Management of Platinum-Sensitive Recurrent Ovarian Cancer

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1 Management of Platinum-Sensitive Jacobus Pfisterer a and Jonathan A. Ledermann b The majority of patients with ovarian cancer will relapse despite state-of-the-art first-line surgery and chemotherapy. There are two subgroups of patients with recurrent ovarian cancer: those with platinum-resistant disease and those with platinum-sensitive disease. Re-treatment with single-agent platinum has long been considered standard therapy for patients with platinum-sensitive disease, and, based on its favorable therapeutic profile, carboplatin has become the treatment agent of choice. High response rates are seen with platinum agents used in combination with paclitaxel or gemcitabine. The International Collaborative Group for Ovarian Neoplasia (ICON) and the Arbeitsgemeinschaft für Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) recently conducted a trial (ICON4/ AGO-OVAR-2.2) comparing platinum monotherapy with platinum plus paclitaxel combined. Results showed that overall survival and progression-free survival are improved by combination therapy. Similarly, a significant benefit in progression-free survival for carboplatin plus gemcitabine versus carboplatin monotherapy was seen in the Gynecologic Cancer InterGroup trial. The toxicity profiles and schedules of carboplatin plus paclitaxel and carboplatin plus gemcitabine are different, with the taxane combination having greater neurotoxicity and alopecia, less hematologic toxicity, and requiring longer drug infusions (although fewer days of treatment per cycle) than the gemcitabine combination. Based on the results of these two trials, combination chemotherapy should be considered the standard treatment of recurrent platinum-sensitive ovarian cancer. The choice of treatment needs to take into account the increase in side effects when using combination chemotherapy compared with carboplatin monotherapy, and the different toxicities of the two combination regimens. Semin Oncol 33(suppl 6):S12-S Elsevier Inc. All rights reserved. espite progress in the first-line treatment of ovarian cancer, the majority of patients relapse and die within 5 D years because relapsed disease is incurable. 1,2 The goal of treatment is to eliminate or reduce symptoms, prolong symptom-free survival, and maintain or improve quality of life (QOL), with the aim of prolonging progression-free survival and overall survival. The management of relapsed ovarian cancer is complex. Once diagnosed, much of the care for patients is in the context of relapsed disease. Given the choice a Klinik für Gynäkologie und Geburtshilfe Campus Kiel, Universitätsklinikum Schleswig-Holstein, Germany. b Cancer Research UK and The University College of London Cancer Trials Centre, Department of Oncology, University College London, London, United Kingdom. Prof Pfisterer has received speaker s honoraria from Eli Lilly & Co. Dr Ledermann has served as a medical consultant and invited speaker for Eli Lilly & Co. Address reprint requests to Prof Dr Jacobus Pfisterer, Klinik für Gynäkologie und Geburtshilfe Campus Kiel, Universitätsklinikum Schleswig-Holstein Kiel, Germany. jpfisterer@ .uni-kiel.de of drugs that are active in ovarian cancer, careful consideration is needed when selecting the most appropriate drug(s) based on the extent and severity of the disease, the potential side effects, and patient preference. Retrospective studies of platinum-based second-line therapies have identified two subgroups of patients with recurrent ovarian cancer: those with platinum-resistant disease and those with platinumsensitive disease 3,4 ; the latter is defined by a relapse-free period of 6 months following a response to the final dose of platinum treatment. Considerations for the Management of Platinum-Sensitive Treatment decisions over the last 15 years have been based on empirical observations of platinum sensitivity. These have S /06/$-see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.seminoncol

2 Platinum-sensitive recurrent ovarian cancer S13 not been tested prospectively and it should be noted that platinum sensitivity in relation to the platinum-free interval is a discontinuous variable. Until recently, there were few practical alternatives to re-treatment with platinum, and platinum-based compounds remain the most active single agents for relapsed ovarian cancer. The decision to re-treat women with relapsed disease is based on the presence of symptoms and the volume of disease, rather than purely on the basis of a rising CA-125 level. The rationale for considering combination therapy at relapse is to overcome the relative resistance to platinum-based therapy. Higher response rates could control symptoms more quickly and might increase the time without chemotherapy and extend survival time. However, any benefit needs to be considered carefully against the risk of increased toxicity with combination chemotherapy. Any true benefit can be assessed only by including patients in prospective randomized studies and having a full discussion of the benefits and side effects with individual patients. Treatment of Platinum-Sensitive For platinum-sensitive patients, re-treatment with singleagent platinum is considered to be standard therapy. The expected tumor response rate (depending on the platinumfree interval) 3,4 is between 22% and 59%, which is somewhat higher than that seen with non-platinum drugs such as topotecan, paclitaxel, or pegylated liposomal doxorubicin. 