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Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3517-3523 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.074 The Activity of Taxanes in the Treatment of Sex Cord-Stromal Ovarian TumorsFrom the Departments of Gynecologic Oncology, Pathology, and Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Jubilee Brown, MD, Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 440, Houston, TX 77030; e-mail: jurobinso{at}mdanderson.org
PURPOSE: To determine the efficacy and side effects of taxanes, with or without platinum, for the treatment of sex cord-stromal tumors of the ovary. PATIENTS AND METHODS: We conducted a retrospective review of all patients seen from 1985 to 2002 at The University of Texas M.D. Anderson Cancer Center with ovarian sex cord-stromal tumors. Eligible patients underwent pathology confirmation and clinical evaluation at M.D. Anderson and received a taxane for initial or recurrent disease. RESULTS: Of 222 patients identified, 44 were eligible for analysis. For nine patients treated in the first-line adjuvant setting, median progression-free survival (PFS) was not reached at 51 months. Of two patients treated for measurable disease in the first-line setting, one had a complete response. Median PFS was 34.3 months; median overall survival (OS) was not reached. Median follow-up was 90.3 months (range, 39.4 to 140.5 months). Response rate for 30 patients treated with a taxane ± platinum for recurrent, measurable disease was 42%. Median PFS was 19.6 months; median OS was not reached. Median follow-up was 100.7 months (range, 8.1 to 361.3 months). The presence of platinum correlated with response in the recurrent, measurable disease setting. The number of patients was insufficient to detect relative efficacy of paclitaxel and docetaxel. Adverse effects of paclitaxel included neutropenia (n = 6), anemia (n = 1), thrombocytopenia (n = 1), myelodysplasia (n = 1), and hypersensitivity (n = 1). CONCLUSION: Taxanes seem to be active agents in the treatment of patients with sex cord-stromal tumors of the ovary. The combination of taxanes with platinum in the treatment of this disease deserves additional investigation.
Ovarian cancer is the most frequent cause of death from gynecologic cancer among women in the United States and is projected to account for 25,580 new cases and 16,090 deaths in 2004.1 Ninety percent of these malignancies are epithelial, with the remaining 10% comprising germ cell tumors, soft tissue tumors not specific to the ovary, unclassified tumors, metastatic tumors, and sex cord-stromal tumors (SCSTs). SCSTs can occur as an isolated histologic tumor type or in combination with other tumor types, but together they account for only 7% of all ovarian malignancies.2 Because SCSTs are so rare, clinical trials designed to determine which treatment regimens are best suited to specific histologic subtypes are not feasible, and determining the optimal treatment has been difficult. Most published studies have combined most or all subtypes of SCSTs, so the recommendations for treating specific tumors have been based on limited data. Most data have been gathered from patients with adult granulosa cell tumors, but when other tumor types have been encountered they usually have been treated similarly. Another reason for the difficulty is that many of these tumors are clinically indolent, so long-term follow-up is required to interpret outcomes data accurately. Surgery remains the cornerstone of initial treatment for SCSTs, and since the 1980s, platinum-based chemotherapy has been the most widely used postoperative treatment.3-6 Studies in 1986 and 1990 investigated combinations of cisplatin, vinblastine, and bleomycin for treating advanced and metastatic granulosa cell tumors of the ovary.7,8 In 1996, Gershenson et al9 reported a high response rate to bleomycin, etoposide, and cisplatin (BEP) in patients with poor-prognosis SCSTs of the ovary. Etoposide was substituted for vinblastine on the basis of earlier findings of reduced toxicity and equivalent efficacy in patients with testicular germ cell tumors.10 The BEP combination was further investigated by the Gynecologic Oncology Group (GOG) for treating incompletely resected stage II to IV or recurrent SCSTs of the ovary.11 This trial found that 14 of the 38 patients who underwent second-look laparotomy had negative findings and that the six complete responders had a 24.4-month median duration of response. The conclusions in 1999 from the GOG trial led to the commonly used treatment option for patients with advanced SCSTs of the ovary: surgery followed by three to four courses of BEP.11 Unfortunately, the GOG trial also showed that only one of seven patients with advanced disease experienced a durable remission and that nearly half of the patients with recurrent disease experienced disease progression. Likewise, despite this study's high response rate, Gershenson et al9 noted similar limitations in durable remission. Both trials also revealed significant toxicities related to bleomycin: two patients with pulmonary toxicity and two deaths as a result of bleomycin-related pulmonary fibrosis.9,11 Unfortunately, etoposide has been linked to the development of subsequent secondary malignancies. In view of the limited activity and significant toxicity associated with BEP, for the last several years at our institution, we have treated patients who have newly diagnosed and recurrent SCSTs with a taxane, either as a single agent or in combination with other drugs, including platinum. To our knowledge, the use of paclitaxel to treat SCSTs has been reported only once before for a patient with a recurrent juvenile granulosa cell tumor.12 The purpose of this study was to review our experience with and assess the efficacy and adverse effects of taxane chemotherapy, administered either as a single agent or in combination with platinum or with other drugs, for SCSTs of the ovary.
