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© 2000 American Society for Clinical Oncology Oxaliplatin or Paclitaxel in Patients With Platinum-Pretreated Advanced Ovarian Cancer: A Randomized Phase II Study of the European Organization for Research and Treatment of Cancer Gynecology GroupFrom the Institut Jules Bordet and European Organization for Research and Treatment of Cancer, Brussels; Universitaire Ziekenhuis Gasthuisberg, Leuven, Belgium; Clatterbridge Hospital, Bebington; Western Infirmary, Glasgow, United Kingdom; Hospital General de Asturias, Oviedo; Universidad Hospital 12 de Octubre, Madrid, Spain; Libera Universita "Campus Bio-Medico," Rome; Ospedale Civile Maggiore, Verona; Spedali Civili di Brescia, Brescia, Italy; Instituto Portugues, Lisbon, Portugal; and Debiopharm, Lausanne, Switzerland. Address reprint requests to M.J. Piccart, MD, Institut Jules Bordet, 1 rue Héger Bordet, 1000 Bruxelles, Belgique; email mpiccart{at}ulb.ac.be
PURPOSE: This was a multicentric, open, randomized, phase II study of single-agent paclitaxel and oxaliplatin to evaluate the efficacy of oxaliplatin in a relapsing progressive ovarian cancer patient population and to analyze the safety profile and impact of both agents on quality of life, time to progression, and survival. PATIENTS AND METHODS: Eighty-six patients with platinum-pretreated advanced ovarian cancer were randomly assigned to two arms: 41 received paclitaxel at 175 mg/m2 over 3 hours every 3 weeks, and 45 received oxaliplatin at 130 mg/m2 over 2 hours every 3 weeks. For inclusion, patients had to have a performance status of 0 to 2 and to have received at least one and no more than two prior cisplatin- and/or carboplatin-containing chemotherapy regimens within the last 12 months. RESULTS: Seven confirmed responses were observed in each arm, for an overall response rate in the total treated population of 17% (95% confidence interval [CI], 7% to 32%) in the paclitaxel arm and 16% (95% CI, 7% to 29%) in the oxaliplatin arm. Median time to progression was 14 weeks and 12 weeks, and overall survival was 37 weeks and 42 weeks in the paclitaxel and oxaliplatin arms, respectively. Among 63 patients with a 0- to 6-month progression-free, platinum-free interval, there were five objective responses with paclitaxel in 31 patients and two objective responses with oxaliplatin in 32 patients. Nine patients (22%) in the paclitaxel arm had grade 3 or 4 neutropenia (National Cancer Institute of Canada [NCIC] Common Toxicity Criteria). Two patients (4%) experienced grade 3 thrombocytopenia in the oxaliplatin arm. Maximum grade (grade 3) NCIC neurosensory toxicity was experienced by three patients (7%) in the paclitaxel arm and by four patients (9%) in the oxaliplatin arm. CONCLUSION: Single-agent oxaliplatin at 130 mg/m2 every 3 weeks is active with moderate toxicity in patients with cisplatin-/carboplatin-pretreated advanced ovarian cancer.
