Ovarian and extragonadal malignant germ-cell tumors in females: A single-institution experience with 43 patients

Annals of Oncology 5: 225-231, 1994. O 1994 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Ovarian and extragonadal malignant germ-cell tumors in females: A single-institution experience with 43 patients J. I. Mayordomo, L. Paz-Ares, F. Rivera, M. Lopez-Brea, E. Lopez Martin, C. Mendiola, M. T. Diaz-Puente, P. Lianes, M. D. Garcia-Prats1 & H. Cortes-Funes Divsion of Medical Oncology and ' Department of Pathology, 12 de Octubre University Hospital, Madrid, Spain Summary

relapsed at a median follow-up of 43 months. EG tumors: None of the pts underwent radical surgery. Radiotherapy was applied to 4 pineal tumors and BEP or PVB were given to all 10 pts. To date 6 pts are disease-free, 1 is alive with mature teratoma, 2 are alive with disease and 1 died of toxic effects. The projected overall survival of the series as a whole is 89% at 10 years, and it is significantly higher for pts without EST (p < 0.02) and for pts with AFP <1000 (P < 0.01) and age <22 years at diagnosis (p < 0.01). The projected event-free survival at 10 years is 80.4% (87.7% for ovarian rumors vs. 54% for extragonadal, p =• 0.05). No events were recorded after 28 months. Conclusions: The present results reflect the dramatic effectiveness of cisplatin-based chemotherapy for ovarian MGCT and confirm that unilateral oophorectomy can preserve fertility without compromising cure. Age >22 years, histology (EST) and serum AFP > 1000 ng/ml are possible prognostic factors (univariate analysis) to be tested in an independent body of data on cisplatin-treated patients.

From 1978 to 1992, 276 patients (pts) with MGCT were treated in our institution. Forty-three of the pts were female (15,5%). Median age at diagnosis was 20 years (newborn70). Histology was dysgerminoma (D) in 14 pts (including 2 anaplastic D), endodermal sinus tumor (EST) in 9 pts, immature teratoma in 10 pts and mixed tumors in 10 pts. Primary locations were as follows: ovary (O) 33 pts and extragonadal (EG) 10 pts (pineal in 4 cases, mediastinum in 3, sacrum in 2 and pharynx in 1). Stage: I in 20 (16 0 , 4 EG), U in 7 (5 O, 2 EG), IE in 12 (10 O, 2 EG) and IV in 4 (2 O, 2 EG). Serum AFP was elevated in 20/22 non-dysgerminoma pts, HCG in only 5 pts and LDH in 15/36 pts. Treatment results: Ovarian tumors: all but one pt (biopsy only) underwent surgery: unilateral oophorectomy was performed in 15 pts and bilateral oophorectomy (+/— hysterectomy, + / - others) in 17 pts. Fourteen pts were rendered disease-free, 8 pts had residua] tumor (RT) <2 cm and 11 RT >2 cm. Chemotherapy (PVB or BEP) was given to 28 pts, radiotherapy to 2 pts and no additional treatment to 3. Final- Key words: germ-cell tumors, ovary, extragonadal, females, ly, 30 pts achieved complete response (CR) and none have cisplatin, toxicity, prognosis

Introduction Malignant germ cell tumors (MGCT) in women are uncommon, accounting for 3%-5% of ovarian carcinomas [1]. Extragonadal origin is even less frequent. Treatment results with surgery and radiotherapy have been unsatisfactory except in patients with stage I dysgerminoma or stage IA grade I immature teratoma [2, 3]. The advent of combination chemotherapy including vincristine, dactinomycin and cyclophosphamide has dramatically altered the outcome of these patients [4,5]. Since the successful incorporation of cisplatin in the treatment of testicular MGCT [6], multiple reports have corroborated the effectiveness of cisplatin in combination with other drugs in ovarian and extragonadal MGCT [7-13]. At present, except in particular circumstances, the standard management of ovarian MGCT includes cisplatin-based chemotherapy as front-line treatment or as adjuvant therapy [8]. Other issues such as the role of debulking surgery, second-

look operations and preservation of fertility remain controversial. The purpose of the present report is to evaluate the long-term results of two well-known cisplatin-based regimens (PVB and BEP) in females with MGCT seen in a single institution between 1978 and 1992. We also performed a search for prognostic factors in the cisplatin era.

