0022-5347 /87 /1376-0070$02.00/0 Vol. 138, July Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1987 by The Williams & Wilkins Co.
FERTILITY STATUS OF PATIENTS WITH CLINICAL STAGE I TESTIS TUMORS ON A SURVEILLANCE PROTOCOL PETER R. CARROLL,* MICHAEL J_ MORSE, WILLET F. WHITMORE, JR., PRAMOD C. SOGANI, LAWRENCE KLOTZ, HARRY W. HERR, WILLIAM R. FAIR, ROXANNE FELDSHUH AND R. S. K. CHAGANTI From the Urology Service, Department of Surgery and Laboratory of Cancer Genetics and Cytogenetics, Department of Pathology, Memorial Sloan-Kettering Cancer Center, and !dent Corporation, New York, New York
A potential benefit of a surveillance protocol for the management of patients with clinical stage I testis tumors is the avoidance of ejaculatory disturbances and infertility resulting from retroperitoneal lymph node dissection, the standard treatment for patients with this stage of disease. To address this issue we evaluated 22 patients with clinical stage I testis tumors on a surveillance protocol with history, physical examination and semen analysis. Previous fertility was unknown or it had not been tested in the majority of the patients (74 per cent). Ten patients (45 per cent) had abnormal spermatogenesis on the basis of a low sperm count or sperm motility. Of 6 patients with oligospermia or azoospermia 3 had recovered normal spermatogenesis when they were re-evaluated 4 to 19 months later. Although in this group of carefully staged cases the incidence of subfertile sperm counts seems to be similar to those with higher stage disease, some patients with abnormal counts clearly recover. The avoidance of retroperitoneal lymph node dissection seems to spare fertility in at least a small percentage of these patients. J. Ural_, 138: 70-72, 1987 grams (CT) of the abdomen and pelvis. 1 Patients without clinical, radiographic or biochemical evidence of metastatic tumor were offered entry into the protocol after informed consent was obtained. Patients with pure choriocarcinoma or seminoma, T2 to T4 tumor categories, or a history of orchiopexy or scrotal violation were excluded. Patients were followed monthly for 2 years and every 3 months for 1 year. Physical examination, chest radiographs and serum markers were performed at each visit. CT was performed periodically as described previously. 1 Patient age, previous fertility status, testicular volume and consistency, and presence of gynecomastia were recorded along with any history of testicular injury, maldescent or surgery. The duration of followup, evidence and site of relapse, treatment of relapse, and paternity while on the protocol also were recorded. A group of patients with oligospermia or azoospermia at entry into the protocol underwent repeat semen analyses during followup to assess for return of normal spermatogenesis. Semen analyses were performed with a Coulter counter or a standard Neubauer counting chamber. When a low sperm concentration (that is less than 40 million per cc) was found with the Coulter counter, a repeat analysis was performed with the Neubauer chamber. Semen volume, sperm density and motility were recorded. When more than 1 semen analysis was performed the results were averaged. A semen volume of less than 1.5 cc, a sperm concentration of less than 20 million per cc and a sperm motility of less than 50 per cent were considered abnormal. Total sperm count (volume X concentration) was compared to sperm motility for the final evaluation of spermatogenesis.