OVARIAN CANCER is the fourth most common cancer among women and the leading cause of death from gynecologic malignancy.1 In the West, the incidence of this disease is increasing (10.8 of 100,000 women in 1982, compared with 3.2 of 100,000 in 1952). The absence of symptoms in early-stage ovarian cancer results in most patients presenting with advanced disease. Standard first-line chemotherapy for women with advanced ovarian cancer (AOC) has been a combination of cyclophosphamide and platinum analogs. Although many women with AOC respond to platinum-based chemotherapy, most eventually die of progressive disease.2-5 Since the definitive incorporation of platinum compounds into the treatment of ovarian cancer, many strategies have been developed with the aim of increasing disease control and survival. Paclitaxel (PXL) represents an important recent therapeutic development for patients with stage III or IV ovarian cancer, and its combination with cisplatin has been shown to be superior to cisplatin/cyclophosphamide in first-line cisplatin-based treatment.2-6 Among patients with progressive ovarian cancer after platinum-based chemotherapy, single-agent PXL is an active salvage compound, with a reported objective response rate ranging between 14% and 33%.7,8 Retreatment with platinum, which is frequently attempted in patients who are considered to have potentially platinum-sensitive disease, offers a response rate of approximately 30%, with a better prognosis for women with greater progression-free and treatment-free intervals.9 Most patients, however, eventually develop platinum resistance, and salvage chemotherapy in this group is much less effective than first-line therapy.10 Oxaliplatin (oxalato- [trans-l-1,2-diaminocyclohexane] platinum; OXA) (Eloxatine; Sanofi-Synthelabo, Paris, France), a diaminocyclohexane (DACH) platinum,11 was recently approved in France for the treatment of patients with colorectal cancer. The relative absence of cross-resistance with cisplatin and carboplatin has been demonstrated in vitro in a cisplatin-resistant subline of the A2780 human ovarian cell line, which showed 2.4-fold resistance to OXA, compared with 18-fold resistance to cisplatin.12 Its DACH nonleaving ligand causes DNA adducts that are not recognized by the mismatch repair complex.13-15 Its interaction with cisplatin or carboplatin has been shown to be additive and/or synergistic in preclinical models.16,17 Clinical data have shown that OXA does not exhibit renal or auditive toxic effects and is only marginally hematotoxic at the recommended dose18,19; its main side effects are acute cold-triggered dysesthesias and cumulative neurosensorial toxicity.20 The mismatch repair defect, which usually occurs through the loss of hMLH1 and hPMS2 gene functionality, is observed in ovarian cancer, and its frequency increases after cisplatin and carboplatin treatment.21 This mismatch repair deficiency is significantly associated in vitro and in vivo with resistance to cisplatin and carboplatin.22 A preliminary communication has reported OXA as inducing objective responses in four of 15 patients with cisplatin-resistant AOC (resistant disease being defined, according to the criteria of Markman et al,9 as progression during or in the 6 months after cisplatin or carboplatin therapy).23 In a previous study,24 single-agent OXA at 100 to 135 mg/m2 every 3 weeks elicited an objective response in nine of 34 assessable patients (26% objective response rate) who were refractory or with disease relapse within 6 months of prior cisplatin/carboplatin therapy. This randomized phase II study of PXL versus OXA as single-agent therapies was initiated to further assess the efficacy and safety of OXA in patients with pretreated AOC, when benchmarked against PXL, with eligibility criteria similar to those of trials that established PXL as an active agent in patients pretreated with cisplatin/carboplatin.5,7,8
Between January 22, 1996, and December 11, 1997, 86 patients were randomized for entry onto the study in 17 European centers from six countries, after the protocol was approved by each relevant ethics committee.
Eligibility Criteria Patients were not included if they had had prior treatment with platinum derivatives other than cisplatin and carboplatin or with PXL, docetaxel, or high-dose chemotherapy with hematopoietic stem cell support. Other exclusion criteria included the following: brain or leptomeningeal metastasis; previous or concurrent malignancies at other sites, including abdominal adenocarcinoma of unknown origin (except cone-biopsied in situ cervix carcinoma and basal or squamous cell skin carcinoma); and symptomatic peripheral neuropathy more than or equal to grade 2 (NCIC criteria) or any other serious illness. Furthermore, the original histopathologic slides were submitted to an independent panel of histopathologists who verified the diagnosis and the histologic tumor type.
Treatment and Dose Adjustments This regimen was to be continued until the time of disease progression, unacceptable toxicity, or patient refusal. The initial PXL and OXA doses could be reduced in subsequent cycles, or the cycles could be delayed by 1 or 2 weeks, depending on toxicity. When dose reduction was required, no subsequent dose escalation was allowed. Dose reduction could be cumulative from cycle to cycle, if required by hematologic or nonhematologic toxicities, but doses could not fall below the established minimum doses per cycle (90 mg/m2 PXL and 75 mg/m2 OXA); patients who required doses lower than the minimum went off-study.
