1Institut Curie, Paris, 2Hôpital Bretonneau, Tours, 3Centre Paul Strauss, Strasbourg, 4Jean Perrin, Clermont-Ferrand, 5Hospitaux Civils, Colmar, 6Centre René Huguenin, Saint-Cloud, 7Centre Eugène Marquis, Rennes, 8Hôpital Paul Brousse, Villejuif, 9Cvitkovic and Associates, Consultants, Kremlin-Bicêtre and 10Sanofi-Synthelabo, Chilly-Mazarin, France
Received 6 February 2001; revised 20 July 2001; accepted 23 August 2001.
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Abstract |
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Patients and methods: Forty-eight patients received oxaliplatin 130 mg/m2 intravenously every 3 weeks, 94% having a performance status (PS) 01. All were pretreated with cis/carboplatin and 21 (44%) with paclitaxel. The median number of involved organs was two, 18 (38%) had liver metastasis, 23 (48%) were platinum-resistant and 14 (29%) were taxane-resistant. Forty-two patients were evaluable for a response, 18 (43%) were platinum-resistant and 11 (26%) were taxane-resistant.
Results: A total of 253 cycles was administered (median: 5.5/patient). Median cumulative oxaliplatin dose was 666 mg/m2. National Cancer InstituteCommon Toxicity Criteria toxicity analysis showed that seven patients (15%) had grade 3/4 thrombocytopenia, two patients (4%) had grade 3 neutropenia, and one patient had grade 3 anaemia. Eleven patients (23%) experienced grade 3 neurosensory toxicity. Of the 29 patients with peripheral neuropathy at the end of treatment, 55% had recovered or improved 1 month later. Eleven objective responses (two complete) were obtained in the 42 evaluable patients [ORR 26%, 95% confidence interval (CI) 14% to 42%], with 10/24 (42%, 95% CI 22% to 63%) in platinum-sensitive, and 1 of 18 (5.6%, 95% CI 0% to 27%) in platinum-resistant patients. Median response duration was 9.2 months (95% CI 6.6% to 11.8%), and median progression-free and overall survival in all treated patients were 4.3 months (95% CI 3.0% to 5.7%) and 15.0 months (95% CI 11.1% to 18.8%), respectively.
Conclusion: Oxaliplatin has a good safety profile and is active in cis/carboplatin ± paclitaxel-pretreated AOC patients.
Key words: diaminocyclohexane platinum, neurotoxicity, salvage chemotherapy, taxanes
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Introduction |
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Over 80% of patients relapse, requiring further treatment. Retreatment with cis/carboplatin, often attempted when the disease is considered to be potentially platinum-sensitive, offers a response rate of approximately 30%, although the prognosis is better for women with longer progression-free intervals [5]. Most patients eventually develop platinum resistance, making salvage chemotherapy in this group much less effective than first-line therapy [6]. Secondary response in patients with ovarian cancer whose tumours are clinically resistant to cis/carboplatin is below 20% for most agents tested, and is short-lasting [7, 8]. Chemotherapeutic agents offering novel mechanisms of action therefore represent attractive prospects for the treatment of these multidrug-resistant tumours.
Oxaliplatin (trans-1-oxalato-diaminocyclohexane platinum; EloxatinTM; Sanofi-Synthelabo, Chilly-Mazarin, France) a diaminocyclohexane (DACH) platinum analog, has a mechanism of action similar to classical platinum compounds [9]. Like other DACH platinum compounds, it has a partial lack of cross-resistance with cisplatin and carboplatin in many tumour models [10] (including both in vitro and in vivo in cisplatin-resistant human ovarian cell lines [11]), thought to be related to its efficacy in the treatment of mismatch repair-deficient tumours, which are cisplatin-resistant [12]. Data from preliminary clinical studies using single-agent oxaliplatin in patients with cisplatin-pretreated and resistant ovarian cancer have been encouraging [13, 14]. Given that mismatch-repair deficiency is thought to be one of the determining factors in patients failing cis/carboplatin-based treatment [15, 16] and in light of these preclinical and clinical results, a phase II study of oxaliplatin was initiated to determine its safety profile and efficacy in cis/carboplatin ± paclitaxel-pretreated ovarian cancer patients.
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Patients and methods |
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Patients were defined as taxane-resistant if their disease had progressed under taxane-based treatment, or if they had stable disease or an objective response but had progressed or relapsed within 6 months of discontinuing taxane treatment. Taxane-sensitive patients were those who progressed or relapsed 6 months after taxane-based chemotherapy. Clinical platinum resistance status was determined using the Markman criteria [17].