Careful periodic surveillance after orchiectomy instead of retroperitoneal lymph node dissection or radiation has emerged as a treatment option for patients with clinical stage I nonseminomatous testis tumors. 1- 5 Such a treatment policy is based on observations that approximately 70 to 85 per cent of the patients with carefully evaluated stage I nonseminomatous testis tumors are cured with orchiectomy alone so that they can be spared unnecessary treatment, and that multimodal therapy offers a high probability of cure for those who have relapse. 1 A potential benefit of surveillance alone is the preservation of fertility, since a certain proportion of patients will lose either seminal emission or antegrade ejaculation as a result of damage to sympathetic nerve fibers during retroperitoneal lymph node dissection. We attempted to determine the incidence of abnormal spermatogenesis in carefully evaluated patients with stage I nonseminomatous testis tumors, whether infertility per se might be a risk factor for relapse and whether patients with abnormal spermatogenesis at orchiectomy may regain normal spermatogenesis at a later date. To address these issues we examined 22 patients with clinical stage I nonseminomatous testis tumors on a surveillance protocol with respect to previous fertility status, semen analysis before or just after orchiectomy and paternity while in the protocol. In addition, a small group of patients with abnormal semen analyses at entry into the protocol had repeat semen analyses performed during surveillance. MATERIALS AND METHODS
Patients with clinical stage I nonseminomatous testis tumors treated by orchiectomy alone in whom a semen analysis was performed at entry into a surveillance protocol were selected for study. Clinical staging measures included history, physical examination, serum tumor markers (a-fetoprotein, human chorionic gonadotropin and lactic dehydrogenase), chest radiographs, ipsilateral lymphangiograms, and computerized tomo-
Of 96 patients with clinical stage I nonseminomatous testis tumors 22 underwent semen analysis at the time of entry into our surveillance protocol. Median patient age was 26 years, with a range of 17 to 36 years. The tumor was on the right side in 12 patients and on the left side in 10. Fertility status was unknown or untested in 16 patients (73 per cent), while 2 previously had induced pregnancies. The fertility status of the
Accepted for publication December 15, 1986. * Requests for reprints: Department of Urology, Box 0738, University of California, San Francisco, California 94143. 70
FEftTILITY STATUS OF PATIEl'~TS \VITI-l STAGE I TESTIS TUtYlORS
remaining 4 patients was unknown but all 4 had had unprotected intercourse with the same partner for a variable interval without inducing pregnancy. There was little delay in referral for patients whose orchiectomy was performed elsewhere. The average delay from diagnosis to evaluation at our hospital was 9 days. Three patients had contralateral testicular atrophy, 2 of whom had varicoceles. Two patients had gynecomastia. No patient had a history of cryptorchidism. Eight patients (36 per cent) underwent 1 and the remainder underwent 2 or more semen analyses. Of the 22 patients 11 (50 per cent) displayed defective spermatogenesis on the basis of 1 or a combination of low semen volume, sperm concentration or motility. Two patients were azoospermic and 5 were oligospermic (1 had low concentration alone, 5 had poor motility, and 1 had poor motility, low concentration and low volume). All but 1 of these 7 patients had a sperm motility of less than 50 per cent. Three patients had a sperm motility of less than 50 per cent but a normal sperm concentration and volume. One patient had a low semen volume alone and a sperm concentration (120 million per cc) that placed the total sperm count in the normal range. When the total sperm count was calculated and compared to sperm motility, only 10 patients possessed defects in spermatogenesis (fig. 1). Four patients (18 per cent) had relapse at 3 to 6 months: 3 in the retroperitoneum and 1 on the basis of elevated serum tumor markers. These patients were treated with retroperitoneal lymph node dissection alone (1) or a combination of retroperitoneal lymph node dissection and chemotherapy (3). Of the patients 3 are without evidence of disease and 1 is dead 600
en C ~
300 1:: :::, 0
100 0 0
FIG. 1. Semen analyses reveal total sperm count (volume X concentration) compared to sperm motility. Normal ranges of both parameters are marked within shaded area. Asterisk represents 2 patients who were azoospermic.
Months FIG. 2. Initial and repeat sperm counts in 6 patients with azoosper-
mia or oligospermia at entry into surveillance protocol. All 3 patients who achieved normal counts also had normal sperm motility and volume.
