Cisplatin, etoposide, ifosfamide, vincristine and bleomycin combination chemotherapy for far advanced testicular carcinoma

Annals of Oncology 2: 197-202, 1991. O 1991 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Cisplatin, etoposide, ifosfamide, vincristine and bleomycin combination chemotherapy for far advanced testicular carcinoma A. Harstrick,1 H.-J. Schmoll,1 C.-H. Kohne-Wompner,1 L. Bergmann,2 U. Lammers,3 J. Hohnloser,4 G. Dolken,5 P. Reichhardt,6 W. Siegert,7 F. Natt,8 U. Rath,6 H. Wilke1 & H. Poliwoda1 1

University of Hannover, Hannover; 2 University of Frankfurt, Frankfurt; 3 University of Miinster, Miinster; AKlinikum lnnenstadt, Mu'nchcn; University of Freiburg, Freiburg; 6 University of Heidelberg, Heidelberg; 1 Klinikum Chartottenburg, University of Berlin; ^Hospital Sanderbusch, Sanderbusch, Germany 5

Summary. Forty-eight patients with advanced testicular cancer, defined as abdominal mass > 10 cm, mediastinal mass > 5 cm, more than 20 lung metastases, or visceral organ involvement were treated with an intensive, alternating five-drug regimen consisting of cisplatin 50 mg/m2 d 1-3, etoposide 170 mg/m2 d 1-3, ifosfamide 5 g/m2 d 15, vincristine 2 mg weekly, bleomycin 15 mg/m2 weekly, q d 28. Thirty-four (71%) of the patients attained tumor-free status. This was achieved by chemotherapy alone in 14 patients and by surgical resection of residual disease in the remaining 20 patients (histology of resected tissue: necrosis 12, mature teratoma 7, viable carcinoma 1). Patients with pure seminoma responded better than patients with nonseminoma (CR 100% vs. 67%, respectively). In a univariate analysis only the value of HCG ( 10 000 U/L) and the number of involved organ sites (<2 vs >2) had significant influence on the response rate. After a minimum follow-up of 24 months 3 patients (9%) have relapsed. The survival rate is 76% after 36 months, with 61% remaining disease-free. Though this intensive regimen might bestow some of the therapeutic advantages of standard three-drug protocols in far advanced testicular cancer, the results are still less than optimal and warrant the exploration of new therapeutic strategies. Key words: testicular cancer, germ cell tumors, cisplatin, etoposide, ifosfamide Introduction Metastatic testicular carcinoma has become a highly curable disease since the introduction of cisplatinbased combination chemotherapy. In unselected patient populations about 85% of patients will be cured if adequately-dosed cisplatin-based chemotherapy is given [1-4]. Nevertheless, this also means that 10% to 15% of the patients will fail standard chemotherapeutic approaches and ultimately succumb to their disease, Several investigators have analysed their patient populations in an attempt to identify risk factors that can predict for treatment failure. It is the universal finding of all these studies that the initial tumor burden is the most important factor for outcome of therapy [5-8]. Unfortunately there are different definitions of what constitutes advanced tumor and the cut-off values for good and poor prognoses; there is no universally accepted standard by which to define the better-prognosis patient. Factors found in most of these investigations to be correlated with poor prognosis are advanced abdominal disease, multiple lung metastases, involvement of visceral organs, excessively elevated values of HCG and AFP and nonseminomatous

mediastinal primary. Several investigators have attempted to improve the results in these high-risk patients by giving more intensive chemotherapy, with partially promising results. In 1988 Ozols and coworkers published the results of a randomized trial comparing standard cisplatin/vinblastine/bleomycin therapy with an intensified regimen containing doubledose cisplatin, vinblastine, bleomycin and etoposide for patients with advanced disease. They found a significant survival advantage for the intensified regimen which might be an indication that high-dose chemotherapy could be beneficial for patients with badprognosis factors [9]. In 1985 the German Cooperative Group for Testicular Carcinoma initiated a multicenter trial using an intensified regimen for patients with advanced testicular cancer. The rationale for the treatment design was to shorten the therapy-free intervals by giving additional therapy on day 15; to include ifosfamide, with its high activity in pretreated patients [10], in the first-line regimen and to include vincristine, which had shown high activity in heterotransplanted testicular carcinomas [11]. Fifty-two patients were entered into the trial and all have had a minimum follow-up of 24 months