We obtained permission to proceed with data acquisition and analysis through the University of Texas M. D. Anderson Cancer Center Institutional Review Board. We retrospectively reviewed the medical records of all patients diagnosed with SCSTs of the ovary at M.D. Anderson Cancer Center from January 1985 through July 2002. Patients were identified through the institutional medical records database and the institutional pathology database. The identified patient charts were reviewed, and pertinent information was abstracted. Data collected included demographic information; clinical, surgical, and radiotherapy information; and dates and nature of follow-up. The inclusion criteria were as follows: patients must have had their pathology specimens reviewed at M.D. Anderson and have received a diagnosis of SCST, including adult or juvenile granulosa cell tumor, Sertoli-Leydig tumor, ovarian sex cord tumor with annular tubules, malignant thecoma, or an unclassified SCST of the ovary; patients must have been seen at M.D. Anderson for evaluation and treatment of this diagnosis; and patients must have received a taxane agent, with or without platinum, during treatment for initial or recurrent SCST. Patients were excluded for failure to fulfill the inclusion criteria or for the presence of a second gynecologic malignancy. Two hundred twenty-two patients were identified. Fifty-eight patients were excluded: 49 underwent a pathologic evaluation only and were never seen clinically, five had a confirmed history of granulosa cell tumor but were seen clinically for a different malignancy, two had a concurrent epithelial ovarian cancer, and two had a malignancy other than SCST. Thus, 164 assessable patients remained, 44 of whom had received a taxane (paclitaxel or docetaxel) as a single agent or in combination with platinum and were included in this study. Given that the clinical profiles of the patients treated for initial versus recurrent disease and measurable versus nonmeasurable disease were different, four patient groups were designated on the basis of these characteristics at the time of their treatment with a taxane agent. These groups were as follows: newly diagnosed patients with no measurable disease after surgery (n = 9); newly diagnosed patients with measurable residual disease after surgery (n = 2); patients with recurrent nonmeasurable disease after surgery for recurrence (n = 7); and patients with recurrent measurable disease (N = 30). The end points selected for analysis included complete response, partial response, response rate, progression-free survival (PFS), and overall survival (OS). Complete response was defined as the disappearance of all gross disease for at least 1 month. Partial response was a 50% or more reduction in the size of each lesion, with duration of reduction of at least 1 month. Progression was a 50% or more increase in the size of any lesion or the appearance of any new lesion. Stable disease was disease not meeting any of the above criteria. PFS was defined as the time from the first chemotherapy of interest to physical or radiographic evidence of disease progression, death as a result of any cause, or last contact, with events defined as progressive disease or death. OS was the time from histologic confirmation of diagnosis to death from any cause. Data were analyzed using SAS software version 8.2 (SAS Institute, Cary, NC). Descriptive statistics were calculated for all patients and for specific subgroups. The differences between groups with respect to OS and PFS were assessed using the log-rank test. Length of follow-up, number of courses of therapy, and age were compared among different groups with the Kruskal-Wallis test. Race and diagnosis were compared using Fisher's exact test. Statistical significance was set at a P < .05.
