- Email: [email protected]
Fertility after chemotherapy for testicular germ cell cancer
Modern trends Edward E . Wallach,
.0. ,
Vol. 68. No.1, July 1997
FERTILITY AND STERILITY® Copyright
0
1997 American Society for Reproductive Medicine
ociat Editor
Printed on acid-free paper in U. S. A.
Published by Elsevier Science Inc.
Fertility after chemotherapy for testicular germ cell cancer -Iorg Pont, M.D.*t Walter Albrecht, M.D.t Kaiser Franz Josef Spital and Rudolfstiftung, Vienna, Austria
Objective: To investigate the impact of cytostatic chemotherapy on long-term fertility in patients with testicular germ cell cancer. Background: Many patients with testicular germ cell cancer show impaired spermatogenesis before undergoing cytotoxic chemotherapy. The known infertility before treatment and the reversibility of the fertility problems observed in some of them after successful anticancer treatment so far have prevented an assessment of the true impact of chemotherapy on longterm fertility. The introduction of a wait-and-see strategy (surveillance) for patients with testicular cancer and recent prospective trials comparing patients with and without cytotoxic chemotherapy now have provided the means for estimating the extent to which chemotherapy itself affects long-term fertility. Result(s): Whether spermatogenesis is impaired irreversibly by chemotherapy is determined by the cumulative dose of cisplatin. At cumulative doses >400 mg/m'', irreversible impairment of gonadal function should be expected. Conclusion(s): At cumulative cisplatin doses <400 mg (equivalent to 4 courses of state-ofthe-art treatment), chemotherapy is unlikely to cause irreversible damage to fertility. (Fertil Steril'" 1997;68:1-5. © 1997 by American Society for Reproductive Medicine.) Key Words: Testicular cancer, chemotherapy, cisplatin, spermatogonial damage, fertility
As cytotoxic chemotherapy for malignant disease has improved the chances of long-term remission or cure in young patients who have not yet established a family, chemotherapy-induced impairment of fertility has gained increasing clinical importance. Although the time to conception and the rate of conception per unit time are the best measures of fertility in couples seeking parenthood (1), this approach is hardly helpful in the practical setting, because no more than one third of testicular cancer patients express a wish to father a child after completing treatment (2-6).
Received February 10, 1997. * Department of Medical Oncology, Kaiser Franz Josef Spital. t Reprint requests: Jorg' Pont, M.D., 3. Medizinische Abteilung, Kaiser Franz Josef Spital, KundratstraBe 3, A-llOO Vienna, Austria (FAX 43-1-60191-2319). t Urological Department, Rudolfstiftung.
0015-0282/97/$17.00 PH S0015-0282(97)00061-7
In most studies, fertility was therefore evaluated on the basis of laboratory tests, i.e., sperm cell concentration and morphology in the ejaculate and/or FSH serum levels for exocrine gonadal function, as well as T and LH levels for endocrine function. However, these have limited value as predictors of'fertility (7). Most of the patients undergoing cytostatic chemotherapy become azoospermic approximately 7 to 8 weeks after beginning treatment. This is in keeping with the kinetics of human spermatogenesis, because the anticancer agents act mostly on the sperm cells during cell division and thus destroy mainly the rapidly proliferating type B spermatogonia. If all stem cell spermatogonia (type A spermatogonia) survive, spermatogenesis can be expected to recover 12 weeks after treatment. Partial or complete destruction of type A spermatogonia will, however, cause a sustained or irreversible loss of sperm cell
1
production. The severity and duration of cytotoxic agent-induced long-term impairment of spermatogenesis correlate with the numbers of type A spermatogonia that are destroyed (8, 9). Preclinical data and clinical trials in patients with lymphoma and sarcoma showed that busulfan and procarbazine hydrochloride caused stem cell damage and thus produced long-term impairment of spermatogenesis. However, these studies failed to provide information on the tolerated cumulative doses. Of the alkylating agents, chlorambucil, cyclophosphamide, and cisplatin were found to cause irreversible infertility at doses of 400 mg, 7,500 mg/m", and 600 mg/m", respectively (10-12). Antimetabolites, topoisomerase inhibitors, vinca alkaloids, dacarbazine, and bleomycin were not associated with a persistent reduction of sperm cell production at doses in the conventional dosage range. INFERTILITY IN PATIENTS WITH TESTICULAR CANCER: "TESTIS, TUMOR, OR TREATMENT?"