Statistical Methods and Randomization Procedure
Toxicity and Response Evaluation Complete response (CR) was defined as the disappearance of all known disease, without the appearance of new lesions, lasting more than 4 weeks. Although the CA 125 serum level evolution was not used to determine response, an elevated CA 125 serum level had to regain normal levels for a response to qualify as complete. Partial response (PR) was defined as a decrease of at least 50% of the sum of the products of the largest perpendicular diameters of all measurable lesions, being confirmed by a further observation no less than 4 weeks later, without any new lesions. No change was defined, in the case of bidimensional lesions, as a decrease of less than 50% and an increase of less than 25% in the sum of the products of the largest perpendicular diameters of all measurable lesions. Progressive disease (PD) was defined as an increase of at least 25% in the sum of the products of the largest perpendicular diameters of measurable lesions or the appearance of a new lesion. The occurrence of positive cytology pleural effusion or ascites was also considered as PD.
Time-Related Parameters
Patient Characteristics Between January 1996 and December 1997, 86 patients were randomized for entry onto the study: 41 in the PXL arm and 45 in the OXA arm. Four patients (5%) were ineligible because of major protocol deviations: one had relapsed disease later than 1 year after her last platinum-based chemotherapy regimen, and three had no measurable target lesions at study entry, according to independent radiologic experts. Patient characteristics are summarized in Table 1. Patients were defined as potentially platinum-sensitive if they presented a relapse more than 6 months but less than 12 months after their last platinum-based chemotherapy regimen and platinum-refractory if they had PD after a minimum of two cycles of chemotherapy, no change under chemotherapy for at least four cycles, or a relapse that occurred less than 6 months after the end of prior chemotherapy.
The median age was 62 years in the PXL arm and 59 years in the OXA arm. Although distribution of disease stage according to the International Federation of Gynecology and Obstetrics was similar in both arms, with a majority having initial stage III (26 patients [63%] in the PXL arm and 29 [64%] in the OXA arm), an imbalance was found in the histologic distribution, with 17 patients (41%) in the PXL arm and 33 (73%) in the OXA arm having a serous tumor histologic type. Of note, 18 (30%) of 61 histopathology slides that were externally reviewed had their histology reclassified. The majority of patients in each group had only one involved organ, and most presented a tumor recurrence in the pelvi-peritoneum area. Most of the patients had a serum CA 125 level of greater or equal to 20 IU/mL at study entry (71% in each arm). The majority of patients had received previously one platinum-based chemotherapy regimen (30 [73%] in the PXL arm and 29 [64%] in the OXA arm), with similar total cumulative doses in each arm. Most patients (31 [76%] in the PXL arm and 32 [71%] in the OXA arm) were assessed as being refractory to platinum therapy.
Extent of Exposure
Toxicity All 86 patients each received at least one treatment cycle and were assessable for the safety analysis. A summary of hematologic and nonhematologic toxicities is given in Table 3. Severe neutropenia (grade 3 or 4 NCIC) occurred only in the PXL arm, in nine patients (22%), whereas grade 3 thrombocytopenia (NCIC) was only reported in the OXA arm, in two patients (4%). Severe anemia was rare, with grade 4 in one patient (2%) in the PXL arm and grade 3 in one patient (2%) in the OXA arm. There were no febrile neutropenic episodes in either arm. The patient in the PXL arm who experienced grade 4 anemia (after one cycle) entered the study with a low baseline hemoglobin value (6.1 g/dL). Nausea and vomiting were mild to moderate, grade 3 occurring in a total of two patients (5%) in the PXL arm and in a total of five patients (11%) in the OXA arm. Grade 3 (the maximum in the NCIC scale) neurosensory toxicity was reported in three patients (7%) in the PXL arm and in four patients (9%) in the OXA arm.
Treatment Delays and Dose Modifications Dose reduction because of neurotoxicity was applied in two patients (5%) and two cycles (1%) in the PXL arm and in three patients (7%) and three cycles (2%) in the OXA arm. There were delays in 16 cycles (8%) in the PXL arm and in 26 cycles (14%) in the OXA arm, for 12 patients in each arm. Nonhematologic toxicity accounted for most side effect–related delays in both arms.
