Treatment of Malignant Germ Cell Tumors of the Ovary With Bleomycin, Etoposide, and Cisplatin By David M. Gershenson, Mitchell Morris, Ayten Cangir, John J. Kavanagh, C. Allen Stringer, Creighton L.Edwards, Elvio G. Silva, and J. Taylor Wharton Since 1984, we have treated 26 patients with malignant ovarian germ cell tumors with a combination of bleomycin, etoposide (VP-16), and cisplatin (BEP) at The University of Texas MD Anderson Cancer Center (UTMDACC). The median age of the patients was 19 years (range, 8 to 32). All patients underwent initial surgery (unilateral salpingo-oophorectomy in 14, unilateral salpingo-oophorectomy plus abdominal hysterectomy in one, and bilateral salpingo-oophorectomy with or without hysterectomy in 11 patients). Twenty patients had no residual disease, three had 2 cm Serum tumor marker status HCG (mlU/mL) Elevated/(total) Median (range) AFP (ng/mL) Elevated/total Median (range)

3t

6/26 (23%) 36 (4.5-280) 9/26(35%) 262 (14.5-3794)

Abbreviations: USO, unilateral salpingo-oophorectomy; TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; HCG, human chorionic gonadotropin; AFP, alpha-fetoprotein. *Includes one patient each with dysgerminoma, mixed germ cell tumor, and immature teratoma. tlncludes two patients with dysgerminoma and one with endodermal sinus tumor.

as judged by complete radiographic disappearance of masses (three patients) or complete disappearance of a palpable mass (one patient). Four patients, three of whom had negative serum tumor markers at the start of chemotherapy, underwent second-look laparotomy; all had negative findings. The median follow-up time from the start of BEP chemotherapy for the study population is 22.4 months, with a range of 10.4 to 54.4 months. Twenty-five patients (96%) remain in sustained remission. One patient with a stage IIIa mixed germ cell tumor (endodermal sinus tumor plus grade 3 immature teratoma) died of progressive tumor 14 months after beginning chemotherapy. Table 2. Histologic Type and Stage Distribution of Study Population Histologic Type

I

Dysgerminoma Endodermal sinus tumor Immature teratoma Mixed germ cell tumor Total

5 3 2 0 10

Progressive II I11 IV or Recurrent

Total

1 0 0 2 3

14 5 3 4 26

6 1 0 2 9

0 0 0 0 0

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2 1 1 0 4

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BEP IN OVARIAN GERM CELL TUMORS

She had been noncompliant throughout therapy, delayed her second cycle because of psychosocial problems, and refused all further treatment or follow-up after four cycles. Toxicity associated with the BEP regimen was very tolerable and was similar to other reports. Alopecia was universal. Likewise, all patients experienced some degree of nausea and vomiting, although these were considered severe (>48 hours' duration) in only five patients. One patient developed a severe sleep disturbance after two cycles of therapy, and all further therapy was discontinued. One patient experienced mild transient bleomycin pulmonary toxicity after completing three cycles of chemotherapy. No significant ototoxicity, neurotoxicity, or nephrotoxicity occurred in this patient population. Five patients developed severe neutropenia (with granulocyte counts < 500/mm 3) on six occasions, with dose reductions of 25% on the next cycle. On two of these occasions, patients developed associated fever and required hospitalization and intravenously administered antibiotics for prompt resolution. One patient with stage Ic endodermal sinus tumor received six cycles of BEP after developing progressive disease on VAC with a rising alphafetoprotein level and palpable pelvic disease. She became pregnant and delivered a healthy baby girl weighing 6 lb 7 oz 1 year after completing chemotherapy. DISCUSSION

During the 1970s, VAC was the most commonly used chemotherapy regimen for patients with nondysgerminomatous germ cell tumors of the ovary seen at UTMDACC. An analysis of our experience with this regimen showed a high sustained remission rate for patients with stage I disease but a disappointingly low sustained remission rate for patients with advanced disease.'" After Einhorn and Donohue 20 reported excellent results in patients with testicular cancer, several studies 21"32 documented similar success with the VBP combination regimen for patients with malignant ovarian germ cell tumors. Especially remarkable was the apparent superiority of the VBP regimen over the VAC regimen for patients with advanced disease, although evidence from randomized trials was lacking.

When reports 3338 - of activity of VP-16 against refractory testicular cancer began to emerge, its eventual use in the treatment of malignant ovarian germ cell tumors was inevitable. Smith et al"4 treated three patients for recurrent germ cell tumors with VP-16-containing regimens; all three achieved remissions ranging from 9 to 50 months. Pinkerton et a141 described a complete response to the BEP regimen by a patient with stage III mixed germ cell tumor. At UTMDACC, two patients with metastatic dysgerminoma were initially treated with BEP; both experienced a complete remission and remain disease-free. 4 3 Shortly thereafter, Smales and Peckham 42 reported sustained remissions of 6 to 62 months in eight of nine patients with malignant ovarian germ cell tumors treated with VP-16, bleomycin, and either cisplatin or carboplatin. At about the same time, Williams et a139 reported that when compared with the VBP regimen, BEP showed equal efficacy and less toxicity in patients with testicular cancer. The results observed with the BEP regimen have been very encouraging and seem to mimic the experience noted in testicular cancer patients. However, a few points deserve emphasis. First, the doses and schedules used in our patients differ somewhat from those reported for testicular cancer patients. We administer cisplatin at a dose of 100 mg/m2 on day 1 instead of 20 mg/m 2 daily for 5 days. This is done in an effort to limit the duration of potentially severe nausea and vomiting. We have also continued to administer bleomycin as a 24-hour continuous IV infusion over 3 days rather than as a weekly bolus injection. VP-16 is administered daily for 3 days instead of 5 in an effort to decrease the incidence of neutropenia without sacrificing efficacy. Thus far we are pleased with our results, but would caution that the majority of our patients had a minimal tumor burden (20 had no gross residual disease) before starting chemotherapy or had metastatic dysgerminoma (which may be more chemosensitive than other malignant germ cell tumors). For patients who are starting chemotherapy with bulky nondysgerminomatous tumors, 5 days of VP-16 administration may be justified. Second, the optimal number of cycles of BEP chemotherapy may differ from that required for testicular cancer patients. Although the optimal