In patients with testicular germ cell cancer, studies of chemotherapy-induced long-term infertility are fraught with a number of problems. First, about half of all patients with testicular germ cell tumors show unequivocal evidence of impaired spermatogenesis before any treatment (13, 14) or after orchiectomy and before cytotoxic chemotherapy (2, 1321) (Table 1). Second, the mechanisms underlying the preexisting reduction in sperm cell production are still poorly understood. Likely candidates include disorders of urogenital development and/or primary endocrine dysfunction (22) as well as contralateral testicular pathology (atrophy and testicular intratubular neoplasia) (1), tumor-related factors (endocrine activity of ,B-hCG, tumor-mediated cytokine produc-
Table 1 Fertility of Patients With Testicular Cancer Before Cytotoxic Chemotherapy Elevated FSH
Elevated LH
First author
Oligospermia
Azoospermia
Fossa (2) Scheiber (13) Carroll (14) Jewett (15) Fritz (16) Horwich (17) Nijman (18) Hansen (19) Drasga (20) Dearnaley (21) Total*
102/147 32/42 9/15 23/86 6/36 47/97 18/25 51/97 32/41 38/75 358/661 (54)
25/147
9/60
15/60
1/15
1/15
5/15
30/60
10/72
40/135 (30)
30/147 (20)
11/97 7/41 4/75 48/375 (13)
* Values in parentheses are percentages.
2
Pont and Albrecht Testis cancer: subsequent fertility
Table 2 Fertility Data >2 Years After Chemotherapy: Comparison of Patients with Testicular Cancer Treated with and Without Cytotoxic Chemotherapy First author
No. of courses
Pont (6) Aass (29) Nijman (18) Aass (29) Hansen (37) Hansen (3)
2x PEB* 3-4x PEBIPVBt 4x PVB >4x PEBIPVB sx PVB sx PVB
% Sperm cell Azoospermia concentration FSH
NS* NS NS Sign
NS NS
NS NS NS Sign§ Sign Sign
LH NS NS NS NS Sign Sign
* PEB, cisplatin, etoposide, and bleomycin. t PVB, cisplatin, vinblastine, and bleomycin. :1: NS, not significant. § Sign, significant; P < 0.05.
tion, and antisperm autoantibodies) (23-25), and emotional stress. Third, in some patients, improvement or recovery of sperm cell production was reported after the removal and/or other successful treatment of germ cell cancers (26-28). Aass et al. (29) found that the impairment of gonadal function 3 years after treatment for germ cell cancer correlated with the fertility parameters before treatment rather than with the type of treatment. A significant correlation with the type of treatment was seen only in patients who received more than four courses of cisplatin-based chemotherapy and/or adjuvant radiotherapy. The numerous published fertility data 2 years after completing cisplatin-based combination chemotherapy (3, 18-21, 29, 30-36) thus have failed to provide an answer to the question Schilsky posed in the title of an editorial: "Infertility in Patients with Testicular Cancer: Testis, Tumor, or Treatment?" (36). COMPARATIVE STUDIES OF CHEMOTHERAPY· TREATED TESTIS CANCER VERSUS TESTIS CANCER WITHOUT CYTOTOXIC TREATMENT
To evaluate the long-term impairment of gonadal function caused by cytotoxic chemotherapy in patients with germ cell cancer, comparative studies are needed using (age-matched) patients with testicular cancer who went into or stayed in remission without chemotherapy, i.e., patients treated by surgery alone or enrolled in a surveillance program. The outcome of such studies is shown in Table 2 (3, 6, 18, 29, 37). They clearly document that 2 years after chemotherapy with up to four cisplatin-based combination chemotherapy courses at a cumulative cisplatin dose of 400 mg/m'', the sperm concentration, rate of azoospermia, and FSH and LH levels did not differ significantly from those of such patients treated
Fertility and Sterility"
