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Originally published as JCO Early Release 10.1200/JCO.2003.06.077 on July 14 2003 © 2003 American Society for Clinical Oncology
Carboplatin Equals Cisplatin: But How Do I Prescribe It?Royal Marsden Hospital, London, United Kingdom THE FINDINGS of the Gynecologic Oncology Group (GOG) Trial 111 and the European-Canadian study known as OV10 resulted in the adoption of the combination of cisplatin and paclitaxel as the new first-line chemotherapy standard of care for patients with advanced ovarian cancer.1,2 Bill McGuire had hardly left the podium after presenting the early results of GOG 111 at the American Society of Clinical Oncology Meeting in 1993 before the pressure was on to substitute carboplatin for cisplatin.3 There were, of course, good reasons for this: the well-established favorable toxicity profile of carboplatin, evidence from individual randomized trials, and a meta-analysis from the Advanced Ovarian Cancer Trialists Group that demonstrated little difference between the two platinum compounds in terms of efficacy.4,5 However, many were concerned that, as a matter of scientific principle, such a substitution could not be supported without appropriate evidence from randomized trials. There was also the concern that paclitaxel might afford tumors some protection against the cytotoxic effects of carboplatin, because it appeared to confer a protective effect against carboplatin-induced thrombocytopenia.6,7 Some clinicians believed that it was reasonable to exchange carboplatin for cisplatin in patients who had suboptimally debulked, advanced, poor-prognosis disease because chemotherapy in this patient group is palliative. There was also the opposing view that for potentially curable patients with optimally debulked ovarian cancer, mature data from properly sized clinical trials were needed before cisplatin could be abandoned in favor of carboplatin. Despite these legitimate concerns and an absence of randomized data, the combination of carboplatin and paclitaxel came into ever-increasing use for patients who were being treated outside of clinical trials—a testament, perhaps, to the toxicity and inconvenience of cisplatin therapy. Three randomized trials have addressed the substitution of carboplatin for cisplatin: a Dutch-Danish Intergroup Study,8 a trial from the Arbeitsgemeinschaft Gynäkologische Onkologie,9 and GOG 158, whose mature data are published in this issue of the Journal of Clinical Oncology.10 Preliminary results from all of these trials have been known for a number of years; data presented at the American Society of Clinical Oncology Meeting in 1997 strongly indicated that for end points such as response rate and progression-free survival, results were similar whether patients were treated with carboplatin plus paclitaxel or cisplatin plus paclitaxel.9,11 Interim analyses also showed no obvious overall survival differences. The early data from the Dutch-Danish and Arbeitsgemeinschaft Gynäkologische Onkologie trials turned the trickle of patients treated with carboplatin plus paclitaxel into something of a flood, and many international groups adopted carboplatin plus paclitaxel as their preferred platinum plus taxane combination regimen. GOG 158 provides additional data to show that the much less toxic and more convenient regimen of carboplatin and paclitaxel is the treatment of choice for patients with good-prognosis advanced ovarian cancer. The publication of GOG 158 does not simply confirm a widely held prejudice and thus merely draw a line under a detail of therapy; it is an opportunity for us to stop and ask yet again, what is optimal dosing for carboplatin? GOG 158 is part of the canon of pivotal trials that have defined the gold standard chemotherapy for ovarian cancer, but there is no uniformity among the trials as to the precise method of dosing carboplatin and we have no standard target dose. The Calvert formula, which is based on the glomerular filtration rate (GFR), is widely used to determine the dose of carboplatin.12 The drug is mainly eliminated via the kidneys, which is why a method of dosing that uses GFR gives an accurate prediction of both the area under the concentration-time curve (AUC) and the degree of myelosuppression associated with it.12 The Calvert formula has the added advantage of being prescriber-friendly. However, as always, the devil is in the detail; the Calvert formula was developed using GFR as measured by the 51Cr-EDTA method, but some use 24-hour urine collections to measure the creatinine clearance as an alternative, and it is well recognized that these can be inaccurate. The majority of clinical investigators and physicians calculate, rather than measure, the GFR by using formulas such as Jelliffe13 or Cockcroft-Gault14 and then insert these numbers into the Calvert formula, even though the original Calvert calculations were not derived from such sources. A calculated GFR is not the same as one that is measured, and creatinine clearance can exceed GFR by 10% to 40%.6,15–18 The commonly used formulas such as Jelliffe, Cockcroft-Gault, or Chatelut19 use serum creatinine; differences in the methodology for measuring serum creatinine (enzymatic or Jaffe) give different results and are an additional source of discrepancy.20,21 There have been a number of attempts to produce easy-to-use but more accurate formulas that do not depend on measuring the GFR.21–23 It has been suggested that the dose of carboplatin can be underestimated by 20% in 20% to 34% of patients if the Cockcroft-Gault or Jelliffe formulas are used.24 Such inaccuracies would obviously not be a source of error in randomized