Response Response to treatment is summarized in Table 4. There were seven responses in each arm, with response rates of 17% for the PXL arm and 16% for the OXA arm (95% confidence interval [CI], 7% to 32% and 7% to 29% in the PXL and OXA arms, respectively).
Two (20%) of 10 potentially platinum-sensitive patients in the PXL arm and five of 13 (38%) in the OXA arm had PRs. Among the platinum-refractory patients, five (16%) of 31 showed PRs in the PXL arm and two (6%) of 32 in the OXA arm. Three of the responding seven patients in the PXL arm and four of seven in the OXA arm had each received two prior chemotherapy regimens. Responses were seen in abdominal and/or pelvic masses, lymph nodes, and pancreatic and liver metastases. Most of the responses in both arms were seen after two cycles of chemotherapy. One PXL arm patient had a CR in a pelvic mass. In the PXL treatment arm, five of seven responders had a sustained CA 125 serum level decrease, whereas one patient did not show a significant decrease of CA 125 and one was not assessable by this method. Four of the seven responders in the OXA arm had a sustained CA 125 serum level decrease, whereas two did not show a significant decrease in CA 125 and one was not assessable by this method.
Time-Related Parameters
Quality of Life Of the 66 patients who completed baseline, only 47 completed questionnaires at the end of the second cycle and only 31 completed questionnaires at the end of the fourth cycle. The mean QoL score increased by more than 10 points between baseline and cycle 4 for patients in the PXL arm, regardless of the time of study withdrawal. In the OXA arm, mean QoL scores decreased (by < 10 points) through cycle 2 and, then, tended to return to baseline values for the majority of patients after two cycles. The brief decrease in QoL scores at the start of study treatment in the OXA-treated patients seemed to be related to the specific peripheral neurotoxicity. However, functional impairment, such as inability to write, was not implicated in the low rate of completion of the QoL questionnaire.
Patients with pretreated AOC may respond to a number of second-line chemotherapeutic treatments, including cisplatin and carboplatin.4,9 The aim of single-agent salvage chemotherapy is palliative, with QoL preservation or improvement being a major goal.4 The results of this study show that OXA compares favorably with PXL in terms of efficacy and safety in patients with cisplatin-/carboplatin-pretreated AOC. Given that this trial was conceived and initiated before the cisplatin/PXL combination was established as standard therapy in first-line AOC, no patients who were pretreated with PXL were included in the present trial. Furthermore, to evaluate OXA according to the PXL benchmark required the imposition of eligibility criteria similar to those of the trials that established PXL as the therapy of choice. Despite the use of a multicentric recruiting base, accrual became slow in the latter part of the trial because of the prevalence of PXL pretreatment, which rendered impossible an eventual extension to a phase III trial. An evaluation of OXA in the currently prevalent cisplatin- and PXL-pretreated AOC population will be provided by a multicentric European randomized phase II trial of OXA versus topotecan, a trial with similar design and eligibility criteria to the present study and to the study of ten Bokkel Huinink et al,7 except that PXL pretreatment is permitted. Its aim is to confirm the role of OXA as the single agent of choice for cisplatin-refractory patients, given its good tolerance profile. The study design allows for an extension of the trial to a formal phase III comparison of OXA and topotecan if the results for OXA merit investigation in a large patient cohort. The greater proportion of patients treated with OXA with a serous histologic tumor type might have favored this arm in terms of ORR. However, the notion that serous epithelial ovarian cancer responds better than other histologies to salvage chemotherapy is born of a retrospective phase II trial analysis that did not have central pathology review.27 Based on an analysis of all 86 patients, the ORR was similar in both arms (17% in the PXL arm v 16% in the OXA arm), the 95% CIs show complete overlap (7% to 32% and 7% to 29%, respectively), which attests to the significant activity of OXA in this indication. When only the 63 patients who were