Patients and methods Clinical records of all female patients with malignant germ cell tumors treated in our institution from 1978 to 1992 with surgery + / - cisplatin-based chemotherapy or radiotherapy were reviewed. All tissue samples of all of the patients were diagnosed by pathologists at our institution. Several features of patients and tumors were recorded: age, menopausaJ status at diagnosis, clinical stage, postsurgical stage, histopathology of the tumor, residual tumor after first surgery, baseline serum levels of alpha-fetoprotein, beta-HCG and LDH, radiotherapy, chemotherapy, response to chemotherapy, number of cycles to negative markers, residual mass, toxicity of ther-

226 apy, updated status and late toxicities. Patients with incomplete information recorded or who were lost to follow-up were contacted and seen at the clinic. The treatment policy for ovarian tumors included surgery plus cisplatin-based chemotherapy (PVB from 1978 to 1986 and BEP thereafter). Exceptions included: 1) for stage IA dysgerminoma after fertility-preserving surgery and resected grade I stage IA immature teratoma, no further treatment was given after surgery. 2) For stage IA, IB or IC dysgerminoma treated with radical surgery before 1986, radiotherapy (pelvic for stage IA or IB and abdominopelvic for stage IC) was given. Subsequently, all stage IA patients were treated only with surgery, and stage IB and IC with BEP chemotherapy. 3) In stage IA non-dysgerminomatous MGCT with negative postsurgical tumor markers, bleomycin was withdrawn in 1986 and subsequent patients received only VP-16 plus cisplatin (EP) for 3 cycles. For extragonadal primaries, scheduled treatment included surgical resection, to be followed by cisplatin-based chemotherapy. For intracranial MGCT, holocranial radiotherapy was to be given after tumor reduction with chemotherapy. Total survival was measured from the day of histopathological diagnosis. Disease-free survival was counted from the day of documentation of clinical complete response (or day of surgery if no evaluable disease was left) to day of documented relapse. Survival data were analyzed using the Kaplan-Meier life table, and survival differences between subgroups were determined with the log-rank test.

Results From January 1, 1978 to December 31, 1992, 43 female patients with MGCT were treated at our institution. Overall, 276 patients with malignant germ-cell tumors (male and female) were treated during that period, so in our experience female patients comprise 15.5% of all patients. For assessment of clinical features and treatment results, patients were separated according to site of the primary tumor. The median age of those with ovarian tumors (33 pts) (Table 1) was 20 years (range 6-68). Sixteen of them had fertility-preserving surgery (unilateral oophorectomy +/— resection of peritoneal implants, 15 patients; biopsy only, 1 patient) and 17 had radical surgery (hysterectomy plus bilateral oophorectomy + / - resection of omentum and peritoneal implants). Stage (FIGO) was I in 16 patients, 11 in 5, III in 10 and IV in 2. There was no residual tumor in 14 patients, microscopic disease in 5, macroscopic disease <2 cm in 3 and bulky disease >2 cm in 11. No postoperative treatment was given to 3 patients with stage IA tumors (grade 1 immature teratoma, 1 patient, and dysgerminoma, 2 patients); pelvic radiotherapy was given to 1 stage IA dysgerminoma patient and abdominopelvic radiotherapy to 1 with stage IC dysgerminoma. The remaining 28 patients received cisplatinbased chemotherapy (PVB 17 patients, BEP 9 patients and EP 2 patients). The median number of cycles of chemotherapy was 4.5 (range: 2-9). Response to chemotherapy was evaluable in 19 patients (none of the other patients, including the 2 treated with cisplatinetoposide, still had evaluable disease before starting chemotherapy). The response rate was 94.7% (91.6% for PVB and 100% for BEP, p - NS). Fifteen patients (78.9%) achieved complete response (75% with PVB

Table I. Ovarian germ-cell tumors. Patient characteristics and treatment results. 1. Number of patients

33 pts.

