Favorable Outcome of Ovarian Germ Cell Malignancies Treated with Cisplatin or Carboplatin-Based Chemotherapy: A Hellenic Cooperative Oncology Group Study

GYNECOLOGIC ONCOLOGY ARTICLE NO.

70, 70 –74 (1998)

GO985047

Favorable Outcome of Ovarian Germ Cell Malignancies Treated with Cisplatin or Carboplatin-Based Chemotherapy: A Hellenic Cooperative Oncology Group Study M. A. Dimopoulos,* M. Papadopoulou,† E. Andreopoulou,‡ Chr. Papadimitriou,* N. Pavlidis,‡ G. Aravantinos,§ A. Aspropotamitis,† A. Anagnostopoulos,* G. Fountzilas,¶ S. Michalas,* and D. Pectacides† *Departments of Clinical Therapeutics and Gynecology, University of Athens School of Medicine, Athens 11528; †Department of Medical Oncology, Metaxa Cancer Hospital, Botassi, Piraeus 18537; ‡Department of Medical Oncology, University of Ioannina, Ioannina 45110; §Department of Medical Oncology, Agii Anargiri Cancer Hospital, Kifissia, Athens 14564; and ¶Department of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54006, Greece Received September 18, 1997

the disease [1, 2]. The introduction of cisplatin-based chemotherapy (cisplatin, vinblastine, and bleomycin; PVB) led to a significant improvement of survival for male patients with testicular tumors [3]. The PVB regimen was proved to be active and more effective than the VAC regimen in women with OGCT [4 – 8]. Subsequently, the substitution of etoposide for vinblastine proved to be equally active but less toxic in the treatment of patients with testicular cancer; therefore, the combination of bleomycin, etoposide, and cisplatin (BEP) was incorporated into the treatment of patients with OGCT and became the most widely used regimen [9, 10]. In order to avoid the nephrotoxicity and neurotoxicity of cisplatin, several investigators have substituted carboplatin for cisplatin for the treatment of patients with testicular cancer. However, recent studies have shown that the carboplatin-containing regimen was clearly inferior to cisplatin-based chemotherapy [11, 12]. Only anecdotal data regarding the treatment of patients with OGCT receiving a carboplatin-based regimen are available [13]. The purpose of our analysis was to assess the outcome of patients with OGCT treated with cytoreductive surgery followed by cisplatin- or carboplatin-based chemotherapy.

Purpose. To evaluate the outcome and the prognosis of patients with ovarian germ cell malignancies who were treated with platinum-based chemotherapy immediately after initial surgery. Methods. We conducted a retrospective review of patients with ovarian germ cell tumors who were referred for consideration of treatment to the Departments of Medical Oncology participating in the Hellenic Cooperative Oncology Group. Results. Over a 14-year period 53 patients were included in our study. There were 13 patients with dysgerminoma and 40 patients with nondysgerminomatous tumors. Forty percent of patients underwent complete resection of their tumors. Platinum-based chemotherapy consisted primarily of cisplatin, vinblastine, and bleomycin (PVB) in 9 patients; bleomycin, etoposide, and cisplatin (BEP) in 15 patients; and bleomycin, etoposide, and carboplatin (BEC) in 25 patients. With a median follow-up of 39 months, 5 patients developed progressive disease and died of their tumor and 1 patient died of bleomycin-induced lung toxicity with no evidence of active tumor. The 5-year overall survival was 100% for patients with dysgerminoma and 85% for patients with nondysgerminomatous tumors. Eighty percent of patients with advanced nondysgerminomatous tumors and residual disease after surgery remain disease free. Conclusion. With this study we confirm that patients with ovarian germ cell malignancies have a favorable outcome when treated with platinum-based chemotherapy. © 1998 Academic Press

