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© 2003 American Society for Clinical Oncology
Oxaliplatin for Colorectal Cancer in the United States: Better Late Than NeverRoyal Marsden Hospital, London and Surrey, United Kingdom OXALIPLATIN IS a third-generation platinum compound with a 1,2 diaminocyclohexane carrier ligand. This important difference in the molecule, and hence in the DNA adducts formed, confers a different spectrum of activity compared with cisplatin. In advanced colorectal cancer (CRC), two randomized studies from Europe reported promising results with oxaliplatin, fluorouracil (FU), and leucovorin (LV) as first-line treatment compared with FU and LV alone.1,2 Both studies showed significantly superior response rates and progression-free survival by the addition of oxaliplatin, with no improvement in overall survival (although the median survival in the control arms of these studies seemed to be longer than expected from FU/LV alone).1,2 The lack of an overall survival benefit might be partly explained by the high proportion of patients who crossed over to oxaliplatin or received irinotecan as second-line treatment; and in any event, these trials were only powered to show improvement in progression-free survival1 or maximum tumor response.2 On the basis of one of these studies,1 the European license for first-line treatment with oxaliplatin/FU/LV was granted in 1999. However, the Oncologic Drugs Advisory Committee and the Food and Drug Administration (FDA) did not approve the first-line indication of oxaliplatin for advanced CRC in March of 2000 because of the lack of an overall survival advantage. Furthermore, use of infused FU/LV regimens in the control arms of the European studies was difficult to compare with the standard bolus method of FU/LV administration used in the United States. At the same Oncologic Drugs Advisory Committee meeting, approval was granted for the use of irinotecan in combination with FU/LV (by bolus or infusion) as first-line treatment of metastatic disease based on two randomized trials, one European3 and one North American,4 that showed survival advantages to the combination compared with FU/LV. By then, irinotecan/FU/LV had already been approved in Europe. As a result, in Europe, clinicians could choose to use either oxaliplatin or irinotecan in combination with FU/LV as first-line treatment, and many patients were offered the alternative agent on treatment failure. In the United States, irinotecan/bolus FU/LV (IFL) became the new standard first-line treatment, but oxaliplatin remained unavailable. Subsequently, the United States Intergroup study N9741 used IFL as the control arm of the study and compared it with oxaliplatin and infused FU/LV (FOLFOX4) or irinotecan/oxaliplatin in the first-line treatment of CRC. FOLFOX4, compared with IFL, produced a better overall survival (median, 18.6 v 14.1 months, respectively; P = .002), time to disease progression (median, 8.8 v 6.9 months, respectively; P = .0009), response rate (38% v 29%, respectively; P = .03), and safety profile.5 Notably, approximately half of the patients randomly assigned to the FOLFOX4 arm received irinotecan on disease progression, whereas few patients in the IFL arm were given oxaliplatin as second-line treatment, which may, in part, explain the survival differences between each arm.
The EFC4584 study, reported by Rothenberg et al6 in this issue of the Journal of Clinical Oncology, led to the approval by the FDA on August 9, 2002, of oxaliplatin in combination with infused FU/LV for the treatment of patients with metastatic CRC whose disease had recurred or progressed during or within 6 months of completing first-line IFL therapy. In the EFC4584 study, the control arm was composed of bolus and infused FU/LV (LVFU2). Because the eligibility criteria allowed patients to enroll onto the trial within 6 months of finishing IFL, this poses the question of whether these patients were truly resistant to FU or irinotecan. Nevertheless, absence of objective responses and short time to tumor progression in the control arm confirms that these patients were indeed truly FU refractory, and therefore, changing the administration schedule of FU/LV did not yield much benefit. Moreover, 75% of patients in the study progressed on IFL, and only 8% had a treatment-free interval of more than 3 months between stopping IFL and commencing treatment in the EFC4584 study (M. Rothenberg, personal communication; Table 1
Single-agent oxaliplatin has been evaluated in patients with previously untreated or FU-refractory CRC.7–10 In previously treated patients, objective response rates (ORRs) of between 10% and 11% were reported in phase II studies.10 In EFC4584, the oxaliplatin monotherapy arm produced an ORR of 1.3% despite similar intended dose-intensities (43.3 mg/m2/wk in phase II studies v 42.5 mg/m2/wk in EFC4584). This difference in ORR is consistent with the lower response rates reported in randomized controlled trials compared with phase II studies, but this does raise an important issue in oncologic drug development. New drugs are usually first evaluated in advanced refractory disease, and a response rate of 1.3% for a new presumed cytotoxic drug is likely to halt further drug development, yet oxaliplatin has turned out to be an important drug as both first- and second-line treatment for advanced CRC. One of the unresolved issues with oxaliplatin was whether it was necessary to combine it with FU in patients whose disease was ostensibly FU resistant. In the EFC4584 study, oxaliplatin monotherapy was no better than changing the schedule of FU, but combining the two drugs led to improved tumor control, better symptom relief, and prolonged time to tumor progression. The molecular mechanism for this drug synergy is uncertain, but there are a number of candidate hypotheses including thymidylate synthase downregulation11 and reduced FU catabolism to inactive metabolites