2. Histology: • Dysgerminoma • Endodermal sinus tumor (EST) • Immature teratoma • Mixed tumors - Without EST - With EST

10 pts (30%)' 7 pts (21%)b 8 pts (24%) 8 pts (24%) 4 pts 4 pts

3. Stage (FIGO) • I • II • III • IV

16 pts 5 pts 10 pts 2 pts

4. Serum markers • Alpha-fetoprotein > 10 ng/ml • Beta-HCG > 10 IU/1 • LDH > 120 U/l

15/26 pts (57%) 2/23 pts (8%) 9/26 pts (34%)

5. Postoperative treatment None Pelvic radiotherapy Chemotherapy PVB BEP EP

3 pts 2 pts 28 pts (84,8%) 17 pts 9 pts 2 pts

6. Response to chemotherapy • Complete response • Partial response • No response • Non-evaluable disease • Response rate 7. Second-look No tumor Resection of residual mass .. - Necrosis - Mature teratoma - Viable tumorc

15 pts (9 PVB + 6 BEP) 3 pts (2 PVB + 1 BEP) 1 pts (1 PVB) 9 pts (5 PVB + 2 BEP + 2EP) 18/19 (94,7%) (91,6% PVB; 100% BEP) 11 pts (33,3%) 4 pts 7 pts 3 pts 2 pts 2 pts

• Includes 2 pts with anaplastic dysgerminoma. b Includes 2 pts with yolk-sac tumors. c These were the only pts with positive serum markers before second-look.

and 85.7% with BEP, p = NS) and all are presently alive and disease-free. Four patients, three of them with partial response and one with no response, were treated with second-line chemotherapy. All 3 of the patients previously treated with PVB received second-line EAP (etoposide, adriamycin and cisplatin). One of them achieved complete response and is a long-term survivor. The others died 16,18 and 20 months after diagnosis. Characteristics of the patients not achieving complete response to first-line therapy include older age at diagnosis (26, 27, 31 and 32 years) than that of complete responders, histology (endodermal sinus rumor in all 4 cases), preoperative alpha fetoprotein > 1000 ng/ml (3 of 3 tested) and macroscopic residual tumor left after first surgery (> 2 cm, 3 patients; < 2 cm, 1 patient).

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Second-look laparotomy was performed in 11 of 19 patients with residual disease after initial laparotomy. Results are described in Table 1. It is remarkable that the only 2 patients in whom viable tumor was found at second-look were the only ones who had elevated serum tumor markers (alpha-fetoprotein and/or betaHCG) just prior to second-look. With a median followup of 43 months (range: 10-144), 30 patients (90.9%) are alive and disease-free, and 3 have died of disease. Ten patients with extragonadal germ-cell tumors were treated (Table 2). Their median age was 8 years (range: 0-70). Primary sites were pineal region (4 patients), mediastinum (3 patients), sacrum (2 patients) and pharynx (1 patient). In none of the patients was a complete resection performed (partial resection, 5 patients; biopsy only, 5). Postoperative chemotherapy was given to all patients, and in addition all patients with intracranial tumors were given holocranial radiotherapy. In two of these, radiotherapy was given first, so they were not considered evaluable for response to chemotherapy. Both achieved complete response to radiotherapy plus chemotherapy. Six of eight patients with evaluable disease (75%) achieved complete re-