Patient Characteristics and Demographics Characteristics of the 44 patients at the time of diagnosis are summarized in Table 1. The median age at diagnosis was 45 years (range, 13 to 83 years). Age was unrelated to stage of disease (P = .790). Patients with adult granulosa cell tumors were significantly older than patients with juvenile granulosa cell tumors (P < .005).
Operative reports were reviewed for all patients. Among patients whose disease was surgically unstaged, seven seemed to have disease confined to one ovary with no cyst rupture, four seemed to have disease confined to one ovary with cyst rupture, and seven had no further descriptive documentation. Stage of disease did not seem to vary with histologic type. Of the 44 patients, 40 were treated with a taxane, with or without platinum, on one occasion, and four were treated on more than one occasion, resulting in a total of 48 episodes of evaluated chemotherapy administration. Disease status at taxane administration is included in Table 1, and a description of the patient groupings is given in Patients and Methods. Of note, one patient received paclitaxel and platinum therapy for adjuvant treatment of newly diagnosed disease and was later treated for recurrent disease with surgery followed by adjuvant taxane therapy. One patient received paclitaxel and platinum for newly diagnosed disease after suboptimal debulking and was later treated with a taxane for recurrent measurable disease. Two patients received a taxane for multiple recurrences. Demographics and characteristics of patients were compared among groups. Race or ethnicity, stage, and histology were not significantly different among groups. Age at diagnosis was younger in patients with recurrent nonmeasurable disease, but this difference was not statistically significant. The median length of follow-up from diagnosis to last date of contact was 90.3 months (range, 1.6 to 361.3 months). The patient with the shortest follow-up period died as a result of unrelated medical causes. The length of follow-up was significantly different among groups. Patients with newly diagnosed disease had shorter median follow-up (52.2 months) than either patients with recurrent disease treated first with surgery then chemotherapy (90.3 months) or patients with recurrent measurable disease (100.7 months; P = .035).
Newly Diagnosed Patients Treated After Surgery With Paclitaxel and Platinum
Of the nine patients treated in a first-line adjuvant setting with no measurable disease after initial surgery, the median PFS and OS were not reached at 51 months. All 11 patients treated for newly diagnosed disease were alive when the study ended, with a median follow-up of 52 months (range, 2 to 96 months). Two newly diagnosed patients received paclitaxel and a platinum agent for measurable residual disease after surgery. Response was not considered assessable for one patient because she received only one course of paclitaxel on the basis of an earlier assay showing extreme drug resistance. The other patient achieved a complete response but experienced disease relapse at the vaginal cuff after a 9-month disease-free interval; she was alive with disease 18 months after her diagnosis.
Patients With Recurrent Disease Treated With a Taxane, Alone or in Combination
Seven of the 37 patients were first treated for recurrent disease with secondary cytoreductive surgery. None of these seven patients had measurable postoperative residual disease. This was the first episode of recurrence for six patients, whose median disease-free interval after initial treatment was 34.2 months (range, 9 to 71 months), and the second episode of recurrence for one patient. Two patients were treated with paclitaxel and cisplatin, and five were treated with paclitaxel and carboplatin, with a median of six courses of chemotherapy (range, six to nine courses; Table 4). No grade 3 or 4 toxicity was reported for the seven patients.
