© 2005 European Society for Medical Oncology
A phase II study of a paclitaxel and oxaliplatin combination in platinum-sensitive recurrent advanced ovarian cancer patients
1 Institut Paoli-Calmettes, UMR 599, Université de la Méditerranée, Marseille; 2 Centre Paul Strauss, Strasbourg; 3 CAC, Le Kremlin-Bicêtre; 4 Hôpital Bretonneau, Tours; 5 Fondation Hôpital Saint Joseph, Paris; 6 Hôpital St Louis, Paris; 7 Centre Paul Papin, Angers; 8 Hôpital Tenon, Paris, France; 9 University Hospital, Gent, Belgium; 10 Institut Curie, Paris, France
* Correspondence to: Dr. A. Yovine, CAC, 18 rue Pasteur, 94278 Le Kremlin-Bicêtre, France. Tel: +33-1-45-15-40-85; Fax: +33-1-45-15-40-45; E-mail: a.yovine{at}caconcology.com
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Abstract |
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Purpose: A multicentric, phase II study to evaluate the efficacy and safety of the combination paclitaxel and oxaliplatin in patients with platinum-sensitive recurrent ovarian cancer.
Patients and methods: Patients received 175 mg/m2 paclitaxel (over 3 h) followed by 130 mg/m2 oxaliplatin (over 2 h) every 21 days for up to nine cycles without hydration or primary granulocyte colony-stimulating factor prophylaxis. Patients had to have an Eastern Cooperative Oncology Group performance status of 0–2 and to have received no more than one prior cisplatin- and/or carboplatin-containing chemotherapy regimen with a platinum-progression-free interval 
6 months.
Results: Of the 105 patients enrolled and treated, 98 were eligible. An overall response rate of 81% (79 of 98 patients) (95% confidence interval 71% to 88%) was observed according to RECIST criteria (third party reviewed), and 88% (86 of 98) when this was complemented with CA-125 response. With a median follow up of 43.6 months (range 30.2–64.2) the median progression-free survival was 10.2 months (range 0.3–21.4) and the overall survival 32.4 months. Seven hundred and eight cycles were administered (median seven per patient; range one to nine). A total of 67% of patients experienced National Cancer Institute Common Toxicity Criteria grade 3–4 neutropenia, including 8% with concomitant febrile episode, without treatment-related deaths. Ninety-three per cent of patients experienced neuropathy of grade 1 or more, including 25% with cumulative reversible peripheral neuropathy of grade 3–4. Oxaliplatin doses were reduced in 30 patients due to neurotoxicity.
Conclusions: The oxaliplatin/paclitaxel combination can be administered in an outpatient setting every 3 weeks without specific measures. The high level of activity and its duration observed warrants further evaluation of this combination in pretreated platinum-sensitive advanced ovarian cancer patients.
Key words: ovarian cancer, oxaliplatin, paclitaxel, phase II, platinum-sensitive
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Ovarian cancer has the highest mortality rate of any gynecological cancer, with an estimated 25 400 new cases and 14 300 deaths in the USA in 2003 [1
]. The standard treatment for newly diagnosed advanced ovarian cancer (AOC) is maximal debulking surgery and combination chemotherapy with a platinum salt and a taxane [2, 3]. Despite the high response rate (RR) of first-line therapy, more than 50% of patients relapse and die from chemo-resistant disease within 5 years of the initial diagnosis [4, 5]. Patients with recurrent disease are candidates for salvage chemotherapy. Treatment of relapsed disease represents a major therapeutic challenge as treatment is not standardized. Choice of therapy depends on a variety of factors, such as platinum-resistance status, extent and bulk of the disease and the patient's general condition [6]. Currently, most patients (80%) with relapsed AOC have platinum-sensitive disease [4, 5] (6 months platinum- and progression-free interval) and re-treatment with a platinum compound offers an RR of 22–59% depending on the length of the disease-free interval [7]. Overall RRs for most single-agent non-platinum compounds are around 30% in patients with a platinum-free interval (PFI) of between 6 and 36 months [8]. The benefits of combination chemotherapy in terms of RR and progression-free survival (PFS) have recently been shown in randomized trials for the platinum-sensitive population [9–13].
