Results of Retroperitoneal Lymph Node Dissection for Clinical Stage I and II Pure Embryonal Carcinoma of the Testis

0022-5347/03/1704-1155/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 170, 1155–1158, October 2003 Printed in U.S.A.

DOI: 10.1097/01.ju.0000087796.63505.70

RESULTS OF RETROPERITONEAL LYMPH NODE DISSECTION FOR CLINICAL STAGE I AND II PURE EMBRYONAL CARCINOMA OF THE TESTIS KAMAL S. POHAR, FARHANG RABBANI, GEORGE J. BOSL, ROBERT J. MOTZER, DEAN BAJORIN* AND JOEL SHEINFELD† From the Department of Urology (KSP, FR, JS) and Genitourinary Oncology Service (GJB, RJM, DB), Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

ABSTRACT

Purpose: We determined the pathological findings and clinical outcome of patients with pure embryonal carcinoma (EC) of the testis managed by primary retroperitoneal lymph node dissection. Materials and Methods: From January 1989 to February 1998, 45 patients with pure EC underwent primary retroperitoneal lymph node dissection at our institution. Patients presented as clinical stage I in 26, IIA in 17 and IIB in 2. Lymphovascular invasion was present in 29 (64%). Median followup was 36.8 months. Results: Overall the pathological stage was pN0 in 11, pN1 in 10 (4 with microscopic disease) and pN2/N3 in 24 patients (8 with extranodal extension). Nineteen of 26 patients (73%) with clinical stage I and 13 of 17 (77%) patients with clinical stage IIA had retroperitoneal disease. No patient with negative lymph nodes (pN0) has had relapse. Only 1 of 9 (11%) patients with pN1 treated without adjuvant chemotherapy has had relapse. Of 24 patients with pN2/N3 disease only 3 (12%) have required more than 2 cycles of postoperative chemotherapy for persistent or recurrent disease despite complete resection of the retroperitoneum. Conclusions: Patients with low stage pure EC of the testis are at high risk for retroperitoneal disease. However these patients do not appear to be at increased risk for high volume (pN2/N3) retroperitoneal disease, systemic relapse in pN0 or pN1 disease managed without adjuvant chemotherapy (although the number of evaluable patients in this subset is somewhat small), or persistent or recurrent disease in completely resected high volume (pN2/N3) retroperitoneal disease compared to patients with mixed nonseminomatous germ cell tumors. KEY WORDS: carcinoma, embryonal; lymph node excision, retroperitoneal space

Approximately 23% to 37% of patients with clinical stage I nonseminomatous germ cell tumor (NSGCT) are clinically understaged.1, 2 Factors reported to be predictive of retroperitoneal metastases include lymphovascular invasion (LVI) in the primary tumor, percentage of embryonal carcinoma (EC) in the primary, absence of yolk sac tumor in the primary, absence of teratoma in the primary and pathological T stage greater than 1.3–9 At Memorial Sloan-Kettering Cancer Center the decision to treat patients with clinical stage II NSGCT initially by retroperitoneal lymph node dissection (RPLND) or cisplatin based chemotherapy is influenced by the extent and location of retroperitoneal disease, serum tumor marker status and the presence or absence of tumor related back pain.10 Patients with clinical stage IIA disease, selected IIB tumors with ipsilateral disease restricted to the primary landing zone and normal serum tumor markers are candidates for RPLND, while patients with tumor related back pain receive induction chemotherapy.10 The pluripotent EC cell is the most undifferentiated somatic cell type comprising germ cell tumors and is capable of differentiation programs resembling those occurring in embryonal stem cells.11 The cellular characteristics of poorly differentiated and pluripotent connote an aggressive cell type capable of me-

tastasizing and differentiating into various phenotypes. In patients with clinical stage I NSGCT Moul et al reported that patients with less than 45% EC in the primary and no LVI were pathological stage I in 91.5% of cases, while those with greater than 80% EC in the primary and LVI were pathological stage II in 88%.6 We report on the single largest series of patients with clinical stage I and II pure EC of the testis managed initially by primary RPLND to evaluate further the natural history, malignant potential and clinical outcome of patients with this histological subtype. MATERIALS AND METHODS