trials provided the method of dosing was the same in all treatment arms. The GOG has used the Jelliffe formula, at a target AUC of 7.5, for their trials. This is a good strategy to compensate for any underdosing that might occur when GFR is calculated, not measured. However, not all groups aim for this target AUC even when the GFR is calculated, and some have used target AUCs of 5 or 6, with the potential danger of underdosing. All such considerations are only important if there really is a platinum dose-response relationship in ovarian cancer. Devotees of the "more is better" school of oncology must face the uncomfortable truth that the majority of randomized trials have failed to show an overall survival benefit associated with an increase in the total dose or dose-intensity of platinum.25–28 There are exceptions, the best example of which is the Scottish study by Kaye et al,29 which demonstrated a survival advantage for patients treated on a 3-weekly (ie, day 1 every 21 days) cycle of cisplatin with 100 mg/m2 as opposed to 50 mg/m2. This initial survival benefit, however, was almost completely lost with longer follow-up (relative death rate, 0.68; 95% confidence interval, 0.46 to 0.99).30 The authors recommended that the high-dose schedule should not be used because of its associated long-term neurotoxicity, and that a dose of 75 mg/m2 should be the standard. Although this is a prevailing view, some have examined other perhaps less neurotoxic ways of delivering cisplatin in a dose-dense fashion.31 Investigators have also examined carboplatin. Some years ago, Eve Wiltshaw’s group32 performed the only randomized trial that examined dose-response with single-agent carboplatin. The planned increase in dose was 33%, but the actual delivered dose was only increased by 20%, with absolutely no improvement in response rate, progression-free survival, or overall survival. In the GOG 158 report, Ozols et al10 cite perhaps the most interesting study in the literature on carboplatin dose-response, that from Jakobsen et al.33 In this trial, the dose of carboplatin was doubled and the target AUCs were at the extremes of standard practice, AUC 4 and 8. AUC 4 is just below the threshold that most clinicians would normally use and AUC 8 is similarly just above most practice. Furthermore, AUC 8 is above the threshold suggested by Jodrell et al34 in their analysis of the relationship between carboplatin AUC and response. They found that above an AUC of 5 to 7 there was no incremental increase in response rate. The Jakobsen trial was completely negative, and although patients also received cyclophosphamide in this study, the trial indicates rather strong evidence that 20% to 30% differences in delivered carboplatin dose are irrelevant. Any discussion of dose-response in ovarian cancer is incomplete without a reference to the subject that always guarantees a thoroughly entertaining argument: namely, intraperitoneal chemotherapy. The data from randomized trials of intraperitoneal chemotherapy do support the premise that a dose-response exists.35–37 (This author is not a disciple, merely an observer of the intraperitoneal scene, so no letters please!) High-dose chemotherapy is another strategy by which dose-response relationships can be explored and we must await the results of current ongoing randomized trials. However, before rushing headlong into a series of such studies, it is worth pausing to remember that the fanfares that greeted high-dose chemotherapy for breast cancer are now somewhat muted. Nevertheless, there are lessons to be learned from other tumor types. For instance, high-dose chemotherapy does appear to benefit a proportion of patients with chemosensitive relapsed non-Hodgkin’s lymphoma. This paradigm suggests that maybe we should concentrate any trials of dose-response in ovarian cancer on patients with demonstrably chemosensitive disease. The publication of GOG 158 assures us that it is appropriate to treat good-prognosis ovarian cancer patients with carboplatin and paclitaxel. Inadvertently, it also prompts us to re-examine and standardize carboplatin dosing. Balancing the efficacy of carboplatin against its toxicity is obviously important and the Calvert formula (when a measured GFR is used) is ideal for this purpose. Unanswered questions remain, including whether we should measure or calculate GFR, how we should measure GFR, the method for assaying serum creatinine, the target AUC that gives an optimal therapeutic ratio, and the optimal formula. These questions are only relevant if there really is a dose-response relationship for carboplatin that results in an impact on overall survival. The current data from randomized trials indicate no benefit to increasing the dose of platinum, but by current standards, many of these trials are underpowered. The next large international collaborative trial should go back and try to definitively answer this simple but important question. REFERENCES
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36. Markman M, Bundy BN, Alberts DS, et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: An intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19:1001–1007, 2001 37. Armstrong DK, Bundy BN, Baergen R, et al: Randomised phase III study of intravenous (IV) paclitaxel and cisplatin versus IV paclitaxel, intraperitoneal (IP) cisplatin and IP paclitaxel in optimal stage III epithelial ovarian cancer (OC): A Gynecologic Oncology Group trial (GOG 172). Proc Am Soc Clin Oncol 21:201a, 2002 (abstr 803)
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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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