of disease. A total of 18 patients remains without evidence of relapse with a median follovmp of 25 months (range 9 to 60 months). Of 10 patients with low sperm counts or motility 2 (20 per cent) had relapse compared to 2 of 12 per cent) with normal spermatogenesis. Two patients have fathered children since the orchiectomy. Of 7 patients with the more severe defects in spermatogenesis (oligospermia or azoospermia) 6 were re-evaluated between 6 and 19 months after entry into the study (fig. 2). Three of 4 patients with oligospermia achieved a normal semen analysis on the basis of count, volume and motility, while 1 remained severely oligospermic (less than 1 million per cc) and has a varicocele in the remaining testicle. Azoospermia persisted in 1 patient. One patient, although initially azoospermic, was noted to have sperm in the ejaculate 5 months after orchiectomy but the motility was less than 20 per cent. Of the remaining 4 patients with defective spermatogenesis 2 had relapse and they did not undergo repeat analyses. Two patients who remained free of disease and were not re-evaluated had more minor degrees of abnormality in the semen analysis initially (that is motility 35 to 48 per cent). DISCUSSION
Approximately 50 to 70 per cent of the patients with testis tumors will have defective spermatogenesis as assessed by semen analysis after orchiectomy but before additional treatment. 6-9 Defective spermatogenesis seems to be unrelated to any effects of orchiectomy, since Scheiber and Bartsch found pathological semen analyses in 76 per cent of their patients before orchiectomy. 10 Approximately half of our patients had abnormal semen analyses, which is slightly fewer than has been reported previously but this finding seems to be comparable to that found in patients with higher stage disease evaluated at our institution. Previous investigations also have failed to show a correlation between lower sperm counts and tumor stage. 6 ' 7 In our study 3 of 4 patients with oligospermia showed substantial improvement in the semen analyses with time, which suggests that defective spermatogenesis in some patients is a transitory phenomenon related perhaps to tumor burden, stress or hormone production by the tumor. Of the 4 oligospermic patients who showed improvement 2 had elevated human chorionic gonadotropin levels at orchiectomy. Of interest, 1 patient with severe oligospermia and poor motility on 2 semen analyses at entry into the surveillance protocol showed substantial improvement despite clinically evident signs of relapse at re-testing. He had a human chorionic gonadotropin level of 360 ng./ml. at orchiectomy, which was only mildly elevated at relapse (2.1 ng./mL), an observation that suggests that the elevated level of human chorionic gonadotropin rather than the presence of tumor per se contributed to reduced sperm counts. Elevated levels of human chorionic gonadotropin may stimulate Leydig cells to secrete more estrogen relative to testosterone. Elevated estrogen levels may inhibit follicle-stimulating hormone secretion at the level of the pituitary gland and, therefore, they may suppress spermatogenesis. 11 Scheiber and Bartsch showed that patients with human chorionic gonadotropin-secreting tumors had increased estrogen levels per cent), decreased follicle-stimulating hormone levels (90 per cent) and low sperm counts (73 per cent) compared to those with normal serum human chorionic gonadotropin concentrations.10 In our study there was no difference in the relapse rate between patients with normal and pathological total sperm counts or motility. Some patients with initially abnormal semen analyses that fail to improve may harbor carcinoma in situ in the contralateral testis. Patients with carcinoma in situ in the contralateral testis seem to have a higher incidence of antecedent infertility and defective spermatogenesis as assessed by history and contralateral testis biopsy, compared to patients without contralateral carcinoma in situ. 12 If so, a persistently subfertile semen analysis not owing to chemotherapy or irra-
CARROLL AND ASSOCIATES