5,6 Based on its favorable therapeutic profile, carboplatin (rather than cisplatin) has become the agent of choice. 7 High response rates have been reported by combining active drugs with platinum in the treatment of platinum-sensi- in 85% of the experimental group. At the median follow-up tive relapsed ovarian cancer. In a phase II trial, Dizon 8 et al reported a 62% response rate for carboplatin plus paclitaxel in platinum-sensitive relapse. A similar response was seen when gemcitabine was combined with carboplatin. 9 However, the interpretation of results of non-randomized trials is difficult, because patients with relapsed ovarian cancer are usually heterogeneous, and those treated with longer platinum-free intervals respond better to chemotherapy. Bolis et al 10 performed a randomized phase II study in 190 patients with carboplatin plus epidoxorubicin. The response rate to combination chemotherapy was 61.7% versus 56.2% with carboplatin monotherapy. However, there was no significant difference in response rate or time to progression in either group. The benefit of combination chemotherapy over monotherapy has been established in two randomized controlled trials that evaluated combination chemotherapy (platinum plus paclitaxel and carboplatin plus gemcitabine) versus single-agent platinum therapy in relapsed ovarian cancer. Platinum Plus Paclitaxel Combination Chemotherapy The International Collaborative Group for Ovarian Neoplasia (ICON) initiated a randomized trial in 1996 to assess the combination of platinum plus paclitaxel for treating patients with platinum-sensitive relapsed ovarian cancer. The ICON4 trial was coordinated by the Medical Research Council (MRC) in the UK and the Mario Negri Institute (IRFMN) in Italy. The German group Arbeitsgemeinschaft für Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) performed a similar but smaller trial (AGO-OVAR-2.2). A prospective combined analysis was planned for these two parallel studies and the results were published in Patients enrolled in the ICON4/AGO- OVAR-2.2 trial who required platinum chemotherapy were randomized either to standard platinum or to platinum plus paclitaxel. There were differences in the entry criteria: a platinum-free interval of 12 months was required by the IRFMN while the MRC/AGO-OVAR required 6 months; a prior paclitaxel dosage of 175 mg/m 2 was specified by the MRC/ IRFMN while the AGO-OVAR stated 185 mg/m 2 ; and six prior cycles of treatment were needed for the MRC/IRFMN studies while it was six to eight cycles for the AGO-OVAR study. Entry of patients in second relapse was permitted in the MRC protocol. The choice of platinum (cisplatin or carboplatin) was made by the physician at the time of randomization, and the minimum dose of carboplatin given was area under the curve (AUC) 5. The minimum dose of cisplatin alone was 75 mg/m 2, while cisplatin given in conjunction with doxorubicin and cyclophosphamide was given at a dose of 50 mg/m 2. All cycles were planned at 3-week intervals. A total of 802 patients were recruited from five countries for the trial, which closed in 2002; 92% of patients were randomized after first relapse and 75% were randomized more than 12 months after completion of platinum-based chemotherapy. Overall, 43% of patients had previously received a taxane. Carboplatin was used as a single agent in 71% of the control group, and in combination with paclitaxel of 42 months, 530 deaths had occurred. There was a significant survival advantage in favor of platinum plus paclitaxel (hazard ratio [HR], 0.82; 95% confidence interval [CI], ; P.023) (Fig 1A). At 2 years after randomization, the HR indicated an absolute improvement in survival rate in the combination arm of 7%, from 50% to 57% (95% CI for difference, 1% 12%). The difference in median survival time was 5 months, from 24 to 29 months (95% CI for difference, 1 11 months). A significant benefit was also seen in progression-free survival, which increased by 3 months, from 10 to 13 months (95% CI for difference, 1 5 months) (Fig 1B). The addition of paclitaxel to platinum did not cause a significant increase in toxicity, nor did it adversely affect the QOL of the patient. In particular, neurotoxicity was no more prevalent or severe in patients who had previously received a taxane as part of first-line therapy. These results showed, for the first time, that platinum plus paclitaxel improved the progression-free and overall survival of patients with relapsed ovarian cancer, but the reason for this benefit remains unclear. One possibility is that the ICON4/AGO-OVAR-2.2 trial tested the sequential use of paclitaxel. More than half of the patients in the study had not received paclitaxel as part of their first-line therapy, and an

