1 Departments of Gynaecology and Obstetrics, Charité Virchow University Hospital, Berlin; 2 Institute of Clinical Economics (ICE), Department of Trauma Surgery, ErnstMoritzArndt University Greifswald, Greifswald; 3 Hospital of Hoyerswerda, Hoyerswerda; 4 Gynaecological Practice, Berlin; 5 Gynaecological Practice, Finsterwalde; 6 OskarZiethen Hospital, Berlin; 7 Vivantes Friedrichshain Hospital, Berlin, Germany
Received 13 December 2001; revised 21 March 2002; accepted 10 April 2002
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Abstract |
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Second-line chemotherapy for patients with ovarian cancer who failed platinum and paclitaxel treatment remains a therapeutic challenge. We investigated the toxicity profile and therapeutic efficacy of a novel combination regimen, topotecan plus gemcitabine, in a clinical phase II study.
Patients and methods:
Women with relapsed epithelial ovarian cancer after platinum and paclitaxel treatment were eligible to participate in this trial. Topotecan was given at an initial dose of 0.5 mg/m2 daily (days 15), combined with gemcitabine 800 mg/m2 and 600 mg/m2 on days 1 and 8, respectively. Precluding good tolerability, this protocol facilitated subsequent dose increases of topotecan up to 1.0 mg/m2. The primary objective was to determine the dose-limiting toxicity, whereas secondary objectives comprised measurable and CA-125 response rates, disease-free and overall survival.
Results:
The twenty-one patients (median age 57 years, range 3770 years) who were allocated to this trial received a total of 94 courses of chemotherapy. Median follow-up was 20.5 months. Topotecan dosage could be escalated to 0.75 mg/m2 in nine patients and 1 mg/m2 in another two patients. Dose reduction was not necessary in any case. There were no episodes of neutropenic fever, sepsis or chemotherapy-related fatalities. Only one patient developed CTC grade 4 leukopenia after the first treatment cycle, whereas three patients showed grade 3/4 anaemia. Five patients experienced thrombocytopenia grade 4 without clinical sequelae. Non-hematological toxicities were mild and rare. Eleven patients could be evaluated for clinical tumour response, with three complete, and four partial remissions. Two patients each had stable and progressive diseases. The median progression-free survival rate was 8.8 months [95% confidence interval (CI) 6.313.4 months]. The median overall survival rate was 21.1 months (95% CI 14.822.1 months).
Conclusions:
Topotecan combined with gemcitabine has a favourable toxicity profile and encouraging efficacy in patients with recurrent ovarian cancer.
Key words: combination chemotherapy, gemcitabine, ovarian malignancy, topotecan, toxicity
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Introduction |
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Both topotecan and gemcitabine have proven single-agent activity in recurrent and metastatic ovarian cancer. A major advantage of topotecan is that it lacks cross-resistance with paclitaxel and platinum [1, 2], whereas response rates are similar to paclitaxel [36].
Gemcitabine appears to be a promising adjunct to topotecan. In vitro data have demonstrated synergistic cytotoxicity of the combined regimen [7]. At the molecular level, topoisomerase I-dependent single-strand breaks induced by topotecan offer sites for the insertion of gemcitabine triphosphate during relegation of DNA [8].
We have previously investigated the maximum tolerated dose of the topotecan/gemcitabine combination [9]. A topotecan level of 0.5 mg/m2 together with either 800/600 mg or 600/600 mg of gemcitabine administered on days 1 and 8 was well tolerated. Complete or partial response was achieved in six of 11 patients.
We set out to investigate the efficacy and toxicity profile of the topotecan/gemcitabine combination in a multi-institutional phase II trial.
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Patients and methods |
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The protocol should be offered to patients with recurrent disease as soon as possible; however, an intermediary multi-center phase II study was considered mandatory to gain additional confidence on safety and response data. It was assumed that dose-limiting toxicity (DLT) strongly depends on the gemcitabine load. The following issues needed to be addressed. (i) Is dose escalation of the topotecan component feasible and safe after the first course of chemotherapy? (ii) Are response rates associated with a reasonable gain in time to progression?
The primary objective of the present study was to determine the toxicity profile of the topotecan/gemcitabine combination. We had secondary objectives of assessing response rates, time to progression and overall survival.
Patients were enrolled from seven German institutions (three hospitals and four outpatient facilities). The Department of Gynaecology and Obstetrics of the Charité University Hospital, Berlin, was the coordinating centre. The study was performed according to Good Clinical Practice (GCP) guidelines and the Declaration of Helsinki. Approval was gained from all local review boards, and written informed consent was obtained from each participant. An independent monitoring institute was responsible for data control.