PATIENTS AND METHODS This study is a retrospective analysis of patients with OGCT who were referred to eight Medical Oncology Departments participating in the Hellenic Cooperative Oncology Group. Patients with an unequivocal diagnosis of ovarian germ cell tumors who received platinum-based chemotherapy within 6 weeks after the initial surgery were included in the study. Patients with grade 1, stage Ia immature teratoma, and patients with stage Ia or Ib dysgerminoma were not included in our analysis, since we do not treat such patients with chemotherapy. Patients with OGCTs who had received radiotherapy or chemotherapy previously and patients who relapsed after sur-

INTRODUCTION Ovarian germ cell tumors (OGCT) are rare but highly chemosensitive malignancies that usually affect young females. Over the past 30 years, the therapeutic approach has evolved along similar lines to that of testicular germ cell tumors. The first effective combination chemotherapy for patients with advanced OGCT was the VAC regimen (vincristine, actinomycin D, and cyclophosphamide); despite, however, a high response rate, more than 50% of patients with advanced OGCT died of 0090-8258/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.

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CISPLATIN OR CARBOPLATIN FOR OVARIAN GERM CELL TUMORS

gery alone were excluded from our analysis. Information was recorded on standarized data sheets, which were completed by each patient’s physician. Data recorded for each patient included demographic details, pathology of tumor, type of surgery, stage, serum levels of a-fetoprotein (aFP) and of the b-subunit of human chorionic gonadotrophin (bHCG), type of chemotherapy regimen, details of any further therapy and clinical status at follow-up. Pathology data were classified according to the WHO criteria [14]. Staging was determined according to the guidelines of the International Federation of Gynecologists and Obstetricians (FIGO) classification system for ovarian cancer [15]. We also recorded whether at the time of the initial surgery, a comprehensive surgical staging and complete resection of a stage I, II, or III OGCT were performed or whether residual disease remained after surgery. Patients with stages I, II, and III without macroscopic residual disease and with normal serum markers after surgery were considered to have had a complete resection. All patients with stage IV disease, patients with stage III disease and residual tumor after surgery, and patients with stage I or II disease with persistently elevated aFP and/or bHCG levels after surgery were considered to have had an incomplete resection. Chemotherapy was administered according to each department’s protocol and included combination regimens such as PVB, BEP, and BEC as previously described [3, 9, 13]. Patients were considered to be clinically assessable for response TABLE 1 Patient Characteristics No of patients (%) Age (years) Median Range Histology Dysgerminoma Immature teratoma Endodermal sinus tumor Embryonal carcinoma Choriocarcinoma Mixed germ cell tumor Stage I II III IV Initial surgery USO BSO 6 TAH Only biopsy Extent of surgery Complete resection Incomplete resection

20 12–69 13 (25) 13 (25) 12 (23) 1 (2) 2 (4) 12 (23) 19 (36) 3 (6) 25 (47) 6 (11) 31 (58) 20 (38) 2 (4) 21 (40) 32 (60)

Note. USO, unilateral salpingo-oophorectomy; BSO, bilateral salpingooophorectomy; TAH, total abdominal hysterectomy.

TABLE 2 Stage by Histology Stage

All patients

Dysgerminoma

Nondysgerminoma

I II III IV

19 3 25 6

3a 0 10 0

16 3 15 6

a

All three patients had FIGO stage Ic.