Six of these seven patients (86%) had no clinical, radiologic, or serologic evidence of disease at the completion of chemotherapy. Five of the seven experienced a second recurrence after a median progression-free interval of 34.5 months (range, 26.7 to 71.2 months) and required additional treatment. At the time of data analysis, three patients had no evidence of disease, three were alive with disease, and one was dead as a result of disease. The median PFS for all seven patients was 34.3 months and the median overall survival was not reached. The median follow-up for these seven patients was 90.3 months (range, 39.4 to 140.5 months). Thirty patients with measurable recurrent disease were treated with a taxane, either as a single agent or in combination with another drug (Tables 3 and 4). Adjuvant or postoperative chemotherapy at the time of initial diagnosis had been given previously to 12 of the 30 patients (Table 3). This group of patients was treated for measurable recurrent disease after a mean of 1.5 prior recurrences (range, zero to six prior recurrences). The median time from diagnosis to initiation of treatment for recurrent disease was 86 months (range, 4 to 332 months). One of these 30 patients was treated with paclitaxel on three separate occasions for recurrent disease. Therefore, this group included 30 patients, for a total of 32 regimens of evaluated chemotherapy. The mean number of chemotherapy treatments administered per patient including a taxane agent was five (range, one to 12 courses). The mean number of prior chemotherapy courses received by the patient was six (range, zero to 41 courses). The number of chemotherapy treatments including a taxane agent decreased in inverse relation to the number of prior regimens (P = .011). Various dosing regimens and combinations were used. The presence or absence of platinum in the regimen was correlated with outcome. Of the 30 patients with recurrent, measurable disease, 17 patients received non–platinum-containing taxane regimens, and 13 patients received platinum-containing taxane regimens (Table 4). In the 17 patients receiving non–platinum-containing regimens, there was one complete response, two partial responses, three patients with stable disease, 10 patients that experienced disease progression, and one patient who died as a result of unrelated medical causes whose response could not be assessed. This yielded a total response rate for this group of 18%. In the 13 patients who received platinum-containing taxane regimens, there were two complete responses, five partial responses, four patients with stable disease, and two patients that experienced disease progression, for a total response rate of 54%. The difference in these response rates approached statistical significance (P = .056). One of the 13 patients received platinum-containing chemotherapy for three separate recurrences; she had a complete response the first time and partial responses the second and third times. Therefore, if treatment episodes are considered rather than individual patients, a total of 15 treatment episodes resulted in nine responses, yielding a response rate for of 60%. This difference did reach statistical significance (P = .027). Docetaxel was administered to three patients, and paclitaxel was administered to the other 27 patients. All three patients treated with docetaxel had progressive disease but the number of patients treated is insufficient to report comparative efficacy between paclitaxel and docetaxel. Sites of recurrent disease are detailed in Table 3. Overall, for these 30 patients (32 treatment episodes), one patient died as a result of unrelated causes during treatment, leaving 31 treatment episodes assessable for response. Four patients had a complete response, nine patients had a partial response, six patients had stable disease, and 12 patients experienced disease progression. These outcomes represented an overall response rate of 42%. The median progression-free interval for all 30 patients in this group was 16.8 months (range, zero to 68 months). The median follow-up for all 30 patients was 100.7 months (range, 8.1 to 361.3 months). At the completion of the study, three patients had no evidence of disease, 20 patients were alive with disease, five patients were dead as a result of their disease, and two patients were dead as a result of unrelated causes.
Toxicity The reported toxic effects in the 37 patients treated for recurrent disease included four patients with grade 4 neutropenia, one patient with grade 2 anemia and thrombocytopenia, and one patient who developed palmar-plantar erythrodysesthesia secondary to concurrent therapy with paclitaxel and liposomal doxorubicin. All of these adverse effects were seen after treatment with paclitaxel. The three patients who received docetaxel had no reported adverse effects.