Between January 1989 and February 1998, 317 primary RPLNDs were performed at our institution for NSGCT of the testis. The 45 patients (14%) with pure EC of the testis who underwent primary RPLND are the subjects of this report. If the orchiectomy was performed at another institution, slides and/or tissue blocks were submitted and reviewed by our pathology department. LVI was noted in the primary tumor in 29 patients (64%). For the purposes of this analysis patients in whom LVI was absent or not stated were grouped together. The clinical stage before RPLND was I in 26 (58%), IIA in 17 (38%) and IIB in 2 (4%) patients.12 Before orchiectomy 4 patients had an increased ␣-fetoprotein (AFP) level, 6 patients had an increased human chorionic gonadotropin (HCG) level, and 5 patients had AFP and HCG increases. Before RPLND serum tumor markers were increased in 3 patients but decreasing according to appropriate half-life,

Accepted for publication April 4, 2003. Study received institutional review board approval. * Financial interest and/or other relationship with Eli Lilly & Co. and Bristol Myers Squibb. † Corresponding author: Department of Urology, Memorial SloanKettering Cancer Center, 1275 York Ave., New York, New York 10021 (telephone 646-422-4311; e-mail: [email protected]). 1155

1156

RETROPERITONEAL LYMPHADENECTOMY FOR EMBRYONAL CARCINOMA OF TESTIS

AFP in 3 and ␤-HCG in 1 patient. Pathological stage was assigned according to 1997 American Joint Committee on Cancer classification (see Appendix).12 Patients with gross adenopathy or a positive frozen section at RPLND underwent a full bilateral template dissection.10 Patients were followed every month in year 1, every second month in year 2, every third month in year 3, every fourth month in year 4 and every 6 months in year 5 and annually thereafter. At each visit a history, physical examination, chest x-ray and serum tumor markers were performed. The proportion of patients with high volume retroperitoneal disease (pN2, pN3) were compared between the histological subtypes pure EC and mixed NSGCT with or without an EC component using the chi-square test. Estimates of the relative risk of retroperitoneal metastases (and 95% confidence intervals) in patients with pure EC versus mixed NSGCT with or without an EC component were obtained using univariate Cox proportional hazards analysis. Statistical analysis was performed using SPSS statistical software (SPSS Inc., Chicago, Illinois).

FIG. 1. Percent of patients with clinical stage I NSGCT with pathological stage II disease divided into 3 groups: pure EC, mixed NSGCT with EC and mixed NSGCT without EC.

RESULTS

A total of 34 of the 45 (76%) patients with pure EC of the testis had retroperitoneal disease; 22 of 29 (76%) with LVI and 12 of 16 (75%) without LVI. The pathological stage for patients with tumor in the retroperitoneum was pN1 in 10 patients, including 4 with microscopic disease, and pN2 or pN3 in 24 patients, including 8 with extranodal extension. The retroperitoneal pathology was reported as pure EC in 26, pure yolk sac in 1 and mixed germ cell histologies in 7 patients including 3 with teratomatous elements. Clinical stage I. Nineteen of 26 patients (73%) with clinical stage I pure EC had retroperitoneal disease, 13 of 18 (72%) with LVI and 6 of 8 (75%) without LVI in the primary tumor. The pathological stage was pN0 in 7, pN1 in 7 and pN2/N3 in 12 patients (see table). Between January 1989 and February 1998 of 194 selected patients with clinical stage I mixed NSGCT who underwent primary RPLND at our institution, 158 had a component of EC in the primary tumor and 36 patients did not. Of 158 patients (26%) with a mixed NSGCT and an embryonal component 41 had retroperitoneal disease, 29 of 95 (31%) with LVI and 12 of 63 (19%) without LVI in the primary tumor. Nine of 36 patients (25%) with a mixed NSGCT without an embryonal component had retroperitoneal disease, 3 of 8 (38%) with LVI and 6 of 28 (21%) without LVI in the primary tumor. Patients with clinical stage I pure EC of the testis have a higher probability of retroperitoneal lymph node metastases compared to patients with clinical stage I mixed NSGCT with (relative risk [RR] 7.7; 95% CI: 3.0 –19.8, p ⬍0.0001) or without (RR 8.1; 95% CI: 2.6 –25.7, p ⫽ 0.0003) an embryonal component (fig. 1). This finding is also true when comparing patients with pure EC of the testis and LVI to patients with mixed NSGCT with (RR 5.9; 95% CI: 1.9 –18.1, p ⫽ 0.0019) or without (RR 4.3; 95% CI: 0.74 –25.3, p ⫽ 0.10) an embryonal component and LVI (fig. 1). Moreover, figure 1 illustrates that whether LVI is present or absent in the primary tumor, patients with clinical stage I pure EC of the testis have a