sponse to chemotherapy. One, with mediastinal MGCT treated with PVB, had local relapse 3 months after cessation of the therapy and was successfully retreated with EAP plus radiotherapy. Another patient with mediastinal tumor achieved partial response to BEP, but relapsed 8 months later with meningeal carcinomatosis. She was treated with craniospinal irradiation and is currently alive with disease. One patient with pineal tumor with extracranial metastases (peritoneum) relapsed in the mediastinum and is now on second-line chemotherapy; another, who was in complete response, died of neutropenic sepsis after completing radiotherapy and chemotherapy. With a median follow-up of 30 months (range 2-127), 6 patients (60%) are alive and disease-free (including 1 who achieved complete response to second-line chemotherapy), 2 are alive with active disease, 1 is alive with mature teratoma (an infant with immature teratoma of the pharynx who now has unresectable mature teratoma) and there was 1 toxic death. Acute toxic effects of cisplatin-containing chemotherapy in all female patients treated for MGCT were severe, including grade IV neutropenia and fever in 12/38 patients (31%) (1 death) and non-fatal grade IV anaphylaxia in 1 patient (2%). The reproductive status Table 2. Extragonadal germ-cell tumors. Patients characteristics of all 43 patients is shown in Table 3. All patients who and treatment results. had menses at first diagnosis and underwent fertility1. Number of patients 10 pts preserving surgery for ovarian tumors had menses after chemotherapy, as did the patients with extragonadal 2. Histology* Dysgerminoma 4 pts (40%) primaries (except for those with pineal tumors, who Endodermal sinus tumor 2 pts (20%) remain with hypogonadotropic hypogonadism). Three Immature teratoma 2 pts (20%) patients (2 with ovarian tumors and 1 with mediastina] Mixed tumors 2 pts (20%) tumor) have delivered 5 healthy children. In addition, - Without EST 1 pts one of them, who had a healthy child after therapy, had - With EST 1 pts 2 subsequent abortions (1 spontaneous, 1 elective). 3. Stage Concerning patients who were premenarchal at first I 4 pts n 2 pts diagnosis, all 4 patients who are now aged 16 or older m 2 pts have menses. No other clinically evident long-term side IV 2 pts effects of therapy have been recorded. No tests to 4. Serum markers detect subclinical abnormalities were performed. • Alpha-fetoprotein > 10 ng/ml 5/10 pts (50%) Overall survival at 5 and 10 years is 89% for all pa• Beta-HCG > 10 UI/1 3/10 pts (30%) tients (89.5% for patients with ovarian tumors and • LDH > 120 U/l 6/10 pts (60%) 90% for those with extragonadal primaries, p = NS). 5. Postoperative treatment Event-free survival at 5 and 10 years is 80.4% (87.7% Radiotherapy 4 pts b with ovarian tumors and 54% with extragonadal pri(pineal tumors) Chemotherapy (3-17 cycles) PVB BEP EP 6. Response of chemotherapy: Complete response Partial response No response Non-evaluable disease Response rate

10 pts (100%) 5 pts 4 pts 1 pts 6 pts 1 pt 1 ptc 2 pts 7/8 pts (87,5%)

" Since no complete resection was performed, the actual number of mixed tumors might be higher. b Plus 1 pt with mediastinal tumor, given consolidation radiotherapy and 2nd-line chemotherapy. c Persisting mature teratoma.

Table 3. Reproductive status. Updated status

Castrated Fertility-preserving surgery Menstruating No menses 1

Menopausal status at diagnosis Premenarchal

Menstruating

Postmenopausal

1 11 4 7(2P)

14 13 II1 2(2P)

3 1 0 1

Three patients delivered 5 healthy babies. One of them had 1 child, 1 spontaneous abortion and 1 elective abortion. Note: P — number of patients with pineal tumors.