Determining the optimal therapy for SCST of the ovary has been problematic, in part because these tumors are rare, making it difficult to conduct definitive, large-scale studies. The indolent and slowly progressive nature of many of these tumors also requires long-term follow-up information to derive meaningful results from treatment data. These limitations notwithstanding, the use of platinum-based chemotherapy in the form of BEP has emerged as the accepted standard for patients with advanced or recurrent SCST of the ovary. Unfortunately, considerable toxicities can result from the combination of BEP, such as myelosuppression, gastrointestinal toxicity, pulmonary fibrosis, and secondary malignancy. Although the likelihood of such severe and life-threatening morbidity can be decreased by modifying the dosages in this regimen11 and by frequently monitoring hematologic and pulmonary function, the potential for serious adverse effects remains. If BEP were universally effective in providing cures or even durable remissions, such toxicities in these mostly young women might be considered acceptable, and a search for a less toxic, equally effective regimen for SCST would not be so important. However, previous studies have documented limitations even in the efficacy of this regimen. One study revealed that 83% of patients responded to BEP but that only 14% attained a durable remission.9 The multi-institutional GOG trial likewise demonstrated that 69% of patients with advanced-stage primary tumors and 51% of patients with recurrent tumors remained progression free, but the majority of these patients had either a nonmeasurable clinical response or stable disease, and only a few patients had negative results from second-look surgery.11 Because of the results of these studies, the findings of our study suggest some important considerations. First, taxanes with or without platinum may be less toxic than BEP. In the GOG trial, 79% of the patients experienced grade 3 or 4 granulocytopenia, 14% experienced grade 4 gastrointestinal toxicity, and two patients died as a result of pulmonary toxicity.11 In contrast, in our study, although six patients had hematologic toxicity and one patient experienced a hypersensitivity reaction to paclitaxel, there were no sequelae among the seven patients. The one patient with a serious adverse effect resulting in long-term consequences developed myelodysplasia, which was unlikely a direct consequence of paclitaxel chemotherapy. None of the three patients treated with docetaxel had reported adverse effects. Thus, we conclude that the toxicity profile of taxanes, with or without platinum, is acceptable and is preferable to that of BEP. The second consideration was whether treatment with taxanes, with or without platinum, would be effective in treating SCST of the ovary. The median PFS of patients treated in an adjuvant first-line setting was not reached at 51 months; 89% of these patients were disease free at the completion of therapy, and 78% sustained a durable remission. One of two patients with measurable disease in the first-line setting had a complete response to paclitaxel and platinum combination chemotherapy. Given the indolent natural history of this group of malignancies, it is difficult to comment on efficacy on the basis of outcomes after administration in the adjuvant setting. However, this is a part of our collective experience with taxane chemotherapy for the treatment of SCSTs and is therefore reported. More meaningful in terms of efficacy are the outcomes of patients who have received taxane chemotherapy for measurable disease, either as a single agent or in combination with other agents. Of 30 patients treated with such chemotherapy for recurrent, measurable disease, the response rate was 42%. Our data suggest that taxanes may be active agents in patients with ovarian SCST. Disease progression of the three patients treated with docetaxel was not statistically significant but may be clinically important. It would be premature to draw conclusions on the comparable efficacy of paclitaxel and docetaxel because the number of patients in this study was insufficient to allow any comment. However, incorporating docetaxel-treated patients into this study lowered our reported response rate, thereby further supporting the potential role for paclitaxel. The presence or absence of platinum in the regimens of patients treated for recurrent measurable disease is of questionable statistical significance, but the difference in response rates is intuitive because platinum has a demonstrated effect in this group of malignancies.3-9,11 On the basis of the small sample size and retrospective nature of this study, we are unable to draw any firm conclusion on the importance of platinum in this setting. Specifically, this study does not allow a valid comparison between non–platinum-containing taxane regimens and platinum-based regimens. We also cannot ascertain whether taxanes confer added benefit when combined with single-agent platinum. A logical next step would be the investigation of a taxane plus platinum chemotherapy regimen, such as paclitaxel and carboplatin, in patients with advanced or recurrent ovarian SCST. There are limitations to these data. This was not a randomized trial and the sample size was limited. Any retrospective review risks selection bias. In addition, because this was a retrospective review, the precise dosing regimens and combinations of administered drugs varied widely and were determined by individual physician discretion. These issues make it problematic to conclude the relative value of taxanes compared with other regimens, but our data do suggest that taxanes may be active agents in the treatment of ovarian SCST. We do not suggest that taxanes should supplant more conventional regimens, but rather that additional study with the combination of taxanes and platinum is warranted. In addition, the rare nature of this disease required combining separate histologic subtypes into the same treatment and analysis categories. Although multifactorial analysis did not reveal the histologic diagnosis to be significant, the small sample size limited an accurate determination of the role of the histologic subtypes. Finally, the long natural history of ovarian SCST requires extensive follow-up to reflect durable remission and cure accurately; patients may be clinically free of disease without treatment for more than 10 years before a recurrence. We believe that with a median follow-up of 87 months, this study is likely to interpret durable remission accurately, although an even longer follow-up would have been more helpful. Despite such limitations, however, taxanes seem to be active agents in the treatment of patients with SCSTs of the ovary. These findings provide the rationale for a larger prospective trial to investigate further the combination of taxanes with platinum and to refine its indications for the treatment of SCST of the ovary.