3 S14 J. Pfisterer and J.A. Ledermann of non-platinum drugs. The population of cells with mutant p53 is greater in relapsed ovarian cancer, and this could also alter the pattern of drug sensitivity. 12 Despite the benefits of the ICON4/AGO-OVAR-2.2 study, many patients previously treated with paclitaxel were probably excluded from entering the trial because of persistent neurotoxicity. This is a common side effect of platinum plus paclitaxel combination therapy, where grade 1 4 neurotoxicity is seen in 75% of patients treated with carboplatin plus paclitaxel and in 83% of those receiving cisplatin plus paclitaxel as first-line therapy. 1 Neurotoxicity decreased slowly after cessation of therapy but often persisted for 2 years or more. Therefore, even though treatment with platinum plus paclitaxel at relapse improves survival, concerns about neurotoxicity remain, which emphasizes the need to explore other platinum combinations. Figure 1 (A) Overall survival and (B) progression-free survival (PFS) of patients treated with platinum plus paclitaxel (plat tax) or platinum monotherapy (plat chemo) in the International Collaborative Ovarian Neoplasm (ICON)4/Arbeitsgemeinshaft für Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR)- 2.2 trial. (Reprinted with permission. 11 ) exploratory subgroup analysis observed no clear evidence that paclitaxel plus platinum was more (or less) effective in this taxane-naive subgroup. Further subgroup analyses showed no difference in outcome based on several factors: length of time since completion of last chemotherapy, number of lines of previous chemotherapy, intended platinum agent, age of patient, performance status, and randomizing group. Another possibility is that greater benefit was derived from adding a second agent to the treatment regimen for patients with disease partially resistant to platinum therapy. There is clinical evidence for this, as response rates are lower in monotherapy studies. Furthermore, the presence of a tumor with a different biological constitution may favor the use Carboplatin Plus Gemcitabine Combination Chemotherapy The activity of the nucleoside analog gemcitabine in ovarian cancer and its promising phase II results in combination therapy with carboplatin 9,13-15 led to the randomized controlled trial of carboplatin plus gemcitabine versus carboplatin monotherapy. The randomized Gynecologic Cancer Inter- Group study was conducted by the AGO-OVAR, the National Cancer Institute of Canada Clinical Trials Group, and the European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group. 16,17 The primary objective of the trial was to compare progression-free survival between treatment arms in patients with platinum-sensitive recurrent ovarian cancer. Secondary objectives included comparisons of response rate, duration of response, overall survival, QOL, and toxicity. Three hundred sixty-five patients with platinum-sensitive recurrent ovarian cancer were randomized to either carboplatin monotherapy or carboplatin plus gemcitabine. Patients in the experimental arm received gemcitabine 1,000 mg/m 2 on days 1 and 8, and carboplatin AUC 4 on day 1; patients in the control arm received carboplatin AUC 5 on day 1 (based on the Calvert formula). 18 The AUC calculation was based on the glomerular filtration rate calculation according to the formula by Jelliffe. 19 Cycles were repeated every 21 days for six to 10 cycles unless progressive disease was documented, and the arms were well balanced for baseline characteristics. Patients in the carboplatin plus gemcitabine arm received 75.6% of the planned mean dose of gemcitabine (92.8% on day 1, 63.4% on day 8) and 96.2% of the planned dose of carboplatin. Patients in the carboplatin monotherapy arm received 98.2% of the planned dose. Grade 3/4 hematologic toxicities were significantly more frequent in the gemcitabine plus carboplatin arm than the carboplatin monotherapy arm. Neutropenia was the predominant toxicity but had minimal clinical relevance. No significant difference between treatment arms was seen in the frequency of febrile neutropenia and use of intravenous antibiotics. The overall incidence of grade 3/4 non-hematologic toxicities was modest, with less than 5% of patients in either

4 Platinum-sensitive recurrent ovarian cancer S15 arm experiencing nausea, vomiting, motor/sensory neuropathy, or renal toxicity. Of note, grade 2 alopecia was reported in 14.3% of carboplatin plus gemcitabine patients and 2.3% of carboplatin monotherapy patients. With a median follow-up of 17 months, the HR for progression-free survival was 0.72 (95% CI, ; logrank, P.0031), indicating a statistically significant improvement of 39% in the carboplatin plus gemcitabine arm. Median progression-free survival was 8.6 months (95% CI, months) for the carboplatin plus gemcitabine arm and 5.8 months (95% CI, months) for the carboplatin monotherapy arm, which was a significant improvement for the combination Fig ( 2A). Overall survival was assessed when 71% of the study population had died. The study was not designed or powered to detect overall survival differences between treatment arms. The HR for overall survival was 0.96 (95% CI, ; log-rank, P.7349). Median overall survival was 18.0 months (95% CI, months) for the carboplatin plus gemcitabine arm and 17.3 months (95% CI, months) for