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true complete response rate being 20% [17], although a minority of long-term survivors was reported. The discovery of cisplatin's antitumor activity in testicular tumors led in 1975 to the development by Einhorn and Donohue [6] of a new combination chemotherapy, PVB, by the addition of cisplatin to a combination of two active drugs, vinblastine and bleomycin. In 1980, the literature began reporting on pts with nondysgerminomatous ovarian MGCT treated with PVB. All reports [7-13, 17-20] documented a very high response rate, with complete response in about 90% of cases. That was even more remarkable since many of such patients had previously failed VAC. The issue of whether PVB was superior to VAC was discussed for many years. Concerns about the toxicity of the new regimen were the basis of a proposal that PVB should be used as first-line therapy only in patients with advanced-stage tumors containing endodermal sinus tumor, with VAC remaining the standard therapy for all other patients [14]. Bearing in mind that the rarity of ovarian MGCT has prevented randomized trials, the response rate to PVB seems definitely higher than for VAC, and that can be seen in successive reports using both regimens [4, 12]. Short-term toxicity is higher for the PVB regimen, but treatment-related mortality remains below 2% in experienced hands, and long-term toxicity, specifically, preservation of fertility, is clearly better achieved with PVB than with the alkylating Tim* (morthi) agent-containing VAC, in spite of early fears [14]. Severe pulmonary toxicity is rare if bleomycin is Fig. I. Event-free survival of 43 women with malignant germ cell stopped before the limiting cumulative dose is reached. tumors. Even the few authors who still feel that the superiority of PVB over VAC is not yet proven [16] report some patients failing VAC who achieved long-term remission Discussion with salvage PVB.

maries, p - 0.05) (Fig. 1). There is a plateau in both overall survival and event-free survival beyond 28 months. Significant unfavorable prognostic factors for survival, tested through univariate analysis, included age older than 22 years at diagnosis (p < 0.01), diagnosis of endodermal sinus tumor (p < 0.02) and serum alpha-fetoprotein over 1000 nanograms/ml at first diagnosis (p < 0.01). Factors without significant prognostic value in the present series included stage, betaHCG, LDH, type of surgery, residual tumor after primary surgery and schedule of chemotherapy (PVB vs. BEP). Tumor site (ovary vs. extragonadal) had no prognostic value for survival, but it did have prognostic value for event-free survival, with extragonadal tumor patients faring worse (10-year event-free survival = 54% vs. 87.7%, p < 0.05).

Ovarian MGCT are highly malignant neoplasms presenting most often in girls or young women [1]. Prognosis with surgical resection only was dismal [2], except for stage 1 dysgerminoma and grade I stage 1A immature teratoma. Endodermal sinus tumor of the ovary was associated with a dire prognosis, with only 9 of 65 patients surviving beyond 2 years (only 1 survivor had disease beyond stage I) [2]. Combination chemotherapy for nondysgerminomatous ovarian MGCT was first used in the mid 1970s. The regimen combining vincristine, actinomycin D and cyclophosphamide (VAC), first proposed by the MD Anderson Hospital [3] was considered for many years to be the standard chemotherapy for ovarian MGCT. Results were reported by several groups [4, 5, 14-16]. Overall, more than 50% of patients with completely resected stage I-II non-dysgerminomatous MGCT treated with VAC as adjuvant postoperative therapy were long-term survivors. As for advanced disease (stage FII-IV), about one-half of patients treated with VAC achieved complete response, but if gross disease was present at the beginning of chemotherapy less than 25% of patients obtained durable response [12]. The prognosis of advanced endodermal sinus tumors remained poor, the

