of chronomodulated sinusoidal delivery of 5-FU alone as reported by Levi et al7 and Garufi et al,8 supporting a possible benefit over constant-rate 5-FU infusion. However, survival was not dissimilar to that reported for standard 5-FU schedules. Nonetheless, these trials were from a time when useful second-line therapy was not available. In recent times, second- and third-line chemotherapy for colorectal cancer has been increasingly used. In this current trial, 65% of patients received second-line therapy. Grothy et al9 recently reported a randomized phase III study of MAYO schedule 5-FU/folinic acid versus oxaliplatin/5-FU in abstract form. In the MAYO 5-FU/folinic acid arm a median survival of 16.4 months was reported. The use of sequential second- and third-line therapy, including oxaliplatin and CPT-11, was considered to be the prime reason for the much better overall survival than would be expected from previous trials using the MAYO schedule. Furthermore, aggressive hepatic resection has become acceptable in recent times and in Curé et al,4 12% of patients were able to have complete resection of metastasis. Second- and third-line chemotherapy and the use of hepatic resection may impact on survival, and thus, the results may not necessarily indicate superiority of the chronomodulated 5-FU regimen but merely reflect additional treatment options. Chronomodulation of drug delivery, in particular 5-FU, remains a promising method by which to attempt to maximize effectiveness of current chemotherapy agents. However, although Curé et al report encouraging RR, toxicity, and survival results for their regimen, it seems difficult to assess whether there is any superiority of this complex 5-FU delivery over simpler 5-FU schedules until a randomized phase III trial of a standard infusion or bolus 5-FU versus chronomodulated 5-FU is performed. Moreover, there are alternate schedules that are less toxic and have similar results. It would seem that the next step would be to take this regimen and compare it with a nonchronomodulated infusion 5-FU schedule to truly define a role for chronomodulation. Furthermore, the addition of a capecitabine or uracil and tegafur (UFT) arm would be very attractive. Having said this, in the era of combination regimens and novel targeted agents, it may be difficult to perform single-agent chemotherapy trials. REFERENCES
1. De Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or with out oxaliplatin as first line treatment in advanced colorectal cancer. J Clin Oncol 18: 2938-2947, 2000 2. Saltz LB, Locker PK, Pirotta N, et al: Weekly irinotecan (CPT-11), leucovorin (LV), and fluorouracil (FU) is superior to daily x5 LV/FU in patients (PTS) with previously untreated metastatic colorectal cancer (CRC). N Engl J Med 543: 905-912, 2000 3. 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]
4. Curé H, Chevalier V, Adenis A, et al: Phase II trial of chronomodulated infusion of high-dose fluorouracil and l-folinic acid in previously untreated patients with metastatic colorectal cancer. J Clin Oncol 20: 1175-1181, 2002 5. Price T, Cunningham D, Hickish T, et al: Phase III study of mitomycin-C with protracted venous infusion 5 fluorouracil or circadian timed infusion 5 fluorouracil in advanced colorectal carcinoma. Proc Am Soc Clin Oncol 18: 262a, 1999 (abstr 1008) 6. Levi F, Zidani R, Misset J: Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil and folinic acid in metastatic colorectal cancer. Lancet 350: 681-686, 1997[CrossRef][Medline] 7. Levi F, Soussan A, Adam R, et al: A phase I-II trial of five-day continuous intravenous infusion of 5-fluorouracil delivered at circadian rhythm modulated rate in patients with metastatic colorectal cancer. J Infus Chemother 5: 153-158, 1995 (suppl 1)[Medline] 8. Garufi C, Levi F, Aschelter AM, et al: A phase I trial of 5-day chronomodulated infusion of 5-fluorouracil and 1-folinic acid in patients with metastatic colorectal cancer. Eur J Cancer 33: 1566-1571, 1997[Medline] 9. Grothey A, Buechele T, Kroening H, et al: Phase III trial of bolus 5-fluorouracil (5FU)/folinic acid (FA) (MAYO) vs. weekly oxaliplatin plus high dose 24hr 5 FU infusion/FA in patients with advanced colorectal cancer. Eur J Cancer 37: S257, 2001 (suppl 6, abstr 954)
Response
Centre Jean Perrin, Clermont-Ferrand, France In Reply:Chronomodulated delivery schedules have indeed pioneered the recent progress in the chemotherapy for advanced colorectal cancer. In 1992, Lévi et al1 first reported a 58% objective response rate in patients with previously untreated metastatic colorectal cancer receiving a chronomodulated infusion of oxaliplatin (l-OHP), combined with fluorouracil (5-FU) and folinic acid (FA), given as a 5 days on, 16 days off regimen. This modality of administration was chosen, because (1) conventional delivery methods had then failed to show good activity or acceptable tolerability of l-OHP and (2) preclinical studies had shown a marked circadian dependency of the toxicity and the efficacy of both oxaliplatin and 5-FU.2-4 Therefore, the exploration