similar probability of having retroperitoneal lymph node metastases. Whether this similarity is due to pathological sample error or lack of independence of LVI as a predictor in this subset of patients cannot be determined from this analysis. In patients with clinical stage I pure EC of the testis and pathological stage II disease, high volume retroperitoneal disease (pN2/N3) was reported in 12 of 19 (63%) RPLND specimens, and in 20 of 41 (49%) and 4 of 9 (44%) RPLND specimens in patients with a mixed NSGCT with or without an embryonal component, respectively (see table). No significant difference was found in the proportion of patients with high volume retroperitoneal disease among the 3 groups (chi-square test, p ⫽ 0.52, fig. 2). Clinical stage II. Thirteen of 17 patients with (76%) clinical stage IIA had retroperitoneal disease, 7 of 9 (78%) with LVI and 6 of 8 (75%) without LVI in the primary tumor. The pathological stage was pN0 in 4, pN1 in 3 and pN2/N3 in 10 patients. In patients with clinical stage IIA pure EC of the testis and pathological stage II disease, high volume retroperitoneal disease was reported in 10 of 13 (77%) RPLND specimens, and in 20 of 31 (65%) and 4 of 8 (50%) RPLND specimens in patients with a mixed NSGCT with or without an embryonal component, respectively. No significant difference was found in the proportion of patients with high volume retroperitoneal disease among the 3 groups (chi-square test, p ⫽ 0.45, fig. 2). Both patients with clinical stage IIB disease had LVI in the primary tumor and high volume embryonal carcinoma in the retroperitoneal specimen. Clinical outcome. Pathological Stage I (pN0) Disease: None of the 11 patients with pure EC of the testis and pN0

Distribution of pathological nodal staging in patients with clinical stage I NSGCT pN0 No. lymphovascular invasion (%): Pure EC Mixed NSGCT with EC Mixed NSGCT without EC No. no lymphovascular invasion (%): Pure EC Mixed NSGCT with EC Mixed NSGCT without EC

pN1

5 (28) 4 (22) 66 (69) 15 (16) 5 (63) 2 (25) 2 (25) 51 (80) 22 (78)

3 (37.5) 6 (10) 3 (11)

pN2/N3 9 (50) 14 (15) 1 (12) 3 (37.5) 6 (10) 3 (11)

FIG. 2. Percent of patients with clinical stage I and IIA NSGCT with pathological stage II and high volume retroperitoneal disease (pN2/N3) divided into 3 groups: pure EC, mixed NSGCT with EC and mixed NSGCT without EC.

RETROPERITONEAL LYMPHADENECTOMY FOR EMBRYONAL CARCINOMA OF TESTIS

disease received adjuvant chemotherapy. Three patients have been lost to followup. During a median followup of 45 (range 4 to 91) months none of the remaining 8 patients had relapse to date while 14 (8%) relapses have been noted in 178 patients with pN0 disease with a mixed NSGCT and a median followup of 26 months. Low Volume (pN1) Retroperitoneal Disease: With a median followup of 61 (range 7 to 98) months, 9 of 10 patients with pure EC of the testis and pN1 disease were managed by observation and 1 (11%) had relapse. The tenth patient received 2 cycles of adjuvant chemotherapy. In comparison, 10 (24%) relapses have been noted in 41 patients with a mixed NSGCT and pN1 disease, managed without adjuvant chemotherapy with a median followup of 31.4 months. High Volume (pN2/N3) Retroperitoneal Disease: A total of 24 patients with pure EC of the testis had pN2/N3 disease and received postoperative chemotherapy. Two cycles of cisplatin based adjuvant chemotherapy was administered to those patients without evidence for clinical disease after RPLND. Any patient with evidence for clinical disease and/or an increased AFP or ␤-HCG after RPLND were considered to have persistent disease, and received cisplatin based induction chemotherapy (ie more than 2 cycles of chemotherapy). Comparing the proportion of patients with pure EC of the testis and persistent disease (3 of 24) to the proportion of patients with a mixed NSGCT and persistent disease (12 of 49) after primary RPLND, no difference was noted between the groups (chi-square test, p ⫽ 0.19). The 3 patients with pure EC of the testis and persistent disease after primary RPLND are currently without disease following cisplatin based induction chemotherapy. Of 21 patients with pure EC of the testis and pN2/N3 disease 1 (5%) had relapse with an increased AFP and a hepatic mass after 2 cycles of adjuvant chemotherapy. He received 4 cycles of taxol, ifosphamide and cisplatin, and remains no evidence of disease (NED) 74 months after resection of a residual mass (fibrosis). All patients with pure EC of the testis and pN2/N3 disease remained NED during a median followup of 84 (range 25 to 117) months. Overall, 44 of 45 patients (98%) remain NED. One patient who was NED died in a motor vehicle accident and 3 patients (7%) have been lost to followup. DISCUSSION