The protocol was approved by the Ethics Review Committee (CCPPRB) of Cochin-Port Royal Hospital (France). Written informed consent was obtained from each patient before accrual.
Treatment
All patients received oxaliplatin (130 mg/m2) as a 2 h intravenous (i.v.) infusion every 3 weeks. Dose reductions of 25% (after recovery) were implemented for grade 2/3 thrombocytopenia, grade 3 diarrhoea and/or grade 4 neutropenia, and of 50% (after recovery) for grade 4 thrombocytopenia and/or diarrhoea. Study treatment was discontinued if haematological toxicity persisted after a maximum 2-week delay or for neurtoxicity increasing to grade 2 (NCI-CTC). In the case of a complete response (CR) or partial response (PR), the study treatment was continued until tumour progression, or the onset of limiting toxicity, and in the case of disease stabilisation, treatment was continued for six cycles. If, after the sixth cycle, the evaluation still showed no change, it was up to the investigator to decide whether or not to continue the treatment. Antiemetic treatments (usually a single dose of setrons ± corticosteroids), analgesics and analgesic radiotherapy were the only concomitant treatments allowed during the study.
Toxicity and response evaluation
All patients were reviewed by external radiological and clinical experts for major protocol eligibility deviations, imaging evidence of clinical platinum and taxane resistance status, and study treatment efficacy. Safety assessments according to NCI-CTC [18] were made before each cycle for all patients who had received at least one study treatment cycle. Blood chemistry analyses, including renal and liver function measurements, were performed every 3 weeks, and blood counts were performed weekly. Serum Carcino Antigen 125 (CA125) levels were determined before each 3-week cycle.
Tumour response was determined according to World Health Organization (WHO) criteria [19], every three treatment cycles by clinical evaluation and an abdominopelvic computed tomography (CT) scan and/or any imaging technique used to measure the initial target(s). Complete response was defined as the disappearance of all known target tumours, confirmed by two consecutive examinations 4 weeks apart. Partial response was defined as a decrease of at least 50% in the sum of the total bidimensionally measurable surface areas of tumours, or 50% decrease in evaluable (unidimensionally measurable) disease, confirmed by subsequent imaging examination
4 weeks later. Stable disease was defined as a decrease of <50% or an increase of <25% in the sum of measurable surface area of lesions, without the appearance of any new lesions. Progressive disease (PD) was defined as an increase of
25% of at least one measurable tumour, or the occurrence of new lesions or clinical/radiological evidence of progression between scheduled evaluations. Although serum CA125 level evolution was not used to determine response, it could be used to corroborate imaging assessments. Elevated serum CA125 levels had to return to normal for a response to be complete. After the study treatment was discontinued, all patients were followed up at least every 3 months.
Time-related parameters
Progression-free survival (PFS) was the time that elapsed between the start of study treatment and the first documented signs of disease progression, while overall survival (OS) was calculated from the start of study treatment until death, both determined by the KaplanMeier method.
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Results |
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The demographic, pretreatment and disease history characteristics of all 48 treated patients are detailed in Table 1. The median age was 58 years (range 3374), with 94% of patients having a performance status (PS) (ECOG) of 01. Seventy-five per cent of patients had advanced locoregional and/or metastatic disease at initial diagnosis (FIGO stage IIIc or IV), with the majority of the tumours (54%) being serous. The median number of involved organs per patient was two (range 15), and 75% of patients had two or more involved organs. The most common disease site was the peritoneum (34 patients; 71%), while 18 patients (38%) had liver metastases. All patients had received prior cis/carboplatin-based regimens. In addition, 21 patients (44%) had also been pretreated with taxane-containing chemotherapy regimens. Fourteen patients (29%) were taxane resistant and seven (15%) were taxane sensitive. Four patients (8%) had received prior radiotherapy. Among 37 patients with known elevation of CA125 levels at baseline (77%), 19 had serum CA125 levels >10 x ULN.
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Toxicity
Details of grade 3/4 haematological and non-haematological toxicity by patient and cycle in all 48 treated patients are given in Table 3. According to NCI-CTC, grade 3/4 thrombocytopenia was experienced by seven patients (15%), grade 3 neutropenia by two (4%) and grade 3 anaemia by one patient (2%), respectively. Grade 3 vomiting occurred in four patients (8%) but was generally well controlled by 5HT3 antagonists. Grade 4 diarrhoea occurred in one patient (2%). Biochemical liver abnormalities were reported in six patients, with two each (4%) having grade 3 abnormalities in alkaline phosphatase, alanine transaminase and aspartate transaminase levels. Apart from neurotoxicity, no other severe (grade 3/4 NCI-CTC) non-haematological toxicities were observed. Grade 1 and 2 alopecia and cutaneous problems were experienced by four patients (8%).