possibly at the dihydropyrimidine dehydrogenase level,12 although the evidence is conflicting.11–13 In a study by Pendyala et al,14 in esophageal cancer, oxaliplatin was shown to downregulate thymidylate synthase expression. Thus, oxaliplatin may also circumvent FU resistance in addition to exerting direct antitumor activity in CRC. In EFC4584, the effects of cross-over on survival remain to be seen, bearing in mind that the tumor response and time to tumor progression advantages of FOLFOX4 were based on 56% of total patients randomized. Moreover, with the FDA approval of oxaliplatin last year, some patients will have received FOLFOX4 after disease progression. In the absence of an overall survival advantage, is the delay in tumor progression time of 1.9 months that has been observed with FOLFOX4 clinically meaningful? The answer is yes because EFC4584 measured changes in tumor-related symptoms using the clinical benefit response similar to that used in the pivotal study of gemcitabine in advanced pancreatic cancer15 and demonstrated that FOLFOX4 produced more improvement in tumor-related symptoms than either LVFU2 or single-agent oxaliplatin. Neurotoxicity is one of the most important dose-limiting toxicities of oxaliplatin. Severe peripheral sensory neuropathy (grade 3 to 4) normally occurs in 10% to 15% of patients after a cumulative dose of 780 to 850 mg/m2 of oxaliplatin.16 In EFC4584, the median number of oxaliplatin courses administered in the FOLFOX4 arm was six, giving a cumulative dose of 510 mg/m2. This may explain the low incidence of severe peripheral neuropathy. Nevertheless, over half of the patients receiving oxaliplatin either as a single agent or as part of FOLFOX4 developed some degree of cumulative peripheral neuropathy. This is of particular relevance because patients are increasingly treated with oxaliplatin-containing regimens in first-line settings in which they are often treated until disease progression. The median cumulative dose of oxaliplatin in these patients may be 1,000 mg/m2 or more,1,2 which greatly increases the risk of neurotoxicity. Several strategies to decrease the incidence of peripheral neurotoxicity have been evaluated, such as the use of carbamazepine, gabapentin, calcium/magnesium infusions, and glutathione.16,17 Another important issue highlighted in the EFC4584 study was the occurrence of grade 3 to 4 thromboembolic events (8% with FOLFOX4 v 2% with LVFU2 v 1% with oxaliplatin). Most of these events were peripheral deep venous thrombosis. Recent concern has been voiced regarding whether irinotecan might also predispose patients to thromboembolic events.18,19 It seems that these new drugs may subtly alter the coagulation profile in patients with advanced CRC. Awareness and increased vigilance must be promoted to recognize the increased risks of thromboembolism when using these drugs. Despite the benefits seen with FOLFOX4, the infusion schedule used in FOLFOX4 is cumbersome and requires frequent hospital or clinic visits. Simplified infusion schedules of FU/LV have been developed with similar efficacy.20,21 Chronomodulated delivery of oxaliplatin and FU/LV may result in better efficacy and tolerability,22 but it adds extra complexity to the delivery of treatment. The combination of oxaliplatin and capecitabine has been used as first-line therapy, with ORRs of 43% to 55%,23–25 a progression-free survival time of 6 to 7.6 months,24,25 and a median overall survival time of 17.1 to 19.5 months.23,25 In pretreated patients, oxaliplatin plus capecitabine has only been assessed in one published study.23 Results obtained in these studies are comparable with those achieved with FOLFOX 4. Randomized trials are being planned to compare oxaliplatin and capecitabine with FOLFOX4 in both the first- and second-line settings. If proved to have similar efficacy, oral fluoropyrimidines may provide an attractive alternative, allowing one clinic visit every 3 weeks and simplifying the process of drug delivery. Oxaliplatin has been licensed in Europe since 1999, but it only gained FDA approval in the United States in August of 2002. The difference in the regulatory requirement delayed the arrival of this important drug in North America. In England and Wales, the current guidance from the National Institute for Clinical Excellence recommends oxaliplatin/FU/LV to be considered as first-line therapy only in patients with metastases confined solely to the liver, which may become resectable after treatment. Because this constitutes, at most, 30% to 40% of patients with advanced CRC, all other patients cannot routinely obtain oxaliplatin under National Health Service funding. Further efforts to harmonize the new drug-approval process globally may allow active new drugs to be available to cancer patients in a more timely fashion.
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2. Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136–147, 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]
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15. Burris HA III, 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 16. Gamelin E, Gamelin L, Bossi L, et al: Clinical aspects and molecular basis of oxaliplatin neurotoxicity: Current management and development of preventive measures. Semin Oncol 29:21–33, 2002[Medline]
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24. Grothey A, Jordan K, Kellner O, et al: Randomized phase II trial of capecitabine plus irinotecan vs capecitabine plus oxaliplatin as first-line therapy of advanced colorectal cancer. Ann Oncol 13:71, 2002 (abstr 258) 25. Sastre J, Brunet R, Butts CA, et al: Capecitabine-oxaliplatin combination (XELOX), an effective first-line therapy for patietns with metastatic colorectal cancer: Survival update of an international phase II trial. Ann Oncol 13:80, 2002 (abstr 288)
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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