Optimal management of clinical stage I NSGCT remains controversial. The controversy is generated by radiologic understaging of patients, the potential morbidity of various treatments and the overtreatment of patients who are cured by orchiectomy alone. Treatment options include primary RPLND, surveillance and primary chemotherapy. Primary RPLND in clinical stage I NSGCT patients allows for precise pathological staging of the retroperitoneum and is therapeutic in selected patients. Primary RPLND series from the United States indicate that the retroperitoneum is understaged in 23% to 30% of selected patients with clinical stage I NSGCT.1, 13 Our own data from 1989 to 1998 indicate that 69 of 220 (31%) selected patients with clinical stage I NSGCT were pathological stage II. Prospective surveillance protocols of selected and unselected patients with clinical stage I NSGCT report relapse rates of 26% to 35%8, 14 and 27%,7, 15 respectively. Our data indicate that a high proportion (73%) of patients with clinical stage I disease with pure EC of the testis have pathological stage II disease regardless of lymphovascular invasion status in the primary tumor. Similarly, the Testicular Cancer Intergroup reported that 69% of patients with clinical stage I pure EC of the testis had pathological stage II disease.9 Since these patients are at high risk of being clinically understaged, further therapy after orchiectomy is recommended. Although embryonal carcinoma is chemosensitive the capacity of these tumors to undergo differentiation is

1157

reflected by the presence of nonembryonal components in the retroperitoneum, including 3 patients (7%) with teratomatous elements. Teratoma is chemorefractory, may grow, obstruct or invade adjacent structures and become unresectable, carries a risk of malignant transformation and may result in a late recurrence.16 –18 Our data suggest that patients with pure EC of the testis and pN0 or pN1 disease are not at greater risk for systemic relapse compared to patients with a mixed NSGCT, if treated without adjuvant chemotherapy. None of the patients with pN0 pure EC has had relapse to date, compared to an 8% relapse rate for patients with pN0 mixed NSGCT. The Testicular Cancer Intergroup also reported a low rate (7%) of relapse for patients with pN0 disease with pure EC of the testis not receiving adjuvant chemotherapy.9 Similarly, pure testicular EC histology did not predict relapse in 138 patients with pN0 disease reported by Bredael et al.19 Conversely, Sweeney et al reported that lymphovascular invasion and predominant EC in the primary tumor were predictive of disease relapse in patients with pN0 disease.20 However, a multivariate analysis was not performed in this group of 226 disease patients. Primary RPLND alone was therapeutic in 8 of 9 patients (89%) with pure EC of the testis and pN1 disease compared to 31 of 41 (76%) patients with mixed NSGCT. A study from our institution of 50 patients with NSGCT with pN1 disease who did not receive adjuvant chemotherapy after RPLND showed that the only factor predictive of disease relapse was an increased serum tumor marker before RPLND. Pure testicular EC was not predictive of disease relapse in pN1 disease.21 The lower systemic relapse rates in our series of patients with pN0 and pN1 pure EC compared to patients with mixed NSGCT primary tumors may be an artifact of the relatively small number of patients in this subset. Alternatively, the total volume of EC in a small tumor of pure histology may be less than that of a larger tumor with mixed histology and a significant embryonal component. With the exception of the Testicular Cancer Intergroup Study most investigators have reported that the risk of relapse in pathological stage II disease is related to size and/or number of lymph nodes involved by tumor.22 Our data show that despite the high proportion of patients with clinical stage I pure EC of the testis with pathological stage II disease, these patients do not have a higher likelihood of pN2/ pN3 disease compared to patients with clinical stage I mixed NSGCT, with or without an embryonal component. Patients with high volume retroperitoneal disease (pN2/pN3) have a relapse rate of 50% to 90% and are strongly considered for 2 cycles of cisplatin based adjuvant chemotherapy after RPLND.23 Administering adjuvant chemotherapy in patients with fully resected high volume retroperitoneal disease results in a disease-free relapse rate approaching 100%.23 No significant difference was found in the proportion of patients with high volume retroperitoneal disease who had persistent disease after primary RPLND comparing patients with pure EC of the testis to patients with mixed NSGCT (12% versus 24%). Of 24 (83%) patients with pure EC and high volume (pN2/pN3) retroperitoneal disease 12 were cured by the combination of RPLND and 2 cycles of cisplatin based adjuvant chemotherapy. CONCLUSIONS