198 since the end of therapy. Thus, the results given in this report can be regarded as mature. Patients and methods Patients with histologically-proven metastatic germ cell carcinoma and advanced disease were eligible. Advanced disease consisted of one of the following criteria: abdominal mass of more than 10 cm, mediastinal mass of more than 5 cm, more than 20 lung metastases or one or more lung metastases greater than 5 cm, or liver, bone or brain metastases. Additional requirements for eligibility were no prior chemotherapy, adequate liver function (bilirubin < 34 nmol/L), adequate renal function (creatinine < 115 nmol/L) and normal bone marrow function (WBC > 3000/nL and thrombocytes >150.000/nL). No patients were excluded because of reduced performance status. The histology was classified according to the British Testicular Tumor Panel [12]. To make possible a comparison with the results of other recently published trials the patients were retrospectively analysed using the definition for 'moderate' and 'advanced' disease as proposed by the investigators at Indiana University [7], and the individual probability of attaining a complete response was calculated using the formula published by Bosl and colleagues [8]. The treatment protocol is given in Table 1. It consisted of two blocks of therapy. Block I included cisplatin 50 mg/m2 i.v. days 1-3; etoposide 170 mg/m2 i.v. d 1-3; vincristine 2 mg i.v. bolus days 1 and 8 and bleomycin 15 mg/m2 i.v. bolus d 1 and 8. Block II was scheduled to start when the white blood cell count began to rise after passing the nadir, preferably on day 15. It consisted of ifosfamide 5 g/m2 in a 24-hr infusion on day 15, vincristine 2 mg i.v. bolus on days 15 and 22 and bleomycin 15 mg/m2 i.v. bolus on days 15 and 22. Treatment was repeated beginning with block 115 days after the start of block II of the prior cycle. Bleomycin was omitted after the second cycle (total dose 120 mg/ m2). Vincristine was omitted in instances of neurotoxicity. All patients received i.v. hydration with 3000 mL saline/glucose 5%, supplemented with potassium chloride and magnesium. The uroprotector 'mesna' was given as a continuous infusion of 5 g/m2 concurrent Table 1. Treatment protocol. Cisplatin Etoposide Vincristine Bleomycin* Ifosfamide Vincristine Bleomycin*

50 170 2 15

mg/m2

mg/m 2

mg mg/m 2

2

5 g/m 2 mg 15 mg/m 2

i.v. i.v. i.v. i.v.

1 h 1 h bolus bolus

d d d d

i.v. i.v. i.v.

24 h bolus bolus

d 15 d 15; 22 d 15; 22

qd28 Bleomycin to be omitted after 2 cycles.

