1Department of Gynecology & Gynecologic Oncology, Dr-Horst-Schmidt-Kliniken Wiesbaden; 2Department of Gynecology & Obstetrics, St Vincentius Krankenhaus Karlsruhe; 3Department of Gynecology & Obstetrics, ev. Krankenhaus Düsseldorf; 4Universitaetsfrauenklinik München-Grosshadern; 5Department of Gynecologic Oncology, Universitaetsfrauenklinik Hannover; 6Universitaetsfrauenklinik Göttingen; 7Universitaetsfrauenklinik Marburg; 8Department of Gynecology & Obstetrics, Städtische Kliniken Frankfurt-Höchst; 9Universitaetsfrauenklinik Ulm; 10Department of Gynecologic Oncology, Zentralkrankenhaus Bremen; 11Universitaetsfrauenklinik Aachen; 12Universitaetsfrauenklinik Frankfurt; 13Universitaetsfrauenklinik Bonn; 14Universitaetsfrauenklinik Freiburg; 15Universitaetsfrauenklinik Magdeburg; 16Universitaetsfrauenklinik Münster; 17Universitaetsfrauenklinik Dresden; 18Universitaetsfrauenklinik Tübingen, Germany
Received 30 April 2001; revised 8 August 2001; accepted 24 August 2001.
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Abstract |
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The majority of patients with ovarian cancer are not cured by first-line treatment. Until now, no study could demonstrate any substantial benefit when exposing ovarian cancer patients to second-line chemotherapy. However, most treatment regimens induce toxicity, thus negatively influencing the quality of rather limited life spans. Here we evaluate whether a second-line chemotherapy can offer any benefit compared with a less toxic hormonal treatment.
Patients and methods
Patients with ovarian cancer progressing during platinum-paclitaxel containing first-line therapy or experiencing relapse within 6 months were eligible. Patients were stratified for response to primary treatment (progression versus no change/response), and measurable versus non-measurable disease. Treatment consisted of either treosulfan 7 g/m2 infused over 30 min or leuprorelin 3.75 mg injected subcutaneously or intramuscularly. Both regimens were repeated every 4 weeks.
Results
This study began in late 1996, and after 2.5 years accrual an interim analysis was performed when several investigators reported their concern about a suspected lack of efficacy. Following this analysis the recruitment was stopped early and the 78 patients already enrolled were followed up. The majority of patients received treatment until progressive disease was diagnosed or death occurred. Treatment delay was observed rarely and dose reduction was performed only in the treosulfan arm in 5% of 150 courses. Overall, both treatment arms were well tolerated. No objective responses were observed. The median survival time was 36 and 30 weeks in the treosulfan and leuprorelin arms, respectively. Overall survival did not differ between patients with relapse 36 months after first-line chemotherapy compared with patients with progressive disease within 3 months.
Conclusions
The selected patient population represents a subgroup with extremely poor prognosis. Accordingly, results were not impressive. Both treatment arms showed favourable toxicity data, but failed to show remarkable activity, thus adding only limited evidence to the issue of whether patients with refractory ovarian cancer might benefit from second-line chemotherapy. Even stratified analysis did not identify any subgroup of patients in whom the administration of second-line chemotherapy could demonstrate a clinically relevant survival benefit.
Key words: chemotherapy, hormonal treatment, ovarian cancer, relapse, second-line therapy
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Introduction |
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The decision to use an alkylating agent for second-line chemotherapy was based on the assumption that these agents, which had been part of first-line treatment of ovarian cancer for decades, could offer some benefit as second-line agent after removal from first-line regimens. Treosulfan (Ovastat®, medac, Germany) was chosen as alkylating agent because it has been registered and used frequently in older first-line regimens in Germany, due to a more favourable non-haematological toxicity profile compared with cyclophosphamide [8, 9]. The published data for treosulfan as second-line treatment after platinum failure had been partially contradictory. Two studies using intravenous treosulfan reported response rates of up to 20% in 25 and 72 patients, respectively [10, 11]. The latter trial included 43 patients with platinum refractory ovarian cancer and showed a 21% response rate. Orally administered treosulfan resulted in response rates of 3, 14 and 19% in 30, 22 and 16 platinum pre-treated patients, respectively [1214]. The only study reporting results of oral treosulfan in platinum refractory patients observed only one response in 30 patients. Therefore, we decided to use intravenous treosulfan as standard chemotherapy arm in this trial.