Patient eligibility
Women 18 years of age with surgically resected, histologically-confirmed epithelial ovarian cancer and who had failed first-line platinum chemotherapy were allocated to this trial. A maximum of three prior regimens of salvage chemotherapy were allowed. Eligible subjects had received no previous treatment with either topotecan or gemcitabine, were required to have a life expectancy of >3 months, an Eastern Co-operative Oncology Group (ECOG) performance status <2, laboratory parameters within the normal range, including a glomerular filtration rate >60 ml/min, serum creatinine levels <1.6 mg/dl, liver transaminases <2 x upper limit of normal, bilirubin concentration <1.5 mg/dl, adequate bone marrow function, as indicated by a neutrophil count >1500/µl, and a platelet count >100 000/µl.
Patients suffering from secondary malignancy or concurrent serious, uncontrolled medical or psychiatric disease were excluded from the study, as were subjects receiving other chemo-, immuno- or hormonal therapy.
Treatment plan and drug administration
Both study drugs were infused over 30 min in 250 ml of 0.9% saline solution. Gemcitabine was administered on days 1 (800 mg/m2) and 8 (600 mg/m2), followed by topotecan for five consecutive days at an initial daily dose of 0.5 mg/m2 as a 30-min infusion. An intra-patient dose escalation of topotecan to 1.0 mg/m2 was permitted in cases of good tolerability and in the absence of severe toxicities.
Treatment with gemcitabine and topotecan was repeated every 21 days. A 5-HT3-antagonist was given intravenously 15 min prior to chemotherapy. No primary prophylactic use of granulocyte colony-stimulating factor (G-CSF) or erythropoietin was allowed.
Determination of toxicity
Electrocardiogram tracing and blood sampling for the monitoring of haematology and blood chemistry were performed prior to each course of chemotherapy. Laboratory tests were carried out regularly once a week.
Toxicity was graded according to the National Cancer InstituteCommon Toxicity Criteria [11]. All documented side effects were included, regardless of their relationship to study treatment.
Severe side effects were defined as:
Chemotherapy was applied if leukocyte count was >2 x 109/l, and platelet count was >100 x 109/l.
Evaluation of response
Patients with bi-dimensionally measurable lesions or elevated CA-125 levels were evaluated for response after completion of at least two courses of chemotherapy. Response was defined according to the criteria of the International Union Against Cancer (UICC).
Clinical response was determined by physical examination and ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) scans prior to each treatment course and after the completion of therapy. Complete response (CR) was defined as disappearance of all measurable disease. Partial response (PR) was defined as a reduction of 50% in the sums of the product of two perpendicular diameters of the tumour.
Patients who had less than PR but no evidence of progressive disease (PD) were considered to have a stable disease (SD). Progressive disease was defined as an increase of at least 25% in the sums of the product of the measured lesion, or any evidence of a new tumour lesion.
Complete response, PR and SD had to have been confirmed with the same method after 4 weeks.
CA-125 levels were determined prior to each treatment cycle and were analysed according to the recommendations of Rustin et al. [12].
Statistical analysis
The study committee and the institutional review boards mandated the accrual of 21 patients, projecting a total of 100 courses of chemotherapy to be evaluated. At the time of the protocol approval, no data were available on toxicity or response rates relating to topotecan/gemcitabine in patients who had failed treatment with platinum and paclitaxel thereby hampering formal sample size calculations.
Under a non-inferiority assumption for the primary objective of grade 3 and 4 haematological toxicity, it was estimated that the 95% confidence interval (CI) of the actual event rate would fall within 80% and 125% of reported event rates, corresponding to 6094% [3, 13, 14]. The projected sample size ensured binomial exactitude, 95% confidence limits of 53% and 92% in the case of a 77% prevalence of grade 3 and 4 toxicity. The study was of sufficient size to detect an increase in response rates (CR plus PR) from 15% to 40% with a power of 80%.
Outcome data are presented as median, mean values or proportions, where appropriate, with associated 95% confidence intervals. One-sided confidence limits in cases of zero proportions were calculated by the hybrid-score method [15]. Accounting for the small sample size, geometric means were used for comparisons of nadirs between escalated and non-escalated subjects. Paired analyses on CA-125 levels were made by the Wilcoxon signed-rank test. Haematological data were evaluated by the KruskalWallis ANOVA. A two-tailed P value <0.05 indicated statistical significance. Time to progression and overall survival probability were estimated using the KaplanMeier product limit method.
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Results |
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Haematological toxicity
All patients were assessable for analysis of toxicity. There were no episodes of sepsis or chemotherapy-related fatalities. Myelotoxicity, specifically thrombocytopenia and leukopenia, were the major toxicities observed in this group. In general, the complications associated with these side effects were not severe (Table 2).
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Treatment delay
A treatment delay was defined as any delay of 3 days in the scheduled start of a course of chemotherapy. According to this definition, 15 treatment delays occurred among eight patients during the course of this study. A single delay was caused by haematological toxicity (2 weeks). Ten treatment courses were postponed upon a patients request (e.g. during holidays), whereas four other delays were related to infection of central venous port-systems (2 x 2 days and 2 x 2 weeks, respectively).