if, prior to the initiation of chemotherapy, they had tumor mass detectable by physical examination or radiographic studies. For such patients, standard response criteria were used. Time to progression was calculated from the date of initial surgery to the time of progression or to the last follow-up. Survival was calculated from the date of initial surgery to the time of death or to the last follow-up. Time to progression and survival curves were constructed by means of the Kaplan-Meier product limit method [16]. The log-rank method was used to test for the significance of differences in time to progression and survival distributions between patient groups [17]. RESULTS Between January 1983 and December 1996, 53 patients met the inclusion criteria for our study. The patient and disease characteristics are shown in Table 1. One-fourth of the patients had dysgerminoma and the majority of patients had stage III disease, whereas FIGO stages II and IV were uncommon. More than one-half of the patients underwent unilateral salpingooophorectomy. Serum aFP was elevated in 32% of patients and bHCG in 18% of patients with available data. The stage of the disease according to histologic subtype is shown in Table 2. All three patients with early stage dysgerminoma had stage Ic because of rupture of the tumor during surgery; no patient with dysgerminoma had stage IV disease. The number of cycles of chemotherapy administered depended on several factors, including the patient’s FIGO stage, extent of residual disease, clinical response, and patient tolerance. The median number of chemotherapy courses was four (range two to six courses). Among 32 patients who were considered to have had an incomplete resection, 20 patients had clinically assessable disease. Among those patients, 16 achieved a complete response, 2 achieved a partial response, and 2 patients progressed during treatment. The median follow-up from the initial diagnosis for the study population was 39 months with a range of 5 months to 13.6 years. At the last follow-up, 47 patients were alive with no evidence of tumor; 5 patients, whose characteristics are shown in Table 3, developed recurrent disease and died of OGCT. All 5 patients had nondysgerminomatous tumors and advanced stage of disease. Four patients had bulky residual disease; 1 of them achieved a complete response but relapsed 15 months

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DIMOPOULOS ET AL.

TABLE 3 Characteristics of Patients Who Failed Chemotherapy PtNo

Age (years)

OS (months)

Histology

Stage

Chemotherapy

Response

TTP (months)

8 14 21 36 41

68 69 17 25 41

4 36 5 7 12

Embr IT EST MGCT MGCT

III III IV IV III

BEP PVB BEC BEC CyCarbo

PD CR PD PR NA

2 15 2 5 10

Note. TTP, time to progression; OS, overall survival; Embr, embryonal carcinoma; IT, immature teratoma; EST, endodermal sinus tumor; MGCT, mixed germ cell tumor; BEC, bleomycin, etoposide, and carboplatin; PVB, platinum, vinblastine, and bleomycin; CyCarbo, cyclophosphamide and carboplatin; PD, progressive disease; CR, complete remission; PR, partial remission; NA, not applicable.

after diagnosis. One patient died of toxicity. This was a 30year-old woman with stage II immature teratoma who received four courses of adjuvant chemotherapy with BEP. Shortly after completion of the fourth course, the patient developed symptoms and signs of bleomycin-induced respiratory failure which caused her demise. At autopsy, no residual tumor was found. However, when we constructed the time to progression and survival curves, we coded this patient as a failure. Table 4 shows the outcome of patients with dysgerminoma and with nondysgerminomatous germ cell tumors according to the extent of the initial surgery. None of the dysgerminoma patients relapsed. Eighty percent of the nondysgerminoma patients who had incomplete resection remain progression free. The latest relapse occured 15 months after the initial diagnosis. There was no obvious difference in the outcome of the disease among the different chemotherapy regimens used, but the number of our patients was not large enough to make formal comparisons. Overall survival at 5 years was 87% for the entire group. The 5-year survival was 100% for the dysgerminoma patients and 85% for the nondysgerminoma patients. Time to progression and overall survival were calculated for patients with dysgerminoma and for patients with nondysgerminomatous tumors, for patients who had a complete or an incomplete resection, for patients with FIGO stages I and II or III and IV, and for patients who received cisplatin or carboplatin-based chemotherapy regimens. There was no significant difference in time TABLE 4 Progression-Free Survival Disease type

Total No of patients

Progression free (%)

Dysgerminoma Complete resection Incomplete resection Nondysgerminoma Complete resection Incomplete resection

13 2 11 40 19 21

13 (100) 2 (100) 11 (100) 34 (85) 17a (89) 17 (80)

a

The patient who died of bleomycin-incuced lung toxicity was coded as a failure.