Paclitaxel in combination with cisplatin or carboplatin has come to constitute the standard primary treatment for AOC [3–5]. In patients with relapsed disease, paclitaxel has elicited RRs between 13% and 36% on a variety of schedules, depending on the platinum-resistance status [14–17].
Oxaliplatin [oxalato-(trans-l-1,2-diaminocyclohexane) platinum; l-OHP, OXA; Sanofi-Synthélabo, Paris, France] is a new generation platinum compound, characterized by a diaminocyclohexane (DACH) ligand, which binds to DNA, blocking replication and transcription leading to apoptosis [18]. It has demonstrated antitumor activity in cell lines with intrinsic or acquired cisplatin/carboplatin resistance [19]. Oxaliplatin is active against cell lines with mismatch repair (MMR) deficiency, which is prevalent in cisplatin and carboplatin pretreated tumors and associated with resistance to cisplatin/carboplatin [20, 21]. MMR deficiency has been reported in 5–25% of primary AOC tumors [22] and this deficiency increases to over 60% in platinum pretreated tumors, owing to selective sparing of cells with either genomic deficit or epigenetic gene silencing [23, 24].
Oxaliplatin has exhibited preclinical additivity or synergy with most agents tested to date, including paclitaxel [25]. Clinical studies of single-agent oxaliplatin in pretreated patients with AOC have reported objective RRs of 4–46% depending on the platinum sensitivity, and an excellent safety profile [15, 26–28]. The combination of oxaliplatin (100–130 mg/m2) and paclitaxel (135–175 mg/m2) was first evaluated in an investigator-originated program in France [29]. The excellent toxicity profile, associated with a reported 61% RR and a median PFS of 9 months in the platinum-sensitive population, prompted us to undertake the present phase II trial, in which the single agent recommended dose for each agent is administered together every 3 weeks.
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patients and methods |
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patient population
Patients with confirmed epithelial ovarian cancer were required to have had only one previous platinum-containing regimen followed by a minimum progression-free period of 6 months. Treatment with a dose-intense carboplatin-based regimen was allowed if considered part of the strategy for first-line therapy. The patients were to have at least one measurable lesion or non-measurable disease with progressing serum CA-125 levels (>25% increase in two successive measurements at least 4 weeks apart) from a baseline of at least 50 IU/ml. They were also to have an Eastern Cooperative Oncology Group (ECOG) performance status of
2. Patients were also excluded if previous cumulative doses of cisplatin >600 mg/m2, unresolved bowel obstruction, ongoing sensory-neuropathy of National Cancer Institute Common Toxicity Criteria (NCI CTC) grade 2 or higher, any prior history of malignancy, or known brain or leptomeningeal involvement.
Laboratory-based criteria for inclusion included: neutrophil count 2000/mm3, platelet count 100 000/mm3, serum creatinine level 1.5x institutional upper limit of normal (ULN), and alkaline phosphatase and total bilirubin 1.25x ULN (5x ULN and 1.5x ULN, respectively, for patients with liver metastases). The protocol was approved by the ethics committees in accordance with French and Belgian law, and signed informed consent was obtained prior to inclusion.
study design
Patients were to receive 175 mg/m2 paclitaxel intravenously over 3 h followed immediately by 130 mg/m2 oxaliplatin intravenously over 2 h, every 3 weeks. Premedication with prednisolone, dexchlorpheniramine, ranitidine or an equivalent compound, and a 5-HT3 blocker were recommended.
Treatment was to be administered for nine cycles, except in case of disease progression, unacceptable toxicity or patient refusal. No primary granulocyte colony-stimulating factor (G-CSF) prophylaxis was indicated, but in case of febrile neutropenia or grade 4 neutropenia lasting >5 days, a 5-day course of G-CSF was to be administered during the subsequent cycle, and if the toxicity recurred, first paclitaxel and then both drugs were to be reduced by 20% (paclitaxel 140 mg/m2 and oxaliplatin 100 mg/m2). In case of grade 4 thrombocytopenia, the oxaliplatin dose was to be reduced by 20% followed by reduction of the paclitaxel dose and then treatment discontinuation if toxicity recurred. In case of acute pharyngo-laryngeal dysesthesia, the duration of the oxaliplatin infusion was to be extended to 6 h, and in case of grade 2 paresthesia/dysesthesia (oxaliplatin-specific scale) [30] the oxaliplatin dose was reduced by 20% and then discontinued if the toxicity recurred. For other NCI CTC grade 3–4 toxicities, the doses of both drugs were to be reduced by 20%, with a 1- to 2-week delay until recovery to at least grade 1, and treatment discontinuation in case of persistent grade 2 after day +35.
study assessments
Clinical examinations and biochemical analyses were performed at the beginning of each cycle. A complete blood count was performed once a week, or more often in case of grade 4 hematological toxicity. Toxicity was assessed using NCI CTC version 1, complemented by an oxaliplatin-specific scale for peripheral sensory neuropathy [30]. All treated patients were considered evaluable for toxicity.