1-3 1-3

1;8

Block I

i;8

with ifosfamide and 2.5 g/m2 in the 12 hours following ifosfamide administration. To assure adequate urine output, 20 mg furosemid were given i.v. at the beginning of the cisplatin and ifosfamide infusions. Antiemetic treatment was left to the discretion of the treating physician. Almost all patients received dexamethasone, metoclopramide, and dimenhydrinate. Therapy was given for two cycles beyond the maximal response. In the case of CR the patients were followed at regular intervals. In the case of PR with normalisation of tumor markers, resection of all residual disease was attempted. All responders had achieved their maximal response after 4 cycles. The median number of cycles was 4 (range 1-6). Patients with brain metastases received whole-brain irradiation concomitant with the first cycle of chemotherapy. Initial patient work-up consisted of history, physical examination, CT scans of brain, lung, and abdomen, chest x-ray, abdominal ultrasound, bone scan, whole blood count and differential, serum chemistry, creatinine clearance and tumor markers. Blood counts were obtained twice weekly during treatment. Complete serum chemistry, creatinine clearance and tumor markers were taken every two weeks. Prior to each cycle all measurable sites of tumor were evaluated. CT scans of lung and abdomen were repeated every 8 weeks. Follow-up consisted of history, physical examination, blood count, serum analysis, tumor markers, chest x-ray and abdominal ultrasound every 4 weeks during the first year and every 8 weeks thereafter. CT scans of lung and abdomen were performed every two months in the first year and every 4 months thereafter. A complete response was defined as the absence of all radiographic and biochemical signs of tumor for at least 4 weeks. No evidence of disease (NED) means absence of tumor which was obtained by complete surgical resection of histological viable tumor. A marker-negative response (Rm-) was defined as normalisation of all elevated tumor markers for at least 4 weeks and no radiologic signs of tumor progression. This definition was chosen because the major indicator for biologic response in our opinion is the normalisation of tumor markers and not the radiographic change in tumor size, which can remain virtually unchanged in tumors with a high content of teratoma even when all malignant disease has been eradicated by therapy. Patients not achieving normal markers or showing tumor progression were classified as treatment failures. Duration of survival and response were recorded from the beginning of therapy. Survival curves were constructed by the method of Kaplan and Meier [13]. Differences in response between subgroups were checked for statisticaJ significance by the chi-square test. Toxicity was graded by the WHO criteria.

Block II

Results The patient characteristics are shown in Table 2. Fifty-

199 Response

Table 2. Patient characteristics. Age Performance status Histology pure seminoma MTU MTI MTT unclassified Primary gonadal retroperitoneal mediastinal Sites of disease one two three > three HCG> 10 000 U/L AFP> 1000 mg/mL LDH > 500 U/L Liver metastases Bone metastases Criteria for advanced disease* - abdominal tumor > 10 cm - mediastinal mass >5 cm - advanced lung metastases** - visceral metastases

26 yr (17-49) 70% (20-90) 6(12%) 11 (23%) 18(37%) 11 (23%) 2 ( 5%) 40 (84%) 4 ( 8%) 4 ( 8%) 13(27%) 13(27%) 17(35%) 5 (11%) 11 (23%) 19(40%) 31 (65%) 16 (33%) 6(12%) 25 14 17 25

* 24 patients had more than one manifestation establishing advanced disease. ** > 20 lung metastases or one or more metastases > 5 cm.

two patients were registered for the trial, 4 of whom were not evaluable. Two patients did not have advanced disease as defined by the entry criteria (both are in continuous CR); one patient died of a non-tumor and non-therapy-related cause during the first cycle, and in one patient the therapy was changed by the treating physician while the patient was still responding to the study therapy (the patient is in continuous CR). The median age was 26 yr (17-49); the median performance status was 70% (20-90) including 7 patients with a performance status <50%. Histology was pure seminoma in 6; MTU in 11; MTI in 18 and MTT in 11 patients. In two patients histologic classification was not possible. Forty patients had a gonadal primary and 8 patients had an extragonadal primary (retroperitoneal 4; mediastinal 4). The majority had more than one site of disease. Twenty-four patients met one criterium for advanced disease, 16 patients met two criteria for advanced disease and 8 patients more than two (Table 2). The patients with nonseminoma were retrospectively classified according to the Indiana University classification. Eight (19%) patients had moderate disease and 34 (81%) advanced disease. In 41 patients the individual probability for CR was calculated according to Bosl (the LDH value was missing for 1 patient). Sixteen (39%) had a probability >0.5 (good-risk) and 25 patients (61%) had a probability of <0.5 (poor-risk).