to progression or overall survival among the above groups of patients (data not shown). Fourteen patients (26%) underwent a second-look laparotomy at the completion of chemotherapy. No tumor was found in 12 patients while persistent tumor was found in 2 patients. Both these patients received salvage chemotherapy with VIP; 1 is alive with no evidence of disease at 4 years and the other one died because of her disease. DISCUSSION Our analysis of a large number of patients with OGCT treated by a Cooperative Oncology Group indicated that platinum-based chemotherapy following initial cytoreductive surgery can cure almost 90% of these patients. There is an increasing amount of information available on the chemosensitivity of dysgerminoma to cisplatin-based chemotherapy [18]. A more recent report of 20 patients with advanced dysgerminoma, who were treated according to the Gynecologic Oncology Group (GOG) protocols with three to four courses of either PVB or BEP, indicated that 19 patients were disease free with a median follow-up of 26 months [19]. We treated 13 patients with dysgerminoma, 10 of whom had advanced stage III disease. None of our patients developed progressive disease confirming that the prognosis of patients with dysgerminoma is excellent, regardless of the stage of the disease. The majority of our patients had nondysgerminomatous OGCTs. Nineteen patients had complete resection of all macroscopic disease and received platinum-based adjuvant chemotherapy. One patient died of bleomycin-induced lung toxicity and another patient, who received adjuvant treatment with cyclophosphamide and carboplatin, developed progressive disease and died of her tumor. Thus, 95% of these patients were disease free and 89% were alive at the last follow-up. Our data are in accordance with previous reports which suggested that virtually all patients with completely resected nondysgerminomatous ovarian germ cell tumors will remain disease free after platinum-based chemotherapy [20 –23]. The largest prospective series was reported by the GOG and included 93 patients with completely resected stage I, II, or III nondysgerminoma-

CISPLATIN OR CARBOPLATIN FOR OVARIAN GERM CELL TUMORS

tous OGCTs who received three courses of adjuvant BEP. Eightly-nine of the 93 patients (96%) were free of germ cell cancer [10]. The outcome of the disease in patients with advanced nondysgerminomatous OGCTs has significantly improved after the introduction of the PVB regimen. This regimen induced long-term remissions in 70% of patients with stage II disease and 60% of patients with stage III disease [24]. Some of the earlier studies of the PVB regimen have probably underestimated its activity since they included patients who had previously received radiation or chemotherapy [7]. More recently, treatment of these patients with advanced nondysgerminomatous OGCTs with the BEP regimen has resulted in about 80% of patients being free of tumor [9, 21, 22]. Similar results have been reported for patients receiving the POMB-ACE regimen [23]. In 4 of our 21 patients with nondysgerminomatous OGCTs who had an incomplete resection, the disease progressed; 80% of these patients are disease free with a median follow-up exceeding 3 years. A recently published retrospective analysis indicated that chemotherapy regimens which included both cisplatin and etoposide were more effective than non-etoposide cisplatinbased regimens in patients with advanced OGCTs [25]. Eighteen of our 21 patients with advanced nondysgerminomatous OGCTs, with residual disease after surgery, were treated with an etoposide containing regimen. The role of second-look laparotomy in OGCT is controversial because its findings alter subsequent management in only a small percentage of patients. Only one-fourth of our patients underwent this procedure. Viable tumor was found in two patients who received salvage chemotherapy with VIP. One patient died despite this treatment and the other remains with no evidence of disease 4 years later. Gershenson et al. indicated that second-look laparotomy, performed alter completion of chemotherapy in patients without clinical evidence of disease, did not alter the management in any of their patients [26]. A large GOG study indicated that only 8% of patients with a teratoma element in their initial histology and without clinically evident tumor after chemotherapy benefited from a second-look surgery [27, 28]. Therefore, it appears that the role of second-look laparotomy in OGCT is limited. A unique feature of our cohort of patients is that 47% of them were treated with BEC. Two randomized trials compared the efficacy of cisplatin and carboplatin in good-risk patients with testicular cancer. These studies were undertaken because carboplatin has less renal, neurologic, and gastrointestinal toxicity. Both trials clearly showed that chemotherapy programs which used carboplatin had inferior efficacy indicating that substitution of carboplatin for cisplatin is not acceptable [11, 12]. Only anecdotal reports have used a carboplatin-based regimen in the treatment of OGCTs [13]. Although our series represents a retrospective analysis and the number of our patients is not large enough to draw firm conclusions, we did not observe any difference in response and survival among