diation may be an indication for a contralateral testis biopsy. Longitudinal studies of such patients should answer this question. Although 90 per cent of the patients with pathological stage I disease and more than 65 per cent of those with stage IIA disease will be cured with retroperitoneal lymphadenectomy alone, such treatment commonly is associated with loss of either seminal emission or antegrade ejaculation. 13-15 Since ejaculatory disturbances clearly are related to the extent of retroperitoneal dissection, several investigators have attempted to limit the dissection and to reduce the frequency of such side effects. Fossa and associates reported preservation of ejaculation in 100 per cent of the tumors on the right side and 67 per cent of those on the left side with modified retroperitoneal lymphadenectomy.16 Similarly, Pizzocaro and associates performed unilateral retroperitoneal lymphadenectomy in 61 patients with no intraoperative evidence of lymph node metastases and only 11 (18 per cent) suffered loss of antegrade ejaculation. 17 In addition, antegrade ejaculation can be restored in some patients with sympathomimetic agents. 18 Since preservation of fertility is an objective of our surveillance protocol it would be of interest to speculate on the degree of impaired fertility that would have occurred if our 22 patients had been subjected to initial lymphadenectomy. Four patients had relapse and at least those 3 who showed retroperitoneal relapse probably would have been treated with extended lymphadenectomy at exploration with a high likelihood of ejaculatory disturbance. Of the remaining 18 patients 9 had tumors on the right and 9 on the left sides. With the most optimistic results for modified retroperitoneal lymphadenectomy, ejaculation disorders would have occurred in at least a third of those patients with tumors on the left side. To date, 18 of the 22 patients (81 per cent) studied maintained normal ejaculation. Had lymphadenectomy been performed, theoretically 15 of 22 patients (68 per cent) would have been at risk of losing antegrade ejaculation. Such determinations are only speculative, and the exact incidence of ejaculatory and fertility disturbances would depend on intraoperative findings, the extent of dissection, the impact of additional treatment (that is irradiation and chemotherapy) and the success of treatment with sympathomimetic drugs. In summary, defective spermatogenesis is common in carefully evaluated patients with clinical stage I nonseminomatous testis tumors. In this small series there was essentially no difference in the relapse rates between patients with low sperm counts or motility and those with normal semen analyses. Defective spermatogenesis noted at orchiectomy may resolve in a certain percentage of the patients. Orchiectomy alone followed by careful surveillance seems to avoid ejaculatory disturbances in a small group of patients who otherwise would lose antegrade ejaculation if they were treated with retroperitoneal lymphadenectomy. REFERENCES 1. Sogani, P. C., Whitmore, W. F., Jr., Herr, H. W., Bosl, G. J., Golbey, R. B., Watson, R. C. and DeCosse, J. J.: Orchiectomy alone in the treatment of clinical stage I nonseminomatous germ cell tumor of the testis. J. Clin. Oncol., 2: 267, 1984. 2. Peckham, M. J., Barrett, A., Horwich, A. and Hendry, W. F.: Orchiectomy alone for stage I testicular non-seminoma. A progress report on the Royal Marsden Hospital study. Brit. J. Urol., 55: 754, 1983. 3. Raghavan, D.: Expectant therapy for clinical stage-A nonseminomatous germ-cell cancers of the testis. A qualified yes. World J. Urol., 2: 59, 1984. 4. Jewett, M.A. S., Comisarow, R.H., Herman, J. G., Sturgeon, J. F. G., Alison, R. E. and Gospodarowicz, M. K.: Results with orchiectomy only for stage I non-seminomatous testis tumor. J. Urol., part 2, 131: 224A, abstract 483, 1984. 5. Johnson, D. E., Lo, R. K., von Eschenbach, A. C. and Swanson, D. A.: Surveillance alone for patients with clinical stage I nonseminomatous germ cell tumors of the testis: preliminary results. J. Urol., 131: 491, 1984. 6. Hendry, W. F., Stedronska, J., Jones, C. R., Blackmore, C. A.,
7. 8. 9. 10.
13. 14. 15. 16.