Long-term follow-up of patients with nondysgerminomatous ovarian MGCT treated with PVB reported less favorable results [12, 21, 22]. Although almost all patients treated in the adjuvant setting (no gross disease plus negative tumor markers) remained disease-free and the complete response rate in patients with advanced disease treated with PVB as first-line chemotherapy was around 85%, 20%-30% of complete responders subsequently relapsed, so the total percentage of failure was 30%-40%. De Palo et al. concluded that with a 58% 4-year disease-free survival, PVB is an effective but not a satisfactory treatments [22]. The failure rate was especially high in patients with advanced endodermal sinus tumor (7 of 13 patients with stage HI/TV died of disease). A regimen which substitutes etoposide for vinblastine (BEP) has demonstrated in male patients with disseminated MGCT better efficacy and lower myelotoxicity and neurotoxicity than PVB [23]. In addition, anecdotal patients with ovarian MGCT failing PVB were long-term survivors after salvage therapy including cisplatin and etoposide [11]. BEP or other etoposide-containing regimens such as POMB-ACE have been subsequently tested as first-line therapy for ovarian MGCT [22,

229 24-27] with encouraging results, and most authors consider BEP the standard regimen in nondysgerminomatous ovarian MGCT [28]. The safety of sparing early-stage pts adjuvant chemotherapy except for those with grade I stage IA immature teratoma [29-31] remains to be proven, and long-term toxicity of chemotherapy is minimal, especially if bleomycin is eliminated, so it is the current policy of our institution to give 3 cycles of EP in this setting. Ovarian dysgerminoma, the only MGCT which is frequently bilateral at diagnosis (10%-20%) is exquisitely radiosensitive. Postoperative abdominopelvic radiotherapy resulted in almost 100% long-term disease-free survival in stage I-II tumors [32-34]. However, the long-term toxicity of this approach was not negligible, since almost all patients became sterile, and lethal complications such as radiation enteritis have been reported. The observation that testicular seminoma is dramatically sensitive to cisplatin-containing chemotherapy [35] and reports showing that patients with metastatic ovarian dysgerminoma treated with BEP were cured and remained fertile [24], led to reconsideration of the role of adjuvant radiotherapy in early stages. Since postoperative chemotherapy can prevent recurrence without causing sterility, it is now widely accepted that all patients with dysgerminoma who wish to preserve ovarian function should be offered fertilitypreserving surgery plus chemotherapy [28]. Adequately-staged stage IA dysgerminoma should be treated with unilateral oophorectomy only, and as for patients beyond stage IA who have completed childbearing, postoperative chemotherapy seems a wise election, but radiation therapy may also be successful. No doubt, the revolution which has taken place in the management of MGCT of the ovary is mostly due to the introduction of cisplatin-based chemotherapy. It has been the keystone of therapy of ovarian MGCT in our institution since 1978. With the approach described here, 90% of patients can be expected to become long-term survivors. However, failures still occur in advanced disease (3/12 pts with PVB and 1/6 with BEP in the present series). Although there are anecdotal reports of successful salvage therapy with VAC for patients with ovarian MGCT failing BEP [28], we feel that therapy of patients failing BEP remains unsatisfactory. Univariate analysis of our data has defined histology (endodermal sinus tumor), alpha-fetoprotein > 1000 ng/ml and age > 22 years as adverse prognostic factors. It has long been known that the prognosis of endodermal sinus tumor is worse than that of other types of ovarian MGCT for patients treated with surgery only [2, 36] and this seems to be true as well in the cisplatin era. Kawai et al. [37] found that stage II, ITI or TV, presence of residual tumor after primary surgery, presence of more than 100 ml of ascites and certain histological patterns were significant prognostic factors in 29 patients with ovarian MGCT whereas age and preoperative serum alpha fetoprotein were not. It must be noted that most patients in this series were not treat-