the carboplatin monotherapy arm, which did not constitute a significant difference (Fig 2B). The response rate was significantly higher in the carboplatin plus gemcitabine arm than in the carboplatin monotherapy arm (47.2% v 30.9%; P.0016). Median duration of response was 8.4 months (95% CI, months) in the carboplatin plus gemcitabine arm and 7.3 months (95% CI, months) in the carboplatin monotherapy arm (log-rank, P.2511). An exploratory subgroup analysis showed that improved progression-free survival was maintained in patients who received platinum plus taxane therapy in the first-line setting and in patients whose platinum-free interval was less than 12 months. The QOL scores showed no statistically significant treatment differences for baseline scores between treatment arms, or for score changes from baseline to treatment discontinuation between arms. Future Studies These results have led to the Gynecologic Cancer InterGroup conducting the CALYPSO study, comparing standard carboplatin AUC 5 and paclitaxel 175 mg/m 2 administered every 3 weeks versus carboplatin AUC 5 and pegylated liposomal doxorubicin 30 mg/m 2 every 4 weeks. The trial is designed as a non-inferiority study, and its primary endpoint is progression-free survival. Overall survival, toxicity, and QOL will also be compared. Conclusion Figure 2 (A) Kaplan Meier estimates of progression-free survival (PFS) for carboplatin monotherapy (C) versus carboplatin plus gemcitabine (GC). The HR for recurrence in the GC arm, as compared with the C arm, was 0.72 (95% CI, ; log-rank, P.0031). 16 (B) Kaplan Meier estimates of overall survival for C versus GC. The HR for survival in the GC arm, as compared with the C arm, was 0.96 (95% CI, ; P.7349). The study was not powered to detect significant differences in overall survival. 16 Median survival time of patients with advanced ovarian cancer is approximately 44 months. 1 Almost half the patients will have relapsed by 18 months and three quarters by 30 months. 1 Thus, the management of relapsed disease remains a major issue in the care of patients with ovarian cancer. Many of these patients have a good performance status and respond well to chemotherapy, and so should be treated with new agents in combination with chemotherapy. Until recently, single-agent platinum was the primary treatment used until tumor resistance intervened, while combination chemotherapy was used less often and was mainly confined to phase II studies. Improvement in overall survival is the gold-standard for treatment, and this was the primary endpoint of the very large ICON4/OVAR-2.2 trial. The use of multiple therapies after the completion of a randomized study in relapsed ovarian cancer might obscure the benefit of combination therapy. On this basis the carboplatin plus gemcitabine study was

5 S16 J. Pfisterer and J.A. Ledermann Table 1 Efficacy and Toxicity Between Two Randomized Trials of Platinum-Based Combinations in the Treatment of Relapsed Ovarian Cancer Carboplatin Plus Paclitaxel Versus Carboplatin Carboplatin Plus Gemcitabine Versus Carboplatin References Efficacy Effective (PFS, OS) Effective (PFS) Dosing schedule Day 1 every 3 weeks Days 1 and 8 every 3 weeks Toxicity Neurotoxicity Hematologic toxicity Alopecia rate 86% 15% Quality of life No worsening No worsening Abbreviations: OS, overall survival; PFS, progression-free survival. designed to show a significant benefit in progression-free survival. Extension in progression-free survival increases the time without chemotherapy and can be valuable in a situation where patients have several courses of treatment to extend their survival. The results of two recent randomized trials have shown that platinum-based combination chemotherapy has a significant effect on the outcome of platinum-sensitive relapsed ovarian cancer. For platinum plus paclitaxel, there was an increase in survival but this was associated with additional symptomatic toxicity. Alopecia and neurotoxicity were not significant side effects seen with carboplatin plus gemcitabine. However, this combination showed only an increase in progression-free survival, and was associated with greater hematologic toxicities, although they were not usually symptomatic. Although the schedule of attendance for treatment with carboplatin plus gemcitabine on days 1 and 8 was greater, the infusion of platinum plus paclitaxel was longer. When selecting a particular treatment option, careful consideration should be given to the results of these trials, and mainly to the levels of toxicity of both combinations versus carboplatin monotherapy Table ( 1). The benefits of such drugs may be useful at this stage of the disease, and the findings may assist future first-line studies, where progress is much needed. References 1. du Bois A, Lück HJ, Meier W, et al: A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95: , Ozols RF, Bundy BN, Greer BE, et al: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 21: , Markman M, Rothman R, Hakes T, et al: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9: , Gore ME, Fryatt I, Wiltshaw E, et al: Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. 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