Efficacy is reported only for eligible patients. The primary end point was confirmed (two determinations at least 4 weeks apart) objective response rate (ORR). An external response review committee (ERRC) was to assess all patients for eligibility, evaluability and efficacy (ORR, response duration and PFS). Patients were evaluable for response if they had measurable disease according to RECIST criteria [31] or if they had evaluable but non-measurable disease and CA-125 response (baseline CA-125 level 50 U/ml). In patients with a target lesion, response was evaluated using RECIST criteria and CA-125 was taken into account only in order to confirm complete response and to determine disease progression (increase of CA-125 levels 25% confirmed 4 weeks later). Patients with only a non-target lesion were evaluated using an algorithm combining the RECIST criteria for non-target lesions and a CA-125 assessment. CA-125 response criteria were adapted from those proposed by Rustin et al. [32] as follows: complete response (CR), normalization of CA-125 over a period of at least 3 months; partial response (PR), normalization lasting <3 months or decrease of 75% from baseline lasting at least 4 weeks; progressive disease (PD), any increase of 25% above nadir during treatment, confirmed at least 4 weeks later; and stable disease (SD), patients not qualifying for CR, PR or PD. For patients who were not reviewed by the ERRC, the investigator's assessment was employed, provided that all available clinical and biological data corroborated this assessment. Radiological tumor assessment was scheduled for cycles 2, 4, 6 and 9, and every 3 months thereafter until disease progression. The CA-125 serum level was measured on day 1 of every cycle during study treatment and every 3 months after treatment discontinuation. A combined ERRC and CA-125 response was determined, taking the best confirmed response from either method.
PFS and overall survival (OS) were measured from the first day of treatment. Duration of response was measured from the first day that a response was observed. Date of progression was the earlier of progression according to RECIST and CA-125 criteria.
statistical methods
The study sample size was initially determined by applying separate Simon two-stage minimax designs to taxane-pretreated patients and taxane-naive patients [33]. In the first stage, 15 and 19 evaluable patients were to be enrolled in each group, respectively. A total of 25 and 39 patients, respectively, were to be enrolled if sufficient responses were observed in the first stage. However, owing to the impressive efficacy results observed at the interim analysis undertaken following completion of the first stage, the protocol was amended to increase the total number of patients to 100 in order to allow pharmacokinetic analysis (the results of which are not presented here) and better characterize the efficacy and safety profile of the combination.
The planned statistical analysis was purely descriptive; the Kaplan–Meier method was employed to characterize time to event data. No comparisons were planned between treatment groups. Ad hoc comparisons of efficacy parameters in taxane-pretreated and -naïve patients employed the 
2 and log-rank tests, as appropriate.
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patient characteristics
Between March 1999 and October 2002, 105 patients were enrolled and treated in 12 French and two Belgian cancer centers. Seven patients were considered ineligible: three had received more than one prior platinum-based regimen, three had ongoing bowel obstruction and the progression PFI from the last treatment was impossible to determine for two patients (one of whom was already ineligible for the first reason). Out of the 98 eligible patients, 75 (77%) were taxane-pretreated and 23 (23%) were taxane-naïve.
Patients were generally in good condition, with 95% of treated patients having a performance status of 0–1, and 73% being under 66 years old (Table 1). The majority of patients (71%) had received prior carboplatin, which was more frequently used in the taxane-pretreated group (80% versus 40% for the taxane-naive patients). Fifteen patients had received prior high-dose chemotherapy with bone marrow and/or peripheral blood stem cell transplantation. Overall, the taxane-pretreated and -naive patients were quite similar in terms of demographic and disease characteristics, except for the median progression PFI, which was shorter in the taxane-pretreated group. Sixty-six per cent of patients had disease progression more than 12 months after their first-line treatment.