Thirty-three patients (69%) achieved a complete response. In 14 patients the complete response was achieved by chemotherapy alone, and 19 patients required resection of residual disease (12 necrosis, 7 mature teratoma) after chemotherapy. One additional patient was rendered rumor-free by resection of residual viable carcinoma (NED). Thus, overall 34 (71%) were free of disease after completion of therapy. Eight (17%) had a normalisation of their tumor markers but unresectable residual disease. Six patients, including 2 with therapy-associated death, (12%) were treatment failures (Table 3). All 6 patients with seminoma had a CR compared to 28/42 (67%) with nonseminomas. In nonseminoma patients there was no difference in response rate between patients classified as having 'moderate' or 'advanced' disease according to the Indiana University classification. 7/8 (87%) with moderate and 21/34 (62%) with advanced disease achieved CR (p = 0.16). When using the classification of Bosl, patients at good risk (p > 0.5) and patients at poor risk (p < 0.5) showed no differences in CR. 12 of 16 (75%) assigned to the good risk group reached a CR compared to 15/25 (60%) in the poor-risk group. However, when the group of poor-risk patients was further divided using a p of 0.25 as cut-off value, there was a highly significant difference. 14/15 (93%) with a p-value of 0.5 to 0.25 reached a CR compared to only 1/10 (10%) with a p-value <0.25 (p - 0.0001). Nine more variables were checked for prognostic significance in univariate analysis. Only the value of HCG (< 10 000 U/L vs > 10 000 U/L) reached statistical significance in our study (Table 4) and the number of involved sites (< 2 vs > 2) was of borderline significance. After a minimum follow-up of 24 months after the end of therapy 3 patients (9%) have relapsed from CR. The overall survival is 76% at 36 months (Fig. 1) and the continuously disease-free survival is 65%. Six patients received cisplatin-based salvage therapy after relapsing from CR (3) or progressing from Rm-. Salvage therapy consisted of cisplatin/etoposide/ ifosfamide in 4, cisplatin/vinblastine/bleomycin in 1 Table 3. Response to PEBOI. CR - chemotherapy alone - chemotherapy + surgery NED RmTF - progressive tumor - death on therapy

33 (69%) 14 19 1 ( 2%) 8(17%) 6(12%) 4 2

NED : Tumor-free after resection of viable carcinoma. Rm- : Response with normalisation of tumor markers. TF : Treatment failure.

200 Table 4. CR rate in nonseminomatous patients according to risk factors.

Table 5. Hematological toxicity (percentage of cycles). WHO"

1

2

3

4

Block I Leukocytes Thrombocytes

3% 21%

16% 12%

44% 27%

36% 17%

Block II Leukocytes Thrombocytes

20% 17%

22% 5%

30% 0%

22% 0%

p-value Abdominal mass <10cm >10cm absent Lung metastases minimal moderate advanced absent Mediastinal tumor present absent Liver metastases present absent Bone metastases present absent Sites of disease < 2 sites > 2 sites LDH <500 U/L >500U/L AFP <1000ng/mL >1000ng/mL HCG < 10 000 U/L > 10 000 U/L

10/15(66%) 13/20(65%) 5/ 7 (71%)

ns.

2/ 4 (50%) 2/ 3 (67%) 10/17(60%) 14/18(80%)

Table 6. Non-hematological toxicity (percentage of patients).

7/13(54%) 21/29(72%) 10/16(63%) 18/26(69%) 3/ 5 (60%) 25/37 (68%) 16/20 (80%) 12/22(55%)

WHO*

1

2

3

4

N/V Lung Liver Renal Neurotoxicity Mucositis Diarrhoea

0% 41% 20% 22% 61% 36% 26%

31% 9% 6% 4% 15% 9% 0%

63% 2% 0% 0% 6% 0% 0%

6% 0% 2% 0% 0% 0% 0%

0,08

pression. Block I was more myelosuppressive than block II. The hematologic toxicity of 183 evaluable cycles is given in Table 5. Thirty-eight cycles (21%) 15/23(65%) were complicated by granulocytopenic fever which 13/19(68%) could be managed by i.v. antibiotics in all instances. There were two therapy-related deaths. One patient 24/31 (77%) died after resection of 13 lung metastases from uncon4/11 (36%) 0.01 trollable pulmonary bleeding and one patient died after n.s. - not significant, indicating a p-value >0.01. resection of a large residual mediastinal tumor due to disseminated intravascular coagulation. Both patients and high-dose cisplatin/etoposide/cyclophosphamide were recorded as treatment failures. in 1. One durable Rm-, lasting 24+ months, has been Non-hemathologic toxicity is given in Table 6. 51% achieved. The remaining patients showed either no or had a significant decrease in serially measured carbon only short-lived responses and all five have died. monoxide diffusion capacity but only 5 patients had clinical symptoms. Mild neurotoxicity was seen in 76% of patients and severe neurotoxicity occurred in 2 patients. The other toxicities were transient and not a Toxicity clinical problem. As expected, the dose-limiting toxicity was myelosup11/15(75%) 16/26(60%)