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Treatment delays and dose modifications
Only 20 cycles were delayed because of toxicity (10%), nine of which were delayed for more than 9 days (4%). Five patients withdrew from the study due to toxicity (10%), including four for neurotoxicity (8%) (three patients with grade 3 and one patient with grade 2) and one for generalised urticaria (2%).
Response
Responses in the 42 eligible and evaluable patients are presented in Table 4 according to platinum sensitivity. Eleven responses (two CR, 5%; nine PR, 21%) were confirmed by external review (ORR = 26%, 95% CI 14% to 42%), and stable disease was observed in 18 patients (43%).
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Among the 24 platinum-sensitive patients, seven of the 10 responders and eight of the 12 disease stabilisations were seen in those with a PPI of more than 12 months (Table 6). Only one of the two patients with a PPI of <6 months was considered evaluable, and she had disease stabilisation. Among the six platinum-sensitive patients with a PPI between 6 and 12 months, there were three PRs and three disease stabilisations. Among the 14 evaluable patients who had progressive disease during, or within 6 months of ending their prior platinum-based regimen, there was one PR (7%). Among the nine patients with disease progression between 6 and 12 months after their prior regimen, there were three partial responders (33%), and among the 17 patients with a treatment- and progression-free period of >12 months, there were two complete responses and five PRs (a total of seven responders, 41%). Data concerning platinum-free interval were not available for the two other patients.
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Time-related parameters
As of August 31, 1998, with a median follow up of 20 months (range 1033), the estimated median response duration was 9.2 months (95% CI 6.6 to 11.8), with two ongoing responses lasting 13.2 and 13.0 months. The estimated median PFS for the whole treated population was 4.3 months (95% CI 3.0 to 5.7). At the cut-off date, 16 of 48 patients (33%) were still alive, with an estimated median OS in all treated patients of 15.0 months (95% CI 11.1 to 18.8 months). The 1-year survival rate was 58%.
In the 18 platinum-resistant patients the median PFS was 3.0 months, and the median OS 9.7 months. Among the 11 taxane-resistant patients, the median PFS was 4.3 months and the median OS was 9.7 months. In the 24 patients with potentially platinum-sensitive disease, median response duration was 9.2 months, with a median PFS of 7.3 months, and a median OS of 20.2 months. Among the taxane-sensitive patients, the median PFS was 6.9 months and the median OS 10.9 months.
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Discussion |
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The aim of this multicentre phase II study was to evaluate the safety and activity of oxaliplatin administered as a single agent every 3 weeks in a pretreated AOC patient population. Treatment was well tolerated, with a median cumulative oxaliplatin dose of 666 mg/m2 (range 1301430 mg/m2), and has an overall safety and toxicity profile which is in agreement with previous reports in other ovarian cancer patients [14] as well as in other indications (mainly colon carcinomas) [25]. The incidence of severe haematological toxicity was low, consisting of grade 3 and 4 thrombocytopenia seen in 15% of patients, grade 3 neutropenia in 4% and grade 3 anaemia in 2% of patients. This is acceptable in such a heavily pretreated patient population, all of whom had relapsed following platinum treatment with or without taxane-based treatment, with a median cumulative pretreatment dose of cisplatin and carboplatin of 500 mg/m2 and 1850 mg/m2, respectively. It is also of note that this patient population had a median number of two (range 15) involved sites and 75% of patients had two or more involved organs, with a high prevalence of liver involvement.
Ten per cent of patients discontinued treatment due to treatment-related adverse events, including 8% for neurotoxicity. The results of this study concerning cumulative neurotoxicity are consistent with prior experience [14, 23, 25, 26]. Oxaliplatin-related neuropathy was dependent on cumulative dose, with grade 3 neurosensory toxicity being observed in 11 patients (23%). The median cumulative oxaliplatin dose at onset of maximum peripheral neuropathy was 130 mg/m2 for grade 1, 390 mg/m2 for grade 2 and 511 mg/m2 for grade 3. It is of note that 10 patients (21%) had grade 1 peripheral neuropathy at baseline. Twenty-nine (60%) patients experienced peripheral neuropathy at the end of treatment, but only four (8%) were graded as severe (grade 3). Furthermore, 55% (16 of 29) of these patients had either recovered completely or improved after a median time of 1 month following the end of treatment, confirming the characteristic reversibility of oxaliplatin-specific neurotoxicity. It is of note that the safety results in this and other reported studies using oxaliplatin in pretreated AOC compare favourably with those reported in studies of paclitaxel [27], topotecan [28] and liposomal doxorubicin [2931].