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treatment
A total of 708 cycles were administered, with a median of seven cycles per patient (range one to nine; Table 2). Relative dose intensities of paclitaxel and oxaliplatin were 0.97 and 0.95 respectively; 84% of patients received at least six cycles, including 25 patients who received the full nine cycles as planned. Thirty-four patients discontinued due to treatment-related adverse events after a median of six cycles (range two to nine). The most common cause for discontinuation was late-onset cumulative sensory neuropathy in 21 patients, after a median of six cycles (range three to nine). Eight patients discontinued due to hematological toxicity (febrile neutropenia in three patients, grade 3 thrombocytopenia and/or grade 2 neutropenia persistent at day +35 in five patients). Two patients discontinued due to allergic reactions (one related to paclitaxel and the other related to oxaliplatin). Thirty-seven patients out of the 103 receiving two or more cycles (36%) had oxaliplatin dose reductions, mostly due to neurotoxicity (30 patients) and neutropenia (five patients). Eight of these patients also had reductions in the paclitaxel dose, including five due to neurotoxicity. Only 3% of cycles were delayed, most of them (79%) due to neutropenia and/or thrombocytopenia. The majority of delays (70%) were of 1 week duration.
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safety
The most prevalent grade 3–4 toxicity was neutropenia, occurring in 67% of patients and 41% of cycles (Table 3). The incidence of febrile neutropenia was relatively high (eight patients, nine cycles), but of short duration and manageable in an outpatient setting in three of the eight patients. G-CSF was used in 25 cycles (4%). Only two patients required platelet transfusion and one patient red blood cell transfusion. The rate of hematological toxicity was higher among the 15 patients who had received previous high-dose chemotherapy (high-dose carboplatin, cyclophosphamide and/or melphalan) with hematological support. Non-hematological adverse events were mostly mild to moderate and manageable. Treatment-related peripheral neuropathy was observed in 93% of the patients. Grade 3–4 neuropathy was observed in 26 patients (25%), and was related to the cumulative dose of both oxaliplatin and paclitaxel; the rate being 6% (one out of 17) in patients receiving less than six cycles and 26% (23 out of 88) in patients receiving between six and nine cycles. Prior treatment with paclitaxel or cisplatin was not associated with a different rate of neurotoxicity or a different median dose at onset. Neuropathy resolved in 64% of patients who were followed up and improved in 21%, with a median time of 8.5 months (range 0.22–22) to resolution (Table 4). The rate of resolution of all grades of neurological symptoms, estimated according to the Kaplan–Meier method, was 36% at 6 months and 64% at 10 months. At the time of the last follow up, two patients were still experiencing grade 3 neuropathy, at 2.2 and 16.4 months.
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efficacy
Response to treatment in the 98 eligible taxane-pretreated and -naive patients is summarized in Table 5. All but three responses were reviewed by the ERRC. According to RECIST criteria, there were 20 responses (87%) among the 23 taxane-naive patients, and 59 responses (79%) among their 75 taxane-pretreated counterparts. In the 79 patients with a response according to RECIST criteria who were evaluable for CA-125 response, 76 (96%) experienced CA-125 response. Seventy-two out of the 79 CA-125 responses (91%) were associated with a radiological response. A combined RECIST and CA-125 response was observed in 88% [95% (confidence interval) CI 80% to 94%] of the 98 eligible patients. One out of the three ineligible patients who had received more than one prior platinum-based line had a confirmed partial response after eight cycles of study treatment, while another received six cycles and had a CA-125 response. As anticipated, none of the three patients with ongoing bowel obstruction responded to the study treatment [34
]. No difference was observed in ORR (RECIST) according to PFI (83% and 81% in patients with PFI of 6–12 months and >12 months, respectively). The ORR (combined ERRC and CA-125) for the whole treated population was 84% (95% CI 75% to 90%) (21 CR, 65 PR, six SD and six PD).
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As of February 2003, 68 of the 98 eligible patients (69%) had progressed and the median PFS was 10.2 months (95% CI 8.5–11.7; Figure 1). The median PFS was 13.9 months in taxane-naïve patients and 9.1 months in taxane-pretreated patients. Survival was updated in May 2005 for the 98 eligible patients, and with a median follow-up of 43.6 months (range 30.2–64.2); 59 of the eligible patients (60.2%) had died. The estimated median survival is 32.4 months (95% CI 24.7–40).