PEBOI

Discussion

Ov*r*ll surylval (n-48)

O.7S-

•+-UH

0.6-

0.25

10

20

30 Tim* (month*)

40

so

Fig. 1. Survival of 48 eligible patients from start of therapy.

60

Although the majority of patients with metastatic germ cell tumors will be cured with cisplatin combination chemotherapy, treatment results for patients with far advanced disease remain unsatisfactory. Several methods for improving the prognosis of these patients have been investigated. In a randomized study Ozols showed that patients who are treated with a very intensive induction chemotherapy have a higher CR rate and a longer survival than those treated with conventional PVB (9). Nevertheless, a simple doubling of the dose of cisplatin does not seem to be beneficial. Einhorn et al. found no difference in response rate, response duration or survival between patients treated with cisplatin 20 mg/m2 x 5 or 40 mg/m2 x 5 in combination with eto-

201 poside and bleomycin [14]. In a non-randomized phase II trial Daugaard et al. reported a high CR rate with an intensive regimen of cisplatin 40 mg/m2 x 5, etoposide 200 mg/m2 x 5 and bleomycin 15 mg/m2 weekly. 77% were alive without tumor at 11 months at the expense of profound, and in 4 cases, lethal, toxicity [15]. Thus, from these data it can not be clearly stated whether the simple intensification of one or more components of a standard three-drug regimen will improve the outcome of poor-risk patients. One major problem in comparing results from several non-randomized trials is that different criteria were used to define poor-risk patients. As has been convincingly shown by Bajorin, the various inclusion characteristics will have a profound impact on the outcome of a non-randomized trial [16]. Thus it will be important to reclassify a patient population using one or more well-characterized definitions for poor prognosis. In our trial the overall CR rate was 71%. Nevertheless, as also described by other groups, patients with even far advanced seminoma seem to have better prognoses than nonseminoma patients and thus are classified by most authors as good-risk [17]. In the present trial all 6 patients with seminoma attained a durable complete response. The CR rate for all nonseminoma patients was 67%. If only those patients with advanced disease according to the Indiana University classification are considered, 21/34 (62%) achieved a complete response. Though our data failed to demonstrate a statistically significant difference between moderate and advanced disease, this is more likely due to the small number of patients than to a true absence of biological differences between those two groups of patients.

the present trial. Logothetis reported impressive results with the alternating regimen CISCA-VB. 33 of 37 (89%) patients with bulky disease ( m b 3 - b 5 ) achieved complete responses [18]. Similar favourable results were published by Newlands using the POMBACE combination. In their series the CR rates were 73% (8/11) for patients with advanced lung and abdominal disease and 75% (9/12) for patients with liver or brain metastases [19]. On the other hand, Bosl et al. saw no superiority in the alternating VAB6-EP regimen over VAB6 alone [20, 21]. The 67% CR rate attained in the present study in patients with advanced nonseminoma is encouraging, even more so because it was achieved in a multicenter trial. Nevertheless, the longterm results are still far from optimal. Since the regimen included several new components such as alternation of drugs or inclusion of ifosfamide and vincristine, the individual contributions can not be assessed. One principal draw-back might have been that cisplatin was given only every 4 weeks. Data from Horwich indicate that the dose intensity of cisplatin at the beginning of the treatment might be essential [22]. They observed 23/27 rumor-free patients (85%) after an intensive induction regimen using weekly cisplatin. This concept of high-intensity cisplatin induction will be evaluated in a randomized trial by the MRC/EORTC. From the data available to date it can not be determined whether intensive induction chemotherapy in its present form will improve the prognosis of poor-risk testicular tumor patients. Nevertheless, although confirmation by a randomized trial is still awaited, the concept of high-intensity cisplatin and rapid alternation appears to offer some improvement and should be further explored.

