Hellenic Co-operative Oncology Group, Athens, Greece
Received 15 January 2003; accepted 4 April 2003
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Abstract |
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This multicenter, prospective phase II study evaluated the safety and efficacy of the combination of docetaxel and vinorelbine in patients with platinum-resistant, paclitaxel-pretreated recurrent ovarian cancer.
Patients and methods:
Treatment consisted of vinorelbine 25 mg/m2 as a 20-min i.v. infusion (days 1 and 8), and docetaxel 70 mg/m2, as a 1-h i.v. infusion (day 8). Granulocyte colony-stimulating factor support was administered prophylactically on days 1216. Treatment was repeated every 21 days.
Results:
Forty-six patients were enrolled. The median number of previous chemotherapeutic regimens was one (range 13) with a median treatment-free interval of 4.3 months. Four chemotherapy cycles per patient were administered. Almost 75% of the planned doses for both drugs were given. Forty-one patients are evaluable for response. Three patients (6.5% of all patients; 7.3% of evaluable patients) achieved complete response and eight (17.4% and 19.5%, respectively) a partial response to chemotherapy, leading to overall response rates of 23.9% and 26.8%, respectively. Another 34.8% (39.0%) had stable disease. At a median follow-up of 30 months, the median disease-free survival was 13 months, relapse-free survival was 5 months, time to progression was 4.5 months, and overall survival was 9.3 months. Severe toxicities included leukopenia (31%), neutropenia (35%) and febrile neutropenia (20%).
Conclusions:
The combination of docetaxel/vinorelbine is an effective regimen with manageable toxicity for the treatment of platinum-resistant, paclitaxel-pretreated ovarian cancer.
Key words: chemotherapy, docetaxel, ovarian cancer, platinum-resistant, vinorelbine
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Introduction |
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Combination chemotherapy regimens have also been used for platinum-resistant patients. It appears that these regimens are usually associated with greater toxicity without increasing efficacy [13]. Nevertheless, recent phase II studies of various combinations have demonstrated encouraging results, suggesting higher complete [14] or overall response rates [15, 16] with combination regimens, and survival appears at least comparable to that achieved with single-agent chemotherapy.
Based on the above information, the Hellenic Co-operative Oncology Group (HeCOG) decided to conduct a phase II study with a combination of docetaxel and vinorelbine in ovarian cancer patients with platinum-refractory or -resistant disease, to assess overall response rate, overall survival and toxicity. Combinations of the two drugs have been studied previously in breast and lung cancer [1719].
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Patients and methods |
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To be eligible for the study, all patients had to meet the following inclusion criteria: (i) histologically confirmed ovarian cancer; (ii) recurrence of disease within 6 months from the previous platinum-based chemotherapeutic regimen or progression while on treatment with a platinum-based regimen; (iii) paclitaxel as part of their previous platinum-based treatment; (iv) measurable or evaluable disease documented with imaging procedures; (v) age between 18 and 75 years; (vi) performance status (PS) 2 according to the Eastern Cooperative Oncology Group (ECOG) scale; (vii) no previous treatment with either docetaxel or vinorelbine; (viii) adequate hematological, renal (creatinine clearance
BORDER="0">50 ml/min), and hepatic function; (ix) absence of other serious illness or active infection; and (x) a life expectancy of at least 3 months.
Exclusion criteria included: (i) sensitivity to platinum, defined as recurrence of the disease >6 months after the previous platinum-based chemotherapy; (ii) previous chemotherapy that did not contain platinum; (iii) elevated serum CA-125 as the only indication of recurrent disease; (iv) presence of central nervous system metastases; (v) other serious illness or medical condition not compatible with entry into the study; and (vi) inability of the patient to comply with scheduled follow-up.
All patients were required to provide written informed consent. This study was conducted in accordance with the Declaration of Helsinki and good clinical practice.
Treatment plan
Vinorelbine was given at 25 mg/m2 on days 1 and 8 as a 20-min i.v. infusion in 100 ml normal saline. Docetaxel was given at 70 mg/m2 on day 8 as a 60-min infusion in 250 ml normal saline or 5% dextrose. Methylprednisone (2 x 8 mg) was given on days 7, 8, 9 and 10. Standard antiemetic treatment (ondansetron 8 mg on day 1, 16 mg on day 8, i.v.) was used. Granulocyte colony-stimulating factor (G-CSF) was given prophylactically on days 1216 (0.263 mg lenograstim). Chemotherapy was repeated every 3 weeks. Treatment was given for six cycles until either progression or unacceptable toxicity occurred, or the patient refused treatment.
On days 1 and 8 of each chemotherapy cycle, if the absolute neutrophil count (ANC) was <1.5 x 109/l or the platelets <100 x 109/l, a maximum of 2 weeks delay was allowed for recovery. If the delay was caused by neutropenia, G-CSF (0.263 mg lenograstin) was given for 3 days. If treatment delay was needed, the dosage of both drugs for the subsequent cycles was reduced by 25%.