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patients who were treated with a cisplatin (PVB or BEP) or a carboplatin-based regimen (BEC). Thus, patients who cannot receive a cisplatin-based combination because of medical reasons may be treated with a carboplatin-based combination. This substitution may not compromise their favorable outcome. However, based on the large experience in male germ cell tumors, we recommend the routine use of cisplatin in the treatment of patients with ovarian germ cell malignancies. ACKNOWLEDGMENTS The authors thank Drs. Gennatas, Economopoulos, Georgoulias, and Cosmas for providing information on the patients they treated, as well as Christina Bamia and Dimitra Gika for assistance with data analysis and preparation of the manuscript.

REFERENCES 1. Slayton RE, Park RC, Silverberg SG, Shingleton H, Creasman WT, Blessing JA: Vincristine, dactinomycin, and cyclophosphamide in the treatment of malignant germ cell tumors of the ovary: A Gynecologic Oncology Group Study (a final report). Cancer 56:243–248, 1985 2. Gershenson DM, Copeland LJ, Kavanagh JJ, Cangir A, Del Junco GD, Saul PB: Treatment of malignant non-dysgerminomatous germ cell tumors of the ovary with vincristine, actinomycin-D, and cyclophosphamide. Cancer 56:2756 –2761, 1985 3. Einhorn LH, Donohue J: cis-Diamminedichloroplatinum, vinblastine and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med 87:293–298, 1977 4. Carlson RW, Siki BJ, Turbow MM, Ballon SC: Combination cisplatin, vinblastine, and bleomycin (PVB) for malignant germ-cell tumors of the ovary. J Clin Oncol 1:645– 651, 1983 5. Taylor MD, Depetrillo AD, Turner AR: Vinblastine, bleomycin, and cisplatin in malignant germ cell tumors of the ovary. Cancer 56:1341– 1349, 1984 6. Gershenson DM, Kavanagh JJ, Copeland LJ, Del Junco GD, Gangir A, Saul PB: Treatment of malignant non-dysgerminomatous germ cell tumors of the ovary with vinblastine, bleomycin and cisplatin. Cancer 57:1731– 1737, 1986 7. Williams SD, Blessing JA, Moore DH, Homesley HD, Adcock L: Cisplatin, vinblastine, and bleomycin in advanced and recurrent ovarian germcell tumors. Ann Intern Med 111:22–27, 1989 8. De Palo G, Zambetti M, Pilotti S, Rottoli L, Spatti G, Fontanelli R, Musumeci R, Kenda R, Donato DP, Re FD: Nondysgerminomatous tumors of the ovary treated with cisplatin, vinblastine and bleomycin: Long-term results. Gynecol Oncol 47:239 –246, 1992 9. Gershenson DM, Morris M, Cangir A, Kavanagh JJ, Stringer CA, Edwards CL, Silva EG, Wharton JT: Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide and cisplatin. J Clin Oncol 8:715–720, 1990 10. Williams S, Blessing JA, Liao SY, Ball H, Hanjani P: Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: A trial of the Gynecologic Oncology Group. J Clin Oncol 12:701–706, 1994 11. Bajorin DF, Sarosdy MF, Pfister DG: Radomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multiinstitutional study. J Clin Oncol 11:598 – 606, 1993 12. Horwich A, Sleijfer DT, Fossa SD, Kaye SB, Oliver RTD, Cullen MH, Mead GM, de Wit R, de Mulder PHM, Dearnaley DP, Cook PA, Sylvester RJ, Stenning SP: Randomized trial of bleomycin, etoposide, and cisplatin commpared with bleomycin, etoposide, and carboplatin in good-prognosis

74

13.