Bosl and colleagues have developed a mathematical model to calculate an individual patient's probability of reaching a CR. This model was tested against an Acknowledgement independent data set using a p-value of 0.5 as cut-off between good and poor prognosis. The model correctly We thank G. Leber, Paderborn, and A. Mayr, Berlin, predicted 36/38 (95%) of responders and 5/11 (45%) for entering patients and Ms. S. Droge for preparing of non-responders [8]. In our patients the threshold of the manuscript. 0.5 was not very discriminative, as 75% of patients with a p > 0.5 and 60% of patients with a p < 0.5 became References tumor-free (p = 0.3). Nevertheless, within the group of patients with a p < 0.5, a subgroup was identified with a 1. Williams SD, Birch R, Einhorn LH et al. Treatment of disseminated germ cell tumors with cisplatin, bleomycin and worse prognosis by using a threshold of 0.25. The CR either vinblastine or etoposide. New Engl J Med 1987; 316: rate for patients with p-values between 0.5 and 0.25 1435-40. was 93% whereas it was 10% for those with a p-value 2. Stoter G, Sleyfer DT, ten Bokkel Huinnink WW et al. High of less than 0.25. This might indicate that by using this dose vs. low dose vinblastine in cisplatin-vinblastine-bleomycin formula, it is possible to identify those patients who will combination chemotherapy of nonseminomatous testicular cancer. J Qin Oncol 1986; 4: 1199-206. be cured by standard regimens only as exceptions and in whom the exploration of new treatment strategies is 3. Peckham MJ, Barrett A, Liew KH et al. The treatment of metastatic germ-cell testicular tumours with bleomycin, etojustified. poside and cisplatin (BEP). Br J Cancer 1983; 47:613-9. In addition to increasing the dosages of one or more 4. Levi JA, Thomson D, Sandeman T et al. A prospective study of cisplatin based combination chemotherapy in advanced germ components of the classical three-drug regimens given cell malignancy-role of maintenance and long term follow up. J every three weeks, another method to improve the Qin Oncol 1988; 6: 1154-60. results in bad-prognosis testicular cancer patients is to 5. The Medical Research Council Working Party on Testicular use rapidly alternating regimens. This strategy has been Tumours. Prognostic factors in advanced non-seminomatous evaluated in several studies and was also the basis of germ cell testicular tumours. Lancet 1985; 1: 8-11.

202 6. Stoter G, Sylvester R, Sleyfer DT et al. Multivariate analysis of prognostic variables in patients with disseminated non-seminomatous testicular cancer: results from an EORTC multiinstitutional phase III study. Int J Androl 1987; 10: 239-46. 7. Birch R, Williams S, Cone A et al. Prognostic factors for favourable outcome in disseminated germ cell tumors. J Clin Oncol 1986; 4:400-7. 8. Bosl GJ, Geller NL, Ciricione C et al. Multivariate analysis of prognostic variables in patients with metastatic testicular cancer. Cancer Res 1983; 43: 3403-7. 9. Ozols R, Ihde DC, Linehan M et al. A randomized trial of standard chemotherapy vs. a high dose chemotherapy regimen in the treatment of poor prognosis nonseminomatous germ cell tumors. J Clin Oncol 1988; 6:1031-40. 10. Schmoll HJ. The role of ifosfamide in testicular cancer. Seminars in Oncol 1989; 16 (Suppl 3> 82-93. 11. Harstrick A, Schmoll HJ, Casper J. Comparative activity of 15 cytostatic drugs in two heterotransplanted human testicular cancer cell lines with different sensitivity to standard agents. Eur J Cancer 1990; 26: 898-901. 12. Pugh RCB. Testicular tumors - introduction. Pathology of the testis, Blackwell Scientific Publications, Oxford, 1976; 139-62. 13. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. 14. Einhorn LH, Williams S, Loehrer PJ et al. Phase III study of cisplatin dose intensity in advanced germ cell tumors (GCT): A Southeastern and Southwest Oncology Group Protocol. Procc Am Soc Clin Oncol 1990; 9: 510. 15. Daugaard G, Roerth M. High dose cisplatin and VP-16 with bleomycin in the management of advanced metastatic germ cell tumors. Eur J Cancer Clin Oncol 1986; 22:477-85. 16. Bajorin D, Katz A, Chan E, Geller NL, Vogelzang N, Bosl GJ.