The ORR of 42% (95% CI 22% to 62%) in the potentially platinum-sensitive patient subgroup was significantly higher (P = 0.012) than that of the platinum-resistant subgroup (6%, 95% CI 0% to 15%), the latter being similar to the range of response rates reported in studies of single-agent paclitaxel (726%) [27, 29, 30], single-agent topotecan (12.4%) [28] and single-agent liposomal doxorubicin (13.7%) [31] for platinum-resistant AOC patients. Direct comparisons of response rates is difficult given that different methods have been used for verifying response and defining platinum resistance status. Note that the present study, unlike those conducted with other registered agents, included a substantial proportion of patients who had failed taxane-based treatment, in whom oxaliplatin activity was confirmed.
The median response duration was 9.2 months (95% CI 6.6 to 11.8). In all treated patients, the median PFS was 4.3 months (95% CI 3.0 to 5.7 months) and the median OS was 15.0 months (95% CI 11.1 to 18.8 months). These parameters are similar to published studies for paclitaxel and topotecan, the two most recently approved drugs in this respect, where median PFS for paclitaxel ranged from 3.4 to 9.4 months [29, 30] and from 2.7 to 4.3 months [30, 32] for topotecan. Median OS for paclitaxel ranged from 8.3 to 14.5 months [27, 30, 33] and from 10.0 to 14.5 months [30, 34] for topotecan.
Among platinum-sensitive patients (all eligible/evaluable patients) the median PFS and OS were 7.2 and 20.1 months, respectively, while in platinum-resistant patients, the median PFS and OS were 3.0 and 9.7 months, respectively. However, the potentially sensitive and resistant patient definitions constitute heterogeneous groups, where the likelihood of objective response and long-lasting clinical benefit appear to be correlated with the length of the patients treatment-free, progression-free interval. This may explain the variability of results in most published phase II studies in pretreated AOC, where apparently minor differences in the eligibility restrictions concerning the disease progression-free, treatment-free interval of potentially sensitive patients favour studies where no limit is placed on such an interval.
A major consideration in the reported response rates of this disease is the difference in assessment and review criteria and methodology. In defining evaluability and for the third-party review, this study has used the most restrictive criteria available. Furthermore, with the small size of cohorts in many of these studies, the ORRs reported (most in the 515% range), are associated with relatively large confidence intervals. In such cases, reported response rates have been accepted as proof of principle rather than proof of efficacy or clinical benefit. Only the duration of response, time to progression (TTP) and risk/benefit ratio considerations have allowed the formal registration of new agents, and in most cases, with prospective randomised trials against the existing standard at the time. In this context and given its safety profile, oxaliplatin is a logical choice for further clinical research. Furthermore, preliminary evidence supports the additive efficacy of oxaliplatin in combination [35, 36]. Trials combining oxaliplatin with gemcitabine and with topotecan are ongoing.
The present phase II study results are greatly strengthened by two reported randomised studies. A phase II study by Piccart et al. [37], where patients were allocated randomly to treatment with either paclitaxel or oxaliplatin, conducted by the European Organization for the Research and Treatment of Cancer (EORTC) Gynaecology Group, with the same design, eligibility and assessment methodology as in the paclitaxel versus topotecan study by ten Bokkel Huinink et al. [30], confirms the safety and activity of oxaliplatin in AOC patients. Likewise, a recently reported phase II study (identical to the former one in design and eligibility), in which either oxaliplatin or topotecan were administered to platinum-pretreated patients, shows that the oxaliplatin regimen is better tolerated than topotecan and appears to be slightly more active [38].
Oxaliplatin has proven to be active and safe when administered in combination with paclitaxel and cisplatin [39], paclitaxel alone [40], cisplatin alone [36] and cyclophosphamide [26]. Given the encouraging results seen here, it is clear that the non-overlapping toxicity profiles of oxaliplatin and cisplatin/carboplatin make them valuable complementary active agents for treatment of advanced ovarian cancer in both untreated and treated patients. In conclusion, the results of the present study confirm both the good safety profile of oxaliplatin as a single agent and its activity in cis/carboplatin ± paclitaxel-pretreated AOC patients.
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Acknowledgements |
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Footnotes |
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