Patients with clinical stage I pure EC of the testis are at high risk (73%) for retroperitoneal metastases. Primary RPLND in patients with low stage pure EC of the testis accurately stages these patients, is curative without adjuvant chemotherapy in low volume retroperitoneal metastases (pN1) and contributes to the high cure rate in high volume retroperitoneal metastases (pN2/N3). Patients with low stage pure EC of the testis are not at increased risk for high volume retroperitoneal disease (pN2/N3) at RPLND com-

1158

RETROPERITONEAL LYMPHADENECTOMY FOR EMBRYONAL CARCINOMA OF TESTIS

pared to patients with mixed NSGCT. Furthermore, the postoperative chemotherapy requirement in patients with pure EC of the testis and completely resected high volume retroperitoneal disease is not increased compared to patients with mixed NSGCT. APPENDIX: PATHOLOGICAL NODAL STAGING 1997 AMERICAN JOINT COMMITTEE ON CANCER CLASSIFICATION 12

Pathological Definition Stage pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Metastasis with lymph node mass ⱕ2 cm AND ⱕ5 positive nodes (all ⱕ2 cm) pN2 Metastasis with lymph node mass ⬎2 cm but ⱕ5 cm OR ⬎5 positive nodes (all ⱕ5 cm) OR extranodal extension of tumor pN3 Metastasis with lymph node mass ⬎5 cm REFERENCES

1. Hermans, B. P., Sweeney, C. J., Foster, R. S., Einhorn, L. E. and Donohue, J. P.: Risk of systemic metastases in clinical stage I nonseminoma germ cell testis tumor managed by retroperitoneal lymph node dissection. J Urol, 163: 1721, 2000 2. Aass, N., Fossa, S. D., Ous, S., Lien, H. H., Stenwig, A. E., Paus, E. et al: Is routine primary retroperitoneal lymph node dissection still justified in patients with low stage nonseminomatous testicular cancer? Br J Urol, 65: 385, 1990 3. Heidenreich, A., Sesterhenn, I. A., Mostofi, F. K. and Moul, J. W.: Prognostic risk factors that identify patients with clinical stage I nonseminomatous germ cell tumors at low risk and high risk for metastasis. Cancer, 83: 1002, 1998 4. Klepp, O., Olsson, A. M., Henrikson, H., Aass, N., Dahl, O., Stenwig, A. E. et al: Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: multivariate analysis of a prospective multicenter study. SwedishNorwegian Testicular Cancer Group. J Clin Oncol, 8: 509, 1990 5. McLeod, D. G., Weiss, R. B., Stablein, D. M., Muggia, F. M., Paulson, D. F., Ellis, J. H. et al: Staging relationships and outcome in early stage testicular cancer: a report from the testicular cancer intergroup study. J Urol, 145: 1178, 1991 6. Moul, J. W., McCarthy, W. F., Fernandez, E. B. and Sesterhenn, I. A.: Percentage of embryonal carcinoma and of vascular invasion predicts pathological stage in clinical stage I nonseminomatous testicular cancer. Cancer Res, 54: 362, 1994 7. Pizzocaro, G., Zanoni, F., Salvioni, R., Milani, A., Piva, L. and Pilotti, S.: Difficulties of a surveillance study omitting retroperitoneal lymphadenectomy in clinical stage I nonseminomatous germ cell tumors of the testis. J Urol, 138: 1393, 1987 8. Sturgeon, J. F., Jewett, M. A., Alison, R. E., Gospodarowicz, M. K., Blend, R., Herman, S. et al: Surveillance after orchidectomy for patients with clinical stage I nonseminomatous testis tumors. J Clin Oncol, 10: 564, 1992