of chronomodulated schedules did not constitute an alternative to the use of new drugs against colorectal cancer but critically contributed to the demonstration of oxaliplatin tolerability and activity against colorectal cancer and to its availability today. Two consecutive international randomized trials have further shown a 51% objective response rate with chronomodulated 5-FU/FA/l-OHP. In both trials, the chronomodulated schedule was several fold better tolerated than constant-rate infusion.5-6 The same international group further achieved an objective response rate of 66% using an intensified scheme (4 days on, 10 days off) as first-line chemotherapy of metastatic colorectal cancer. In this trial, patients were treated near individual maximum-tolerated dose, as a result of an intrapatient dose-escalation scheme, based on individual tolerability.7 In the current trial, we omitted l-OHP from the latter intensified regimen and searched for the antitumor activity of chronomodulated 5-FU/FA alone, as first-line treatment of metastatic colorectal cancer. Using independent review of computed tomography scans, we demonstrated that this two-drug chronomodulated combination achieved 41% objective responses.8 This figure ranks among those currently achieved by several schedules combining 5-FU and irinotecan or oxaliplatin. Because our goal was to treat each patient near individual maximum-tolerated dose, the occurrence of toxic events per patient is a proof of adequate protocol compliance and adequate reporting of toxic events. This strategy led to allow a large increase in dose-intensity.8 We fully agree with Price and Karapetis, however, that a definitive proof of activity increase should result from a randomized trial with conventional 5-FU/FA as a comparator yet that this trial would probably be difficult to achieve presently. Nevertheless, we also believe that this two-drug modality could also be compared at fixed doses with recent combination schedules involving l-OHP or irinotecan in metastatic or adjuvant situations. We agree with Price and Karapetis that many factors play a role on patient survival, beside first-line chemotherapy. These include second- or third-line treatment and surgery of metastases.9 Despite this limitation, the Chronotherapy Group of the European Organization for Research and Treatment of Cancer has just completed an international randomized trial addressing this issue (EORTC 05963). Chronomodulated 5-FU/FA is rather easy to administer to outpatients, using a programmable multichannel delivery pump, currently approved in Europe, the United States, and China. The patient only comes once to the hospital center to be connected to the pump, then returns home or continues his usual activities while receiving chronomodulated therapy. We are currently developing a program of outpatient distant programming and control of chronotherapy delivery through the internet. On another hand, several studies have suggested that this chronotherapy also improves quality of life as compared with conventional chemotherapy delivery.10 Thus, the available technology allows to deliver modern and complex treatments outside the hospital and without exhausting the patients. REFERENCES 1. Levi F, Misset JL, Brienza S, et al: A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump: High antitumor effectiveness against metastatic colorectal cancer. Cancer 69: 893-900, 1992[CrossRef][Medline]
2. Boughattas N, Levi F, Fournier C, et al: Circadian rhythms in toxicities and tissues uptake of oxaliplatin in mice. Cancer Res 49: 3362-3368, 1989 3. Granda TG, d’Attino RM, Filipski E, et al: Circadian optimisation of irinotecan and oxaliplatin efficacy in mice with Glasgow osteosarcoma. Br J Cancer 86: 999-1005, 2002[CrossRef][Medline] 4. Peters GJ, Van Dijk J, Nadal JC, et al: Diurnal variation in the therapeutic efficacy of 5-fluorouracil against murine colon cancer. In Vivo 1: 113-117, 1987[Medline]
5. Lévi F, Zidani R, Vannetzel JM, et al: Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: A randomized multi-institutional trial. J Natl Cancer Inst 86: 1608-1617, 1994 6. Levi F, Zidani R, Misset JL: Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer: International Organization for Cancer Chronotherapy. Lancet 350: 681-586, 1997[CrossRef][Medline] 7. Levi F, Zidani R, Brienza S, et al: A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma: International Organization for Cancer Chronotherapy. Cancer 85: 2532-2540, 1999[CrossRef][Medline]
8. Cure H, Chevalier V, Adenis A, et al: Phase II trial of chronomodulated infusion of high-dose fluorouracil and l-folinic acid in previously untreated patients with metastatic colorectal cancer. J Clin Oncol 20: 1175-1181, 2002
9. Giacchetti S, Itzhaki M, Gruia G, et al: Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10: 663-669, 1999 10. Pugliese P, Garufi C, Perrone M, et al: Quality of life and chronotherapy. Chronobiol Int 19: 299-312, 2002[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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