Leuprorelin (leuproreline acetate; Enantone®, Takeda, Germany), a gonadotropin-releasing hormone (GnRH) analogue, was selected as hormonal treatment in the experimental arm of this study. It could be administered in a similar time schedule as the chemotherapy regimen (monthly injections) and had shown some activity in previously reported studies in platinum pre-treated ovarian cancer. In these trials, leuprorelin had been used either as single agent [1517] or in combination with megestrole acetate or tamoxifen [18, 19]. Overall, nine responses have been reported in 46 platinum pre-treated patients [cumulative odds ratio (OR) 19.6%; 95% confidence interval (CI) 9% to 34%]. A retrospective review reported higher efficacy for leuprorelin compared with goserelin, thus providing further support for selecting leuprorelin in favour of other GnRH analogues [17]. However, platinum resistance had been reported inconsistently in all these studies, thus leaving some questions unanswered regarding efficiency in this particular group of patients. Toxicity profiles of leuprorelin had been uniformely reported as being mild, making this option potentially useful in this strictly palliative setting. Tamoxifen, another hormonal treatment with an 11% overall response rate reported in a meta-analysis in recurrent ovarian cancer [20], was not selected for this study, because the study group felt that the different mode of application could hamper comparability.
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Patients and methods |
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Results |
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Treatment and tolerability
The majority of patients received treatment until progressive disease was diagnosed or death occurred. The mean and median treatment periods, respectively, were 18 and 16 weeks in the treosulfan arm, and 13 and 10 weeks in the leuprorelin arm. Treatment delay was observed rarely and median intervals per course were 30.8 and 28.6 days in the treosulfan and leuprorelin arms, respectively. Dose reduction was performed only in the treosulfan arm in eight of 150 courses (5%) because of myelosuppression.
Overall, 150 chemotherapy courses and 122 hormonal treatment courses were evaluable for toxicity. Haematological toxicities higher than grade 2 were observed in only a few patients. Thrombocytopenia grade 3/4 occurred in four and one courses in the treosulfan and leuprorelin arms, respectively. Neutropenia grade 3/4 was only observed in one course in each arm and no infections or neutropenic fever was reported. Anaemia greater than grade 2 was observed after seven courses in the treosulfan arm and after two courses in the leuprorelin arm.
Non-haematological toxicities grade 3 or 4 were reported in only few patients in both arms. Treosulfan induced nausea and emesis in 9% of patients compared with 6% of patients in the leuprorelin arm. Hot flushes were reported by one patient in each arm. Three further patients in the treosulfan arm reported grade 3 pain (two patients) and neurotoxicity (one). The latter was due to remaining toxicity from prior platinum-paclitaxel. Alopecia was common but was due to prior treatment. Re-growth of patients hair took longer in the treosulfan arm than in the leuprorelin arm. About one-third of patients still had alopecia after treatment with treosulfan compared with 11% in the leuprorelin arm. Fatigue was reported more frequently in the chemotherapy arm (eight of 36 patients versus one of 37 patients, treosulfan versus leuprorelin; P = 0.014, Fishers exact test). Overall, both treatment arms were relatively well tolerated resulting in only one treatment cessation due to toxicity.
Efficacy
No objective responses were observed in either of the treatment arms. Disease stabilisation lasting at least 4 weeks (no change) was reported in nine and four patients in the chemotherapy and hormonal treatment arm, respectively. All but one patient showed progressive disease within a median observation period of 22 months. Median progression-free survival was 17 weeks for treosulfan and 10 weeks for leuprorelin (P = 0.035, Wilcoxon test). The difference between both treatment arms remained significant in favour of treosulfan after adjusting for treatment-free interval before study entry (P = 0.028). However, after 6 months only 23% and 14% of patients in the treosulfan and leuprorelin arms had not progressed; corresponding figures for the 12 month observation period were 9% and 5%, respectively (Figure 1).