Book review The theory and practice of oncology: Historical evolution and present principles. R. W. Raven (ed), The Parthenon Publishing Group, Camforth (UK)/Park Ridge, 1990, 366 pp., £55.00 This ia a beautifully printed and will illustrated book which at first sight will delight anyone who is fond of nice books. But it has more than visual substance alone: it will be attentively read by all of those who are interested in the history of oncology and medical history in general. When was the first case of cancer described? When was the first 'cancer society1 founded? When and where was the first cancer institute established? Have all of the key questions formulated at the beginning ot the nineteenth century by the cancer society regarding etiology and prevention been answered? These and many otherintriguing historical questions have been exhaustively dealt with by the author, who for 50 years has been a distinguished surgeon at the Royal Marsden Hospital in London. Some of the features of the book may be more easily comprehended in light of the author's background. Thus, surgery plays a far more prominent role in this work than other specialties, even

17. 18.

19. 20. 21.

22.

Comparison of criteria for assigning germ cell tumor patients to 'good risk' and 'poor risk' studies. J Clin Oncol 1988; 6: 786-92. Stanton GF, Bosl GJ, Whitmore WF et al. VAB-6 as initial treatment of patients with advanced siminoma. J Clin Oncol 1985; 3: 336-9. Logothetis CJ, Samuels ML, Selig D, Swanson D, Johnson DE, von Eschenbach AC. Improved survival with cyclic chemotherapy for nonseminomatous germ cell tumors of the testis. J Clin Oncol 1985; 3: 326-35. Newlands ES, Bergent RHJ, Rustin GJS, Parker D, Bagshawe KD. Further advances in the management of malignant teratomas of the testis and other sites. Lancet 1983; 1:948-51. Bosl GJ, Gluckman R, Geller NL et al. VAB-6: an effective chemotherapy regimen for patients with germ cell tumors. J Clin Oncol 1986; 4:1493-9. Bosl GJ, Geller NL, Vogelzang NJ et al. Alternating cycles of etoposide plus cisplatin and VAB-6 in the treatment of poorrisk patients with germ cell tumors. J Clin Oncol 1987; 5:43640. Horwich A, Brada M, Nicholls J et al. Intensive induction chemotherapy for poor risk non-seminomatous germ cell tumours. Eur J Cancer Clin Oncol 1989; 25:177-84.

Received 5 September 1990; accepted 6 November 1990. Correspondence to: Dr. A. Harstrick Dept of Hematology and Oncology University of Hannover, Medical School Konstanty-Gutschow-Str. 8 3000 Hannover 61, Germany

Annals of Oncology 2: 202, 1991.

though it is acknowledged throughout that cancer treatment is a multidisciplinary undertaking. The book is less than comprehensive with respect to the systemic treatment of cancer: even though it was published in 1990, it leaves tamoxifen consigned to the status of an experimental drug in breast cancer, with more space being devoted to adrenalectomy that to this well established antiestrogen. This book will not be read for the purpose of becoming acquainted with the 'latest developments'. It is rather a synthesis of all aspects of oncology, from prevention to cancer rehabilitation, and as such may chiefly be of interest ot officials of cancer societies and to students and those who are curious about the evolution of philosophical and medical approaches to cancer from antiquity to the present. It is a book which, as a medical oncologist, you would not necessarily need to keep in your office but which you would be pleased to place on your bookshelf at home. I already have my copy there. F. Cavalli Bellinzona