Barrett, A. and Peckham, M. J.: Semen analysis in testicular cancer and Hodgkin's disease: pre- and post-treatment findings and implications for cryopreservation. Brit. J. Urol., 55: 769, 1983. Fossa, S. D., Abyholm, T. and Aakvaag, A.: Spermatogenesis and hormonal status after orchiectomy for cancer and before supplementary treatment. Eur. Urol., 10: 173, 1984. Berthelsen, J. C. and Skakkebaek, N. E.: Gonadal function in men with testis cancer. Fertil. Steril., 39: 68, 1983. Jewett, M.A. S., Thachil, J. V. and Harris, J. F.: Exocrine function of testis with germinal testicular tumour. Brit. Med. J., 286: 1849, 1983. Scheiber, K. and Bartsch, G.: Exocrine and endocrine functions in patients with testicular tumors. In: Testicular Cancer. Edited by S. Khoury, R. Kuss, G. P. Murphy, C. Charelain and J. P. Karr. New York: Alan R. Liss, pp. 715-725, 1985. Cochran, J. S., Walsh, P. C., Porter, J. C., Nicholson, T. C., Madden, J. D. and Peters, P. C.: The endocrinology of human chorionic gonadotropin-secreting testicular tumors: new methods in diagnosis. J. Urol., 114: 549, 1975. Berthelsen, J. G., Skakkebaek, N. E., von der Maase, H., S~renson, B. L. and Mogensen, P.: Screening for carcinoma in situ of the contralateral testis in patients with germinal testicular cancer. Brit. Med. J., 285: 1683, 1982. 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. Pizzocaro, G. and Monfardini, S.: No adjuvant chemotherapy in selected patients with pathologic stage II nonseminomatous germ cell tumors of the testis. J. Urol., 131: 677, 1984. Lange, P. H., Narayan, P. and Fraley, E. E.: Fertility issues following therapy for testicular cancer. Sem. Urol., 2: 264, 1984. Fossa, S. D., Ous, S., Abyholm, T. and Loeb, M.: Post-treatment fertility in patients with testicular cancer. I. Influence of retroperitoneal lymph node dissection on ejaculatory patency. Brit. J. Urol., 57: 204, 1985. Pizzocaro, G., Salvioni, R. and Zanoni, F.: Unilateral lymphadenectomy in intraoperative stage I nonseminomatous germinal testis cancer. J. Urol., 134: 485, 1985. Nijman, J. M., Jager, S., Boer, P. W., Kremer, J., Oldhoff, J. and Koops, H. S.: The treatment of ejaculation disorders after retroperitoneal lymph node dissection. Cancer, 50: 2967, 1982. EDITORIAL COMMENT
The subject is becoming rapidly a "nonissue". Patients who qualify for a surveillance protocol are the very ones who qualify for a modified or nerve-sparing retroperitoneal lymph node dissection. Preservation of lumbar sympathetic post-ganglionic fibers in the pre-aortic and para-aortic areas permits ejaculation in the majority of patients who undergo retroperitoneal lymph node dissection (currently approximately 90 per cent 1- 6 ). Therefore, the trade-off favoring ejaculation (which was an original stimulus for surveillance studies) becomes progressively negligible. Also, as the authors correctly indicate, surveillance does not guarantee fertility. While some patients will have a normal sperm count after orchiectomy a significant number with testis tumor will remain infertile or hypofertile. John P. Donohue Department of Urology Indiana University Medical Center Indianapolis, Indiana 1. Garnick, M. B. and Richie, J. P.: Toward more rational management for stage I testis cancer: watch out for "watch and wait". J. Clin. Oncol., 4: 1021, 1986. 2. Pizzocaro, G., Salvioni, R. and Zanoni, F.: Unilateral lymphadenectomy in intraoperative stage I nonseminomatous germinal testis cancer. J. Urol., 134: 485, 1985. 3. Richie, J. P. and Garnick, M. B.: Limited retroperitoneal lymphadenectomy for patients with clinical stage I testicular tumor. Proc. Amer. Soc. Clin. Oncol., 4: 110, abstract C-428, 1985. 4. Fossa, S. D., Klepp, 0., Ous, S., Lien, H. H., Stenwig, A. E., Abyholm, T. and Kaalhus, 0.: Unilateral retroperitoneal lymph node dissection in patients with non-seminomatous testicular tumor in clinical stage I. Eur. Urol., 10: 17, 1984. 5. Winfield, H. N. and Lange, P. H.: Modern concepts about fertility after treatment for non-seminomatous testicular cancer. AUA Update Series, in press. 6. Donohue, J.P.: Options in the management of low stage testicular cancer. AUA Update Series, in press.