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GERSHENSON ET AL

number of cycles remains unknown, our experience with BEP continues to confirm our earlier impressions using the VBP regimen. Such factors as FIGO stage, extent of residual disease, histologic type, and serum tumor marker status seem to influence the optimal number of cycles for each patient. For patients with pure dysgerminoma, three cycles seem to be adequate therapy for patients with stage I disease, whereas a minimum of four cycles may be indicated for patients with advanced or recurrent tumor. For patients with nondysgerminomatous tumors, three or four cycles seem to be adequate therapy for most patients with stage I disease, while patients with advanced or recurrent disease may require four to six cycles. For patients with positive serum alpha-fetoprotein at the start of chemotherapy, we now believe that optimal duration of chemotherapy consists of continuing therapy for two cycles after a negative tumor marker level is achieved. However, more experience is required to confirm this clinical impression. The toxicity associated with the BEP regimen is quite acceptable. The incidence of neutropenia was minimal. There were no drug-related deaths, and no patient developed life-threatening pulmonary toxicity or severe nephrotoxicity. However, meticulous monitoring of this regimen should include tests of pulmonary function and of diffusion lung capacity of carbon monoxide (DLCO) before each cycle. If a 25% decrement in either the forced expiratory volume of the first second (FEVI) or DLCO is noted, discontinuation of bleomycin must be considered. Renal function surveillance should include periodic determinations of creatinine clearance. The serum magnesium level should also be monitored and oral replacement administered if necessary. In terms of long-term effects, our preliminary experience with the BEP regimen leads us to believe that, as with the VAC and VBP regimens, most patients will maintain or regain normal menstrual function and retain reproductive potential. The role of initial cytoreductive surgery in the management of advanced disease remains unclear, mainly because of the rarity of ovarian germ cell tumors. We continue to follow the same principles concerning cytoreductive surgery that govern the surgical management of advanced epithelial ovarian cancer, with resection of as much tumor as is technically feasible. However, with more chemosensitive tumors, especially dys-

germinoma, aggressive cytoreduction may be of limited benefit. With less than optimal information available, mature surgical judgment is of utmost importance. There is scant information in the literature to support aggressive cytoreductive surgery. Slayton et al, 17 in a study of the Gynecologic Oncology Group (GOG), found that 15 of 54 (28%) patients with completely resected disease at primary surgery failed chemotherapy with a combination of VAC, as opposed to 15 of 22 (68%) patients with incompletely resected disease treated with the same regimen. Furthermore, a higher percentage of patients with bulky residual disease (82%) failed VAC compared with those with minimal residual disease (55%). We continue to limit the use of second-look laparotomy in patients with malignant ovarian germ cell tumors, as evidenced by the fact that only four of 26 patients underwent this procedure. This philosophy is based on our reported experience with this procedure in patients with ovarian germ cell tumors. 47 A few patients with initially negative serum tumor markers, especially those with advanced or recurrent disease, continue to undergo the operation. Nevertheless, as we gain a better understanding of the optimal number of chemotherapy cycles, second-look laparotomy will become obsolete except in unusual circumstances. The treatment of pure dysgerminoma deserves special mention. Since our early experience with the chemotherapeutic management of patients with metastatic dysgerminoma, 43 we remain certain that dysgerminoma is just as chemosensitive as it is radiosensitive. Furthermore, in patients without tumor involvement of both ovaries and the uterus, fertility potential can be preserved. Indeed, we have taken this philosophy one step further by administering three cycles of adjuvant chemotherapy to patients with stage I pure dysgerminoma in an effort to reduce the approximately 20% recurrence rate reported after treatment with surgery alone. We acknowledge, of course, that reports of even higher recurrence rates after surgery alone for stage Ia disease are probably largely related to inadequate surgical staging. Nevertheless, we believe that adjuvant treatment of patients with apparent stage I disease may be sound management because most patients continue to be referred to oncologists after inadequate surgical staging, and three cy-

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BEP IN OVARIAN GERM CELL TUMORS

cles of BEP is relatively safe when carefully monitored. In addition, the salvage rate for patients who develop recurrent dysgerminoma after surgery alone is not 100%. However, more experience with this approach is necessary to confirm its value. Although no randomized clinical trials exist, the BEP regimen is arguably the most effective chemotherapy available for patients with malignant ovarian germ cell tumors. New drug devel-

opment and methods for limiting both acute and long-term toxicities will probably continue to originate from studies of male patients. Current or imminent randomized studies will clarify such issues as whether bleomycin can be eliminated from current regimens without sacrificing efficacy and the proper role of such drugs as carboplatin and ifosfamide. Cure rates approaching 100% may well be within our grasp during the next decade.

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