14.

15.

16. 17.

18.

19.

20.

DIMOPOULOS ET AL. metastatic nonseminomatous germ cell cancer: A multiinstitutional Medical Research Council/Europen Organization for Research and Treatment of Cancer trial. J Clin Oncol 15:1844 –1852, 1997 Smales E, Peckham MJ: Chemotherapy of germ cell ovarian tumours: first-line treatment with etoposide, bleomycin and cisplatin or carboplatin. Eur J Cancer Clin Oncol 23:469 – 474, 1987 Serov SF, Scully RE, Solvin LH: International Histological Classification of Tumors, No. 9, Histological Typing of Ovarian Tumors. Geneva, Switzerland, Wold Health Organization, 1973 International Federation of Gynaecology and Obstetrics: Changes in definitions of clinical staging for carcinoma of the cervix and the ovary. Ann J Obstet Gynecol 156:263–264, 1987 Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457– 481, 1958 Peto R, Pike M, Armitage P: Design and analysis of randomised clinical trials requiring prolonged observation of each patient. Br J Cancer 35:1– 39, 1977 Gershenson DM, Wharton JT, Kline RC, Larson DM, Kavanagh JJ, Rutledge F: Chemotherapeutic complete remission in patients with metastatic ovarian dysgerminoma. Cancer 58:2594 –2599, 1986 Williams SD, Bleesing JA, Hatch KD, Homesley HD: Chemotherapy in advanced dysgerminoma: trials of the Gynecologic Oncology Group. J Clin Oncol 9:1950 –1955, 1991 Schwartz PE, Chambers SK, Chambers JT, Kohorn E, McIntosh S: Ovarian germ cell malignancies: The Yale University experience, Gynecol Oncol 45:26 –31, 1992

21. Mayordomo JI, Paz-Ares L, Rivera F, Lopez-Brea M, Lopez Martin E, Mendiola C, Diaz-Puente MT, Lianes P, Garcia-Prats MD, CortesFunes H: Ovarian and extraovarian malignant germ-cell tumors in females: A single-institution experience with 43 patients. Ann Oncol 5:225–231, 1994 22. Segelov E, Campbell J, Ng M, Tattersall M, Rome R, Free K, Hacker N, Friedlander ML: Cisplatin-based chemotherapy for ovarian germ cell malignancies: The Australian experience. J Clin Oncol 12:378 –384, 1994 23. Bower M, File K, Holden L, Paradinas F, Rustin GJS, Newlands ES: Chemotherapy for ovarian germ cell tumours. Eur J Cancer 32A:593–597, 1996 24. Gershenson DM: Management of early ovarian cancer: germ cell and sex cord-stromal tumors. Gynecol Oncol 55:562–572, 1994 25. Culine S, Lhomme C, Kattan J, Michel G, Durillard P, Droz JP: Cisplatinbased chemotherapy in the management of germ cell tumors of the ovary: The Institut Gustave Roussy experience. Gynecol Oncol 64:160 –165, 1997 26. Gershenson DM, Gopeland LJ, Del Junco G: Second-look laparotomy in the management of malignant germ cell tumors of the ovary. Obstet Gynecol 67:789 –793, 1986 27. Williams SD, Blessing JA, DiSaia PJ, Major FJ, Ball HG, Liao SY: Second-look laparotomy in ovarian germ cell tumors: The Gynecologic Oncology Group Experience. Gynecol Oncol 52:287–291, 1994 28. Gershenson DM: The obsolescence of second-look laparotomy in the management of malignant ovarian germ cell tumors. Gynecol Oncol 52:283–285, 1994