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The presence of bi-dimensionally measurable disease had a negative impact on treatment results. Patients with measurable disease showed a median progression-free survival of 11 weeks compared with 19 weeks in patients with non-measurable disease (P = 0.0006, log rank test). Again, overall survival was superior in the group of patients with non-measurable disease, but this difference did not reach statistical significance (median 47 versus 24 weeks; P = 0.18, log rank test). Only 29% of patients with measurable disease compared with 46% of patients with non-measurable disease were alive after 12 months (HR 1.93; 95% CI 0.735.16).
Subsequent treatment
In the treosulfan arm, 15 patients received third-line treatments, of whom three were changed over to leuprorelin. The remaining eight patients received: radiotherapy (one), tamoxifen (one) or chemotherapeutic drugs [topotecan (six), etoposide (one), liposomal doxorubicin (one), carboplatin (one), carboplatin-paclitaxel (one)]. Furthermore, 14 patients received fourth-line treatment, including tamoxifen (two), MPA (one), etoposide (two), topotecan (two), and one patient each idarubicin, gemcitabin or mitoxantrone i.p. Finally, three patients received fifth-line cyclophosphamide (one), etoposide (one) or radiotherapy (one). In the leuproreline arm, almost all patients received third-line therapy. Sixteen patients were crossed over to treosulfan, four received intraperitoneal mitoxantrone, two had liposomal doxorubicin and one patient each received etoposide, topotecan, carboplatin, paclitaxel-mitoxantrone or carboplatin-paclitaxel. Two patients received hormonal third-line treatment (one each received tamoxifen and MPA). Fourth-line treatment was offered to seven patients, including radiotherapy (one), topotecan (two), and one patient each liposomal doxorubicin-etoposide, etoposide or etoposide5-fluorouracil (5-FU). Fifth-line treatment was offered to three patients, including paclitaxel, gemcitabin and 5-FUplatinum. The considerable use of third-line therapies after progression of disease might have hampered survival analysis, which in fact showed no significant difference between the treatment arms (although progression-free survival differed).
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Discussion |
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A randomised trial of the National Cancer Institute of Canada has shown an advantage for one arm over another when comparing 3-weekly topotecan days 15 to weekly topotecan in 78 patients, of whom 60% had received prior paclitaxel, and 60% were platinum refractory [23]. This advantage was limited to overall response (23% versus 8%). Progression-free survival differed only at a non-significant level (8 versus 13 weeks), and overall survival did not differ at all. Our trial showed a statistically significant advantage of one arm (treosulfan) with respect to progression-free survival, but failed to show any difference in overall survival. In addition, no differences with respect to response rates were observed. In fact, we did not observe any objective response. The latter could indicate a lack of activity of both study drugs, treosulfan and leuprorelin. However, even higher response rates as reported in the literature did not translate to longer progression-free and overall survival. A prospectively randomised trial comparing liposomal doxorubicin with topotecan included 254 platinum refractory patients; in addition, about two-thirds had received paclitaxel as part of prior therapy [24]. No significant differences were observed in the refractory subgroup: response rates were 7% and 12%, median progression-free survival was 9 and 14 weeks, and median survival was 33 and 37 weeks, respectively. Our observations of median progression free survival of 11 and 17 weeks and median survival of 30 and 36 weeks fit well with the reported data in this poor prognostic subgroup, although we did not observe any objective responses. Another randomised trial in 81 platinum refractory patients comparing paclitaxel with paclitaxelepirubicin reported response rates of 17% and 34% translating to 2-year survival of 10% and 18% [25]. The corresponding 2-year survival in our trial was 19% and 22%, thus indicating the limited value of objective response rates as predictors for survival or progression-free survival in this poor prognostic subgroup of patients with truely refractory ovarian cancer.