ed with cisplatin-containing chemotherapy. The fact that, in this series which included only patients with endodermal sinus tumor, serum alpha fetoprotein had no significant prognostic value suggests that it may not have prognostic value by itself, independently of histology. Older age was found to be an unfavorable prognostic factor in children [38]. The prognostic factors found in our univariate analysis and those found by others are all modelled on small series of patients and need to be tested on an independent body of data. Since most patients with ovarian MGCT are young women and can now be cured, preservation of fertility becomes a most important issue. Many reports [24] show that cure is equally achieved with fertility-preserving surgery (unilateral oophorectomy plus resection of all gross disease, but preserving one ovary and the uterus) and also that women treated with shortterm cisplatin-based chemotherapy (PVB or BEP) can anticipate normal menstrual function and a reasonable probability of having normal offspring [39]. There is a widespread consensus that 'rarely if ever, should any of the reproductive organs be removed in the management of ovarian germ cell malignancy even if the cancer is metastatic' [40]. Monitoring of disease course with tumor markers (alpha-fetoprotein, beta-HCG and LDH) is essential for determining the number of cycles of chemotherapy needed and for follow-up after completion of therapy [22]. For monitoring of pure dysgerminoma with negative alpha-fetoprotein and beta-HCG, serum LDH might be useful [41]. There has been a great deal of controversy about the need for second-look surgery in ovarian MGCT [4244]. There is a consensus that it is not necessary, in view of their excellent prognosis, for patients with no gross residual disease after first surgery. As for patients with gross disease at the start of chemotherapy, we [26] and others [27] have found second-look to be negative in all patients with no residual mass seen on CT scan and negative markers after completion of chemotherapy. Thus, it is our current policy in males and females with MGCT that only those with residual mass and negative tumor markers at completion of chemotherapy must go to second-look laparotomy for aggressive resection of residual masses. If only necrotic tissue or mature teratoma is found, no further chemotherapy is given. Patients with viable tumor found at second-look or those with increasing tumor markers at completion of first-line chemotherapy go to second-line regimens. Aggressive surgical management of residual mass (including mature teratoma) might well be the reason why no late relapses have been seen in our series [26] or in others [27] as compared to those of De Palo et al. [22]. Reports on extragonadal MGCT in women are anecdotal [38, 45]. The largest experience is included in a multi-institutional report on 93 children [38]. The outcome of seventy-one children (41 girls) with extragonadal MGCT (brain primaries excluded) treated

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with multimodal treatments including cisplatin-based chemotherapy was unfavorable, the 4-year event-free survival being 42% versus 63% for ovarian primaries (p - 0.03). The prognosis was bad both for sacrocoxigeal primaries (only 14 of 31 patients remained eventfree) and for mediastinal MGCT (6 of 17). Pinkerton et al. [45] had previously reported 1 relapse out of 6 children (3 girls) with extragonadal MGCT treated with cisplatin-based chemotherapy. Available data on 10 patients treated in our institution (comprising 31% of 32 patients with extragonadal MGCT) suggest that the outcome with current therapy is not satisfactory (40% of failures, which is very similar to that reported in males with extragonadal MGCT) [46,47]. The present results with extragonadal MGCT in women are in agreement also with pediatric reports [38, 45]. The prognosis of mediastinal primaries appears to be especially unfavourable. Reasons for such clinical behaviour as compared to that of ovarian primaries remain speculative, although incomplete resection of the primary rumor presumably containing chemoresistant cells capable of causing relapse might partially explain this. A revolution has taken place in the management of ovarian MGCT for three reasons: the introduction of cisplatin-based chemotherapy, the possibility of monitoring the disease by tumor markers without secondlook surgery and the possibility of preserving fertility without compromising cure [20].

12.

13. 14. 15. 16.

17. 18. 19. 20. 21. 22.