The authors indicated no potential conflicts of interest.
Presented in part at the 32nd Annual Meeting of the Western Association of Gynecologic Oncologists, June 28, 2003, Steamboat Springs, CO. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2004. CA Cancer J Clin 54:8-29, 2004 2. Koonings PP, Campbell K, Mishell DR Jr, et al: Relative frequency of primary ovarian neoplasms: A 10-year review. Obstet Gynecol 74:921-926, 1989[Medline] 3. Jacobs AJ, Deppe G, Cohen CJ: Combination chemotherapy of ovarian granulosa cell tumor with cis-platinum and doxorubicin. Gynecol Oncol 14:294-297, 1982[CrossRef][Medline] 4. Pride GL, Pollock WJ, Norgard MJ: Metastatic Sertoli-Leydig cell tumor of the ovary during pregnancy treated by BV-CAP chemotherapy. Am J Obstet Gynecol 143:231-233, 1982[Medline] 5. Kaye SB, Davies E: Cyclophosphamide, adriamycin, and cisplatinum for the treatment of advanced granulosa cell tumors, using serum estradiol as a tumor marker. Gynecol Oncol 24:261-264, 1986[CrossRef][Medline] 6. Gershenson DM, Copeland LJ, Kavanagh JJ, et al: Treatment of metastatic stromal tumors of the ovary with cisplatin, doxorubicin, and cyclophosphamide. Obstet Gynecol 70:765-769, 1987[Medline] 7. Colombo N, Sessa C, Landoni F, et al: Cisplatin, vinblastine, and bleomycin combination chemotherapy in metastatic granulosa cell tumor of the ovary. Obstet Gynecol 67:265-268, 1986[Medline] 8. Zambetti M, Escobedo A, Pilotti S, et al: Cisplatinum/vinblastine/bleomycin combination chemotherapy in advanced or recurrent granulosa cell tumors of the ovary. Gynecol Oncol 36:317-320, 1990[CrossRef][Medline] 9. Gershenson DM, Morris M, Burke TW, et al: Treatment of poor-prognosis sex cord-stromal tumors of the ovary with the combination of bleomycin, etoposide, and cisplatin. Obstet Gynecol 87:527-531, 1996[CrossRef][Medline] 10. Williams SD, Birch R, Einhorn LH, et al: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316:1435-1440, 1987[Abstract] 11. Homesley HD, Bundy BN, Hurteau JA, et al: Bleomycin, etoposide, and cisplatin combination chemotherapy of ovarian granulosa cell tumors and other stromal malignancies: A Gynecologic Oncology Group study. Gynecol Oncol 72:131-137, 1999[CrossRef][Medline] 12. Powell JL, Connor GP, Henderson GS: Management of recurrent juvenile granulosa cell tumor of the ovary. Gynecol Oncol 81:113-116, 2001[CrossRef][Medline] Submitted December 10, 2003; accepted May 28, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