Nevertheless, achieving an objective response might be beneficial in this palliative setting, especially if bulky tumours induce symptoms such as pain or bowl obstruction. However, objective response rates might not sufficiently reflect this potential benefit. Therefore, different response criteria that better reflect the palliative approach in these patients should be evaluated prospectively (e.g. symptom relief, reduction of pain medication or ability of enteral food intake). The development of better tools for the evaluation of genuine second-line chemotherapies becomes even more necessary when taking into account the fact that ovarian cancer becomes more of a chronic disease: mortality does not change substantially, but median and 5-year survival improves, thus indicating a growing need for efficient second-line and higher treatment. These therapies should allow tumour control and simultaneously should not reduce life quality.
This study reports mild toxicity data for both treatment arms, treosulfan and leuprorelin acetate, but, due to the very poor activity levels observed in both arms, adds only limited evidence to the issue of whether patients with refractory ovarian cancer benefit from second-line chemotherapy at all. Even stratified analysis in patients with progressive ovarian cancer versus patients experiencing relapse 36 months after first-line therapy, or patients with measurable versus non-measurable diseases, did not demonstrate any subgroup of patients in whom the administration of treosulfan second-line chemotherapy could demonstrate a clinically relevant benefit. Although a very short progression-free interval and the presence of bi-dimensionally measurable disease seemed to turn a bad prognosis into a worse prognosis, none of the differences between the strata showed a consistent and clinically relevant difference in survival. Only progression-free survival was influenced by these factors to some extent. Our data did not indicate that patients with a progression-free interval of >3 months but <6 months after first-line therapy have a better prognosis than those patients progressing within 3 months. Therefore, a progression-free interval of up to 6 months after first-line chemotherapy remained the inclusion criteria in our subsequent trials in this population.
However, results were disappointing in all subgroups. A rather small benefit was traded for a higher rate of fatigue in patients receiving chemotherapy. A gain of 6 weeks median progression-free survival in the superior chemotherapy arm in our study and some advantages with respect to response rates in other trials do not convincingly answer the question of whether second-line chemotherapy offers any benefit for patients with refractory ovarian cancer. Further studies are necessary to help to evaluate whether chemotherapy has a role in this subgroup of patients with a very unfavourable prognosis. A randomised comparison between best supportive care and the most active chemotherapy regimen available could theoretically be an appropriate design for such a trial. However, the German AGO investigators did not even broadly accept a randomisation between a hormonal treatment and a chemotherapy arm, as measured by an extremely slow recruitment rate. Furthermore, this study had to be closed prematurely after an interim analysis indicated only very limited activity in both treatment arms. A trial using best supportive care as one treatment arm would probably not be accepted either, although the above-mentioned efficacy data from chemotherapy studies do not provide more optimistic results.
Treosulfan showed an acceptable toxicity profile and at least some activity compared with leuprorelin acetate, thus allowing continuation of clinical research with this alkylating agent. Our subsequent trial in the refractory population compares treosulfan with topotecan (AGO protocol OVAR-2.3) and recruitment is much better, indicating that investigators more easily accept trials comparing two chemotherapy regimens. Quality of life evaluation was included in this protocol in an attempt to improve understanding of the nature of potential gains from second-line therapy.
Besides treosulfan and topotecan, which are further evaluated by our group, several chemotherapy agents have shown some activity in platinum- and paclitaxel-refractory ovarian cancer, and could serve as comparators in pending further trials: ifosfamide [26], hexamethylmelamine [27], gemcitabin [28] and liposomal doxorubicin [23, 29]. The difficult task of recruiting large homogenous patient populations to second-line trials supports the ongoing discussions and activities in cooperative groups and networks, such as the worldwide Gynecologic Cancer InterGroup (GCIG), which is already planning and performing intergroup trials of second-line treatment of ovarian cancer.
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Acknowledgements |
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Footnotes |
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