Dose escalation
Topotecan doses were escalated to 0.75 mg/m2 in nine and 1.0 mg/m2 in a further two patients without the development of severe toxicities. No dose reduction was necessary in any case.
Table 4 shows the impact of dose escalation on haematological parameters. Thrombocyte and leukocyte counts remained virtually unaffected by enhancing the topotecan load.
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Two patients each had either stabilisation or progression of their disease (18%, 95% CI 2% to 52%).
Seven of 14 patients with elevated pre-treatment concentrations of CA-125 had normal levels (<35 U/ml) by the end of therapy (50%, 95% CI 23% to 77%). The 75% CA-125 response rate was 71% (95% CI 42% to 92%). Two patients experienced a tumour marker progression (14%, 95% CI 2% to 43%). Two patients could not be evaluated for CA-125 response.
Three out of five subjects with platinum-refractory tumours had measurable disease, with two subsequent progressions and one complete response. In eight patients with platinum-susceptible tumours, there were two complete responses, four partial responses and two patients with stable disease.
During the follow-up period, 10 patients died of refractory or progressive disease. The median progression-free survival was 8.9 months (95% CI 6.313.4 months). The median overall survival was 21.1 months (95% CI 14.822.1 months). Cumulative survival probabilities are depicted in Figures 3 and 4.
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Discussion |
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Combining non-cross-resistant agents is a promising approach designed to overcome this problem [9, 10, 17].
Besides antitumour activity, attention should be paid to toxicity profiles of drugs used in second-line treatment since quality of life strongly depends on the pattern of non-haematological side effects [18].
Topotecan is one of the most thoroughly investigated drugs in patients with recurrent ovarian cancer, and was approved for this purpose in 1996. Response rates among platinum-sensitive patients treated with topotecan are equivalent to those reported in subjects undergoing re-induction therapy with platinum compounds (progression-free interval: 1324 months) [19].
With regard to its proven activity and favourable non-haematological toxicity profile, immense research effort has been spent world-wide to define the role of topotecan in combination chemotherapy [1, 6, 10, 17, 2022].
In the targeting of solid tumours, gemcitabine has emerged as a frequently used adjunct to topotecan [8, 2224], whereas only a single study has been conducted so far on patients with ovarian cancer. Greggi et al. [25] treated 24 ovarian cancer patients with combined topotecan and gemcitabine. Maximum tolerated dose was reached at dosages of 0.9 mg/m2 and 600 mg/m2, respectively, when gemcitabine was applied on days 1 and 3. Thrombocytopenia and leukopenia were the DLTs, even though leukopenia occurred more frequently than thrombocytopenia. G-CSF was administered in 27% of all cycles. Objective response rate was 13%, comprising one partial and two complete responders. Stable disease was reached in 38% of all study participants.
Recently, thrombocytopenia was identified as a severe sequela in heavily pre-treated patients [26]. Goldwasser et al. [27] reported a 95% prevalence of CTC grade 3 and 4 thrombocytopenia among 21 subjects receiving topotecan 1.25 mg/m2. Interestingly, the risk for grade 4 thrombocytopenia subsequently decreased with the continuation of chemotherapy. Prevalence was 43% and 15% after the completion of the first and second cycles, respectively. Down-regulation of topoisomerase I expression and/or activity in haematopoietic progenitor cells was proposed as the mechanism responsible for the attenuated cytotoxicity.
There is evidence that the cytotoxic potential of both topotecan and gemcitabine is also related to the dosing schedule [21, 24, 28]. This might explain the somewhat different findings made by Greggi et al. [25] compared with the present data.
Thrombocytopenia of CTC grade 4 occurred in five patients. In concordance to the preceding dose finding study, severe toxicities were observed exclusively after the first course of chemotherapy. With the exception of anaemia, cumulative toxicities were absent in this study. In terms of serum creatinine and creatinine clearance, combination chemotherapy did not impair renal function. There was no correlation between renal function and haematological toxicity.
Dose escalation up to 0.75 mg/m2 was realised in nine participants, with two more subjects receiving 1.0 mg/m2. Even this increase in dose was not accompanied by severe haematological toxicity.
In conclusion, the present data support the available evidence of various favourable characteristics of the topotecan/gemcitabine combination. The distinct features of the application schedule chosen for the purpose of this study (including dose escalation) might facilitate long-term treatment with the goal of tumour control. Meanwhile, the planned three-arm, multi-institutional randomised trial was initiated and certified by the German Cancer Society (DKG). Data from the ongoing study will help to determine survival rates gained by either topotecan/gemcitabine, sequential topotecan (1.0 mg/m2) and etoposide (50 mg daily), and topotecan alone (1.25 mg/m2).
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Acknowledgements |
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Footnotes |
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References |
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