For any grade III/IV toxicity on any day of the chemotherapy cycle, the dosage of both drugs was again reduced by 25%. No dosage reductions were recommended for any grade I/II toxicity, with the exception described in the previous paragraph. If grade III or IV toxicity occurred again despite a dose reduction, the patient was taken off protocol treatment.
Evaluation
Tumor response was assessed every three cycles by repeating the baseline procedures unless clear evidence of progression was seen. Patients with either disease progression before the third cycle or discontinuing treatment due to toxicity or personal reasons (refusal) were considered treatment failures.
The primary objective of this study was to assess response rate. Secondary objectives were to evaluate toxicity and overall survival. Sample size was based on response rate according to Simons two-stage design [20]. World Health Organization (WHO) criteria for toxicity were applied to evaluate the toxicity of the treatment. WHO criteria for response were also applied for response determination [21]. Time to progression (TTP) and survival were calculated from initiation of chemotherapy. The TTP and survival curves were derived using the KaplanMeier method [22].
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Results |
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Response rates for eligible and evaluable patients were analyzed relative to various pretreatment characteristics, i.e. performance status (0 versus 1 or 2), number of metastatic sites (1 versus 2), number of previous chemotherapy regimens (1 versus
2), and interval from previous chemotherapy (<1.5 versus >1.5 months). No statistically significant differences were detected.
Disease progression and survival
After a median follow-up of 30 months (range 0.239 months), 43 patients demonstrated disease progression. The median TTP was 4.5 months (0.221 months) (Table 5 and Figure 1). The main sites of recurrence were, as expected, the abdomen and the pelvis. The median duration of response was 8.3 months (2.311 months), whereas the disease-free survival (DFS) and the relapse-free survival were 13 and 6 months, respectively. At the time of analysis 37 patients had died, 35 of them due to disease progression and two from other causes. Median survival was 9.3 months (Table 5 and Figure 1).
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Discussion |
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Ovarian cancer patients with platinum- and/or paclitaxel-resistant disease have a very poor prognosis and the response rates for various agents are low (10%) [23]. Although randomized comparisons are lacking, it appears that combination regimens had similar efficacy as single agents, but with higher toxicity [1, 2]. However, recent phase II studies of combination regimens in ovarian cancer suggest higher complete response rates and even overall response rates compared with single-agent chemotherapy [1416]. Yet, more research is required to assess the efficacy and toxicity of combinations of new active drugs in ovarian cancer.
In general, difficulties comparing results of phase II studies may relate to the fact that these trials often include a mixed population of both chemotherapy-sensitive and -resistant patients, and efficacy results are not reported separately. In addition, variations in observed toxicities may be associated with major differences in the treatment-free interval (TFI). The population of our study was clearly platinum resistant, with a median TFI of almost 4 months.
Approximately 27% of the assessable patients responded to treatment. This figure is comparable to the best results achieved with various monotherapies [13]. For prolonged oral etoposide, which has demonstrated the best results, the overall response rates for resistant patients vary from 0% [24] to 2627% [25]. The complete response rate of 7.3% in our study is comparable to the best results of monotherapy studies [25]. The 39.0% stabilization of the previously progressive disease appears encouraging, as there is evidence that stabilization of disease may translate into a survival benefit, especially in the setting of second-line treatment [26, 27]. The relapse-free survival, TTP and overall survival data are consistent with those expected for this patient population [1, 3].
We analyzed response rate, TTP and survival according to several prognostic factors such as performance status, number of metastatic sites, number of previous regimens and interval from previous treatment. No statistically significant differences were found between the two arms. This may be due to the small size of the study.
The main toxicity was myelosuppression, particularly leukopenia/neutropenia, with 31% and 35% of patients, respectively, suffering from severe (grade III or IV) toxicity. This resulted in 11 episodes of febrile neutropenia (20% of patients or 5.5% of the chemotherapeutic cycles). In contrast, thrombocytopenia was rare. Although myelotoxicity was considerable, it was rather predictable and manageable and, fortunately, with the support of prophylactic G-CSF, did not result in toxicity-related deaths. These figures are comparable to the myelotoxicity induced by etoposide [24, 25] or topotecan [28] monotherapies. Despite myelotoxicity, almost 75% of the planned doses of both drugs were administered. It is possible that a dose reduction of 20% would allow the administration of the combination without prophylactic G-CSF support.
In conclusion, the combination of docetaxel with vinorelbine in platinum-resistant ovarian cancer patients can be given on an outpatient basis and demonstrates encouraging efficacy, along with moderate but manageable toxicity. Additional comparative studies and quality-of-life considerations are required to define clearly the exact role of this combination and generally the role of combination therapies in the management of platinum-resistant ovarian cancer.
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Acknowledgements |
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Footnotes |
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