considered to be platinum-refractory are taken into account (31 in the PXL arm and 32 in the OXA arm), a disparity is evident between the two treatment arms: 16% (five patients) of those in the PXL arm showed PRs, whereas only a 6% response rate (two patients) was achieved in the OXA arm. In the potentially sensitive population (10 in the PXL arm and 13 in the OXA arm), the response rate was 20% for the PXL arm (two patients) and 38% for the OXA arm (five patients). However, the small denominators do not allow conclusions to be drawn concerning differential response in the two platinum-resistance subgroups. Although the less than or equal to 6 month TTP boundary to define platinum resistance status has been a generalized standard since the publication of the criteria of Markman et al,9 the likelihood of response to either cisplatin or carboplatin is a continuous function, with greater likelihood the longer the progression-free survival period. The eligibility criteria of our study established a 12-month maximum PFS, which encompasses only the lower end of the potentially platinum-sensitive patient population. Both the median TTP (14 weeks in the PXL arm and 12 weeks in the OXA arm) and the median OS (37 weeks in the PXL arm and 42 weeks in the OXA arm) were similar in the two treatment arms. In terms of QoL, caution must be exercised when drawing any conclusions, given the small number of responses to the QoL questionnaires (only 47 completed questionnaires at the end of the second cycle and 31 at the end of the fourth cycle). The QoL score increased over time for all patients in the PXL arm, regardless of the time of study withdrawal. The brief decrease in QoL scores at the start of study treatment in the patients treated with OXA seemed to be related to the specific peripheral neurotoxicity; the subsequent improvement in these patients’ QoL scores could possibly be attributed to the patients’ own improved management of the side effects in their daily life. It is of interest to compare the results obtained with OXA in the present study with those of other studies that use new, active cytotoxic agents in patient populations with similar disease and pretreatment characteristics. One such recently registered drug is topotecan.7,28-32 In the phase III trial of ten Bokkel Huinink et al,7 which compared topotecan with PXL, a significant 20.5% ORR was reported for topotecan, compared with 13.2% for PXL. Although not a formal phase III comparison by any means, the almost identical eligibility criteria of the trial of ten Bokkel Huinink et al and our study allows room for fair speculation, given that the PXL arm had similar outcomes in both studies. In a phase II study28 that included more than 100 patients, ORR and TTP for topotecan (13.5% and 12 weeks, respectively), did not seem better than those observed in the present study for OXA (16% and 12 weeks, respectively). A similar ORR and a similar TTP have been reported in a study with PXL (17% and 14 weeks, respectively). Median OS in the present study (42 weeks) compares well with that found in studies with topotecan (61 weeks) and PXL (43 weeks).7 Docetaxel, another active agent in patients with AOC who have failed under prior platinum-based chemotherapy regimens, has shown an ORR ranging from 20% to 32% in phase II studies.33-35 However, the toxicity of docetaxel was high in a previously reported study by us, in which 90% of patients experienced grade 3 or 4 neutropenia and five toxic deaths were encountered.34 Other active available agents that were registered in this indication include hexamethylmelamine, VP16, ifosfamide, and carboplatin. The results obtained with single-agent OXA in the present study are also comparable to the results reported with these cytotoxic drugs, in terms of efficacy, with OXA often comparing favorably in terms of safety. Studies of hexamethylmelamine36-39 have reported ORRs ranging from 10% to 20% with moderate toxicity, whereas studies of VP-1640-42 have reported ORRs ranging from 5.8% to 30.5%, but with high toxicity; for example, in the study by Rose et al,40 45% of patients experienced grade 3 or 4 neutropenia. As for ifosfamide,43,44 reported ORRs range from 13.5% to 19.5%; but in the study of Sutton et al,44 19% of patients experienced grade 3 or 4 neutropenia and three (7%) died of toxicity. ORRs in studies of carboplatin45-47 ranged from 25% to 57%, but high toxicity again was a