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discussion |
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The best choice of treatment for patients with platinum-sensitive recurrent ovarian cancer is still a matter of controversy and requires further investigation [6
]. Many cytotoxic compounds have been demonstrated to be active as single therapy agents in this setting, with comparable ORRs in the range of 20–40% and PFS in the range 3–6 months [7, 8, 15, 27, 35–38]. Combination regimens, especially platinum-based ones, have shown consistently higher ORRs (40–90%) and longer PFS (6–12 months) in phase II/III trials and retrospective analyses [9–13, 39–42]. However, there are only a limited number of published trials of randomization to combination or single-agent chemotherapy. In studies by Bolis et al. [10] and Cantu et al. [9], no statistically significant differences were observed in terms of ORR, PFS or OS. Nevertheless, a trend in favor of the combination regimens was observed. The recently published ICON4/AGO-OVAR-2.2 trial [11], which randomized patients with platinum-sensitive recurrent ovarian cancer to paclitaxel/platinum versus platinum-based chemotherapy without paclitaxel, found a statistically significant difference in favor of the paclitaxel/platinum arm in terms of PFS (12 versus 9 months) and OS (29 versus 24 months). Most patients (77%) in the non-paclitaxel arm were treated with single-agent platinum therapy, providing indirect evidence that the paclitaxel/platinum combination is superior to single-agent platinum in this setting. Preliminary results of a large Gynecologic Cancer Intergroup phase III trial (carboplatin versus gemcitabine/carboplatin) [13] and the phase II randomized trial by the GEICO group (carboplatin versus carboplatin/paclitaxel) [12] appear to confirm the superiority of platinum-based combination. This supports their use in patients with good performance status for whom the symptomatic relief and/or the reduction of the tumor burden associated with a prolonged progression-free period is crucial.
Resistance to cis/carboplatin is an important issue when selecting a second-line treatment. The presence of MMR defects leads to resistance to both compounds and these defects, which usually occur via the loss of hMLH1 and hPMS2 gene functionality, are observed in up to 30% of patients diagnosed with ovarian cancer prior to any chemotherapy, [22] and its frequency increases significantly after treatment with either compound [23, 24]. By contrast, the MMR complex is not implicated in the apoptosis mechanism triggered by the DACH-platinum-DNA adducts formed by oxaliplatin, which partially explains the lack of cross-resistance to oxaliplatin in cis/carboplatin-resistant cell lines [19–21]. Thus, as treatment with cis/carboplatin selects for preexisting MMR-deficient cells contributing to the development of clinical resistance, treatment of relapsed ovarian cancer with oxaliplatin is a rational option. Of interest, oxaliplatin's initial formal clinical development in France in the early 1990s was focused on ovarian cancer, with a phase III trial in first-line AOC comparing its combination with cyclophosphamide versus the old standard cisplatin/cyclophosphamide, showing no difference in efficacy, with an improved safety profile for the oxaliplatin-based combination [43]. Clinical studies of single-agent oxaliplatin in relapsed ovarian cancer have reported encouraging activity and confirmed its good safety profile [15, 26, 27]. Oxaliplatin combined with paclitaxel and cisplatin displayed clinical synergy, with an 85% RR in a limited sample of platinum-sensitive AOC patients [44]. The oxaliplatin/paclitaxel combination was further evaluated in an investigator-originated pilot compassionate-use program that motivated the present study [29], with interesting results in the platinum-sensitive population (ORR 61% and median PFS 9 months).
When the present study was designed, paclitaxel was just beginning in France to gain prevalence as standard primary treatment for AOC patients. Seventy-six per cent of our patients had received previous taxane treatment, reflecting the current standard patient pretreatment profile for second-line therapy.
The activity of the paclitaxel/oxaliplatin combination was remarkable. Confirmed radiological and CA-125 response was observed in 81% and 88% of eligible patients, respectively. Most CA-125 responses (92%) were in agreement with the radiological response, which corroborates the clinical relevance of the assessment based on tumor markers. It has recently been shown that CA-125 levels can accurately predict progression-free survival and correlate with radiological response to single-agent or combination therapy tested in phase II trials for ovarian cancer [45, 46]. In fact, patients can actually be classified as responding or progressing according to either standard radiological or CA-125 criteria, and as these methods of evaluation are not mutually exclusive, the combination of both is an acceptable alternative to either method used on its own. Thus, an 88% rate of combined response was observed. Of note, of the five patients with a clear-cell histology, only two achieved an objective response (40%), the low RR in this histologic type being consistent in other studies results.