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231 34. Gallion HH, van Nagell JR, Donaldson ES et al. Ovarian dysgerminoma: Report of seven cases and review of the literature. Am J Obstet Gynecol 1988; 158: 591-5. 35. Van Oosterom AT, Williams SD, Cortes-Funes H et al. The treatment of metastatic seminoma with combination chemotherapy. In Jones WG, Ward AM, Anderson CK (eds): Germ cell tumors II. Oxford, England: Pergamon 1986; 229-33. 36. Kurman RJ, Norris HJ. Endodermal sinus tumor of the ovary: A clinical and pathological study of 71 cases. Cancer 1976; 38: 2404-19. 37. Kawai M, Kano T, Furuhashi Y et al. Prognostic factor in yolk sac tumors of the ovary. A clinicopathologic analysis of 29 cases. Cancer 1991; 67:184-92. 38. Ablin AR, Krailo MD, Ramsay NKC et al. Results of treatment of malignant germ cell tumors in 93 children: A report from the Childrens Cancer Study Group. J Clin Oncol 1990; 9: 178292. 39. Gerhenson DM. Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 1988; 6: 270-5. 40. Baterman BG, Taylor pT. Reproductive considerations during abdominal surgical procedures in young women. Surg Clin North Am 1991; 71:1053-66. 41. Higgins R, Donaldson ES. Current therapy for dysgerminoma of the ovary (letter). Obstet Gynecol 1988; 71: 287-8. 42. Cain JM, Saigo PE, Pierce VK et al. A review of second-look laparotomy for ovarin cancer. Gynecol Oncol 1986; 23:14-25.

Book review Cancer, chemotherapy and biological response modi-

fiers, Annual 14. H. M. Pinedo, D. L. Longo, B. A. Chabner (eds). Elsevier Publishers, Amsterdam/London/New York/Tokyo, 1993. 692 pp, Dfl. 470.00. A few weeks before Christmas every year I receive the new Annual issue of this book, which has come to be known simply as 'the Pinedo'. This is always greatly appreciated, also because it has grown to be a yearly encyclopedia of something on the order of 700 pages, making it a very expensive book to purchase. Since its beginning, when it was the 'EORTC Annual on Cancer Chemotherapy', it has considerably expanded. About one-third of its pages are now devoted to biological response modifiers - too much for my taste in view of the relatively minor impact this class of drugs has thus far had on routine oncology practice. The greatest expansion, however, has been across the Atlantic: Three-quarters of the authors and two-thirds of the editors are now Americans. This leads in some instances to an under-evaluation of aspects which are of

43. Chambers SK, Chambers JT, Konorn El et al. Evaluation of the role of second-look surgery in ovarian cancer. Obstet Gynecol 1988; 72:404-8: 44. Pippin CH, Cain JM, Hakes TB et al. Primary chemotherapy and the role of second-look laparotomy in non-dysgerminomatous germ cell malignancies of the ovary. Gynecol Oncol 1988; 31: 268-75. 45. Pinkerton CR, Pritchard J, Spitz L. High complete response rate in children with advanced germ cell tumors using cisplatincontaining chemotherapy. J Clin Oncol 1986; 4:194-9. 46. Rivera F, Paz-Ares L, Lianes P et al. Extragonadal germ cell tumors, (meeting abstract). Ann Oncol 1992; 3 (Suppl 5): 165 (A-632). 47. Paz-Ares L, Lianes P, Orlando M et al. Germ-cell tumors with brain involvement (meeting abstract). Second Iberoamerican Congress of Oncology. Oporto 1991; A-274. Received 19 April 1993; accepted 10 November 1993. Correspondence to: Dr. Jose Ignacio Mayordomo Department of Surgical Oncology W1540 Biomedical Science Tower University of Pittsburgh Pittsburgh, PA 15261 USA

Annals of Oncology 5: 231, 1994.

particular interest in Europe, e.g., nasopharyngeal carcinoma in head and neck tumours. Almost all of the contributions to this edition are of the same high quality as in previous years. Of course, with more than 80 authors, there are some discrepancies, some chapters are too short (leukemias, upper gastrointestinal rumours), and others perhaps too long (hematopoietic growth factors). The latter chapter was prepared by an individual who works for a company which produces G-CSF: is this an appropriate link between academia and industry? The best three chapters in my opinion are those on lymphomas, lung cancer and control of growth and differentiation. Notwithstanding minor weaknesses, this book is still an absolute necessity for all oncologists who are aware that they cannot know everything but must have access to updates in every field of oncology. F. Cavalli Bellinzona