problem: in the study of Eisenhauer et al,47 for example, 64% of patients had grade 3 or 4 thrombocytopenia and 4% died of toxicity. Other reported, but not registered, active agents in pretreated AOC include gemcitabine, vinorelbine, CPT-11, and epirubicin.34,48-51 Response rates ranging between 19% and 28% have been reported for gemcitabine.48,52,53 Treatment with vinorelbine,50 CPT-11,51 and epirubicin54 has resulted in grade 3 or 4 neutropenia in 18%, 57%, and 11% of patients, respectively. Our results confirm previous reports of OXA single-agent activity in patients with AOC.23,24,55 The phase II study of Dieras et al,55 for example, reported an ORR of 26%, with 42% response in potentially platinum-sensitive patients and 6% in platinum-resistant patients. The lower ORR observed in all patients may be explained by the more restrictive eligibility criteria regarding platinum-free, progression-free intervals, which resulted in a higher proportion of platinum-resistant patients being treated in the present cohort, and by the third party review of antitumor activity evaluation. Preliminary data from studies of OXA in combination with other agents are of interest. In combination with PXL at the full recommended doses of both drugs,56 an ORR of 48% (95% CI, 31% to 66%) was achieved in 31 assessable patients with cisplatin-/carboplatin-pretreated AOC. The same study57 reported a median PFS of 9.4 months (95% CI, 7 to 12 months), a median OS of 25.2 months (95% CI, 11.8 to 39 months), and a median follow-up of 23 months (range, 7.9 to 53.8 months), with 51% of patients experiencing grade 3 or 4 neutropenia. Of note, a 33% ORR was achieved among 18 platinum-refractory patients. The combination of OXA at full dose (130 mg/m2) with cyclophosphamide at 1,000 mg/m258 and cisplatin59 also seems feasible, with 33.4% and 39% of patients experiencing grade 3 or 4 neutropenia and 5.4% and 34% of patients having grade 3 or 4 thrombocytopenia, respectively. The phase III study by Misset et al,58 which was performed in previously untreated patients and which used the combination of cyclophosphamide (1,000 mg/m2) and cisplatin (100 mg/m2), showed hematologic, renal, and severe neurotoxicity to be inferior in the OXA (130 mg/m2) and cyclophosphamide arm.58 Although preliminary in nature, the reports on OXA in combination with PXL and on both PXL and cisplatin in patients with previously treated AOC60 show the possibility of incorporating this agent into exploratory first- and second-line treatment of patients with AOC. Finally, the availability of topotecan for patients with pretreated AOC has set new standards for second- and third-line regimens in platinum-resistant patients. A PXL/OXA multicentric phase II study in potentially sensitive patients with pretreated AOC, which aims to verify the compassionate use report by Faivre et al,56 is ongoing. To conclude, this study has shown that, when used as a single agent at 130 mg/m2 every 3 weeks, OXA compares well with PXL in terms of efficacy and safety in this pretreated ovarian cancer population. Its further place in AOC treatment will depend on the results of its ongoing development.
Supported by Debiopharm S.A., Lausanne, Switzerland. We thank the following physicians who treated the patients in the present cohort: Paolo Zola, Clinica Universita, Turin, Italy; Nicoletta Colombo, Istituto Europeo di Onc Milan, Italy; Andres Poveda, Instituto Valenciano de Onc, Valencia, Spain; Gordon Rustin, Mount Vernon Hospital, Northwood, United Kingdom; Paule Chinet-Charrot, Centre Henri Becquerel, Rouen, France; Catharina Madroñal, Instituto de Oncologico Corachan, Barcelona, Spain; Jan B. Vermorken, Universitaire Ziekenhuis Antwerpen, Edegem, Belgium; and Costantino Mangioni, Ospedale San Gerardo, Monza, Italy. Furthermore, the editorial comments of E. Cvitkovic are gratefully acknowledged.
Presented at the Twenty-Third Congress of the European Society for Medical Oncology, Athens, Greece, November 6-10, 1998, and, in part, at the Thirty-Fourth Annual Meeting of the American Association for Cancer Research, Los Angeles, CA, May 16-20, 1998.
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ABSTRACT
INTRODUCTION
3 in the case of liver metastasis). Written informed consent was obtained from each patient before accrual along with her agreement to complete a quality of life (QoL) questionnaire at baseline and every two cycles thereafter. 