Interestingly, this regimen showed activity across a wide range of platinum progression-free intervals (from 6 to >24 months), while higher activity was observed in taxane-naive patients. This could possibly be attributed to acquired pleiotropic drug resistance generated by previous exposure to taxanes.
The time-related efficacy results obtained in this large multicenter cohort are encouraging. The median PFS was 10.2 months (95% CI 8.5–11.9) and the median OS was 32.4 months.
Efficacy results of our study are not easily comparable with the results of other published studies and retrospective analysis of combination chemotherapy in this setting, owing to major differences in the methodology used for the evaluation of response and time-related parameters. The most important restrictive methodological difference highlighting the reliability of our results is the absence of external review of efficacy in most published studies and retrospective analyses. An exception is the phase II study of carboplatin/paclitaxel conducted by Guastalla et al. [39], in which a 70% RR was observed in the only 20 evaluable patients out of the 30 with platinum-sensitive disease (all of them with a PFI of >12 months). No information was provided about time-related parameters in this cohort of patients.
With 84% of patients receiving six or more cycles, the outpatient oxaliplatin/paclitaxel regimen is feasible, with toxicity reversible and easily manageable. Grade 3–4 neutropenia was prevalent in this study (67% of patients), but it was complicated by fever in only 8% of patients. G-CSF was infrequently used (4% of cycles), which compares well with other platinum-based combinations in the same setting [9, 11–13], excepting the epirubicin/carboplatin combination that requires systematic administration of G-CSF [3]. Grade 3 and 4 thrombocytopenia was uncommon (16% and 1%), its frequency being lower than that observed with carboplatin/epirubicin (33% and 31%) [10], carboplatin/topotecan (25% and 5%), [47] carboplatin/gemcitabine (35%) [13] and cisplatin/gemcitabine (67% and 30%) [48]. Even if cumulative sensory neuropathy was frequent, it did not prevent the administration of at least six cycles in most patients. Furthermore, the rate of functional impairment (grade 3 oxaliplatin-specific scale or grade 2–4 on the NCI CTC version 2 scale) was comparable to the rate observed after six to nine cycles of cisplatin or carboplatin/paclitaxel therapy (13–50% of patients after six cycles) [5, 49]. Neurotoxicity was reversible after treatment discontinuation, with complete resolution or improvement in most patients after a median of 8.5 months. It appears that previous exposure to cisplatin and/or paclitaxel does not increase the rate of grade 3–4 neurotoxicity and that the frequency and severity of the neuropathy are only slightly increased in comparison with oxaliplatin monotherapy, while still being reversible in the majority of patients [50]. Treatment discontinuation due to allergic reactions was rare and less frequent than generally reported in case of retreatment with carboplatin in this setting [9–11, 39, 51].
In conclusion, the results encourage comparative trials with the current standard approaches such as carboplatin paclitaxel or other promising combinations in platinum-sensitive AOC patients. This combination has a good safety profile and can be administered in an outpatient setting without special safety measures. The oxaliplatin/paclitaxel combination has a good risk/benefit ratio, and is, in our opinion, a new option of choice for the second-line treatment of potentially sensitive ovarian cancer. A controlled clinical trial verifying this hypothesis against the carboplatin/taxane standard could elicit the best progression-free combination. This problem appears of major strategic importance given that the great majority of AOC patients will be potentially platinum sensitive and a multiyear life expectancy is within reach of most recurring AOC patients.
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Acknowledgements |
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The authors wish to thank Dr Véronique Cadic for statistical analysis and Dr Jonathan Simon for assistance with the manuscript. This work was supported by Sanofi-Synthélabo, Paris, France. Presented in part at the ECCO 11; The European Cancer Conference, Lisbon, Portugal, 2001; The Thirty-Eighth Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, USA, 2002; and The Fortieth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, USA, 2004.
Received for publication May 9, 2005. Revision received October 19, 2005. Accepted for publication November 4, 2005.
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