9. Sesterhenn, I. A., Weiss, R. B., Mostofi, F. K., Stablein, D. M., Rowland, R. G., Falkson, G. et al: Prognosis and other clinical correlates of pathologic review in stage I and II testicular carcinoma: a report from the Testicular Cancer Intergroup Study. J Clin Oncol, 10: 69, 1992 10. Bosl, G. J. and Motzer, R. J.: Testicular germ-cell cancer. N Engl J Med, 337: 242, 1997 11. Houldsworth, J., Heath, S. C., Bosl, G. J., Studer, L. and Chaganti, R. S.: Expression profiling of lineage differentiation in pluripotential human embryonal carcinoma cells. Cell Growth Differ, 13: 257, 2002 12. Fleming, I. D., Cooper, J. S., Hensen, D. E., Hutter, R. V. P., Kennedy, B. J., Murphy, G. P. et al: AJCC Cancer Staging Manual, 5th ed. Philadelphia: Lippincott-Raven Publishers, 1997 13. Donohue, J. P., Thornhill, J. A., Foster, R. S., Rowland, R. G. and Bihrle, R.: Retroperitoneal lymphadenectomy for clinical stage A testis cancer (1965 to 1989): modifications of technique and impact of ejaculation. J Urol, 149: 237, 1993 14. Sogani, P. C., Perrotti, M., Herr, H. W., Fair, W. R., Thaler, H. T. and Bosl, G.: Clinical stage I testis cancer: long-term outcome of patients on surveillance. J Urol, 159: 855, 1998 15. Read, G., Stenning, S. P., Cullen, M. H., Parkinson, M. C., Horwich, A., Kaye, S. B. et al: Medical Research Council prospective study of surveillance for stage I testicular teratoma. Medical Research Council Testicular Tumors Working Party. J Clin Oncol, 10: 1762, 1992 16. Logothetis, C. J., Samuels, M. L., Trindade, A. and Johnson, D. E.: The growing teratoma syndrome. Cancer, 50: 1629, 1982 17. Sheinfeld, J. and Bajorin, D.: Management of the postchemotherapy residual mass. Urol Clin North Am, 20: 133, 1993 18. Motzer, R. J., Amsterdam, A., Prieto, V., Sheinfeld, J., Murty, V. V. V. S., Mazumdar, M. et al: Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors. J Urol, 159: 133, 1998 19. Bredael, J. J., Vugrin, D. and Whitmore, W. F., Jr.: Recurrences in surgical stage I nonseminomatous germ cell tumors of the testis. J Urol, 130: 476, 1983 20. Sweeney, C. J., Hermans, B. P., Heilman, D. K., Foster, R. S., Donohue, J. P. and Einhorn, L. H.: Results and outcome of retroperitoneal lymph node dissection for clinical stage I embryonal carcinoma—predominant testis cancer. J Clin Oncol, 18: 358, 2000 21. Rabbani, F., Sheinfeld, J., Farivar-Mohseni, H., Leon, A., Rentzepis, M. J., Reuter, V. E. et al: Low-volume nodal metastases detected at retroperitoneal lymphadenectomy for testicular cancer: pattern and prognostic factors for relapse. J Clin Oncol, 19: 2020, 2001 22. Motzer, R. J. and Bosl, G. J.: Role of adjuvant chemotherapy in patients with stage II nonseminomatous germ-cell tumors. Urol Clin North Am, 20: 111, 1993 23. Williams, S. D., Stablein, D. M., Einhorn, L. H., Muggia, F. M., Weiss, R. B., Donohue, J. P. et al: Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med, 317: 1433, 1987