without chemotherapy. After more than four courses of chemotherapy, however, spermatogenesis and endocrine gonadal function were significantly altered in the chemotherapy versus the nonchemotherapy group. It is true that patients who receive more than four courses of chemotherapy have more advanced disease and possibly higher hCG levels and are less healthy than those patients who receive lower dosages. In theory, these may well be confounding variables for fertility assessment during active disease. However, they are not likely to playa role in patients 2 years after chemotherapy, who have long been in complete remission, as were the patients in the studies quoted. The time it takes for spermatogenesis to recover after chemotherapy, i.e., the time at which the elevated FSH levels return to normal, also correlates with the cumulative cisplatin dose (32). If the azoospermia caused by extremely high cumulative cytotoxic doses persists for more than 3 years, sperm cell production is unlikely to return to normal (12). When administered at conventional doses, vinblastine, etoposide, bleomycin, and ifosfamide do not appear to affect long-term fertility. For vinblastine, etoposide, and bleomycin, there is no reported evidence of type A spermatogonial toxicity. The only report (Hartlapp JM, Brensing KM, Voss R, Deitenbeck R, Mumperow E, abstract) suggesting that platinum, etoposide, and bleomycin were more toxic for long-term gonadal function than platinum, vinblastine, and bleomycin was not confirmed by two other studies (21, 38). Evidence from clinical trials indicated that ifosfamide was less toxic for type A spermatogonia than was cyclophosphamide. Whereas cyclophosphamide was found to cause irreversible infertility at a dose of 7.5 g/m" (11), the median FSH levels in 15 of 16 patients receiving 15 to 30 g/m" ifosfamide returned to normal (33). Except for cyclophosphamide, data on the effects on long-term gonadal toxicity of cytotoxic doses, such as those used for high-dose regimens, are not yet available. Data also are lacking for the taxanes, which will have a future place in the treatment of germ cell tumors. Studies on the effects of adjuvant chemotherapy on the long-term fertility of patients with germ cell cancer are of special interest because about half of them are, in essence, overtreated by adjuvant regimens. To date, three research teams have compared fertility after treatment in a total of 58 patients after two adjuvant cisplatin-based combination chemotherapy courses with a cumulative cisplatin dose of
Vol. 68, No.1, July 1997
200 mg/m'', These studies have assessed either pretreatment fertility (33, 39) or fertility in agematched patients during surveillance (6). These patients did not show any significant losses of gonadal function 9 to >24 months after chemotherapy. In 12 long-term follow-up studies of patients with testicular cancer treated with different cumulative cisplatin doses (3, 4, 6, 18, 20, 21, 29, 32, 34, 35, 40, 41), 145 ofthe total of 680 patients (21%) achieved paternity. However, the number of patients actually seeking fatherhood after completing treatment was not reported. The reported data (2-6) suggest that one third of all patients seek paternity after treatment, and more than half of them apparently achieve it. There is no evidence of an elevated relative risk of malformations in children fathered by patients with germ cell cancer after chemotherapy (42), just as there is no evidence of an increased risk of malignancies in these children (43). WHAT CAN BE DONE TO MINIMIZE THE POTENTIAL CHEMOTHERAPY-INDUCED IMPAIRMENT OF GONADAL FUNCTION IN PATIENTS TREATED FOR GERM CELL CANCER?
Although it is most toxic for type A spermatogonia, cisplatin currently is irreplaceable in the treatment of germ cell cancer. Therefore, the cumulative doses used should be adapted carefully to the risks: At doses below 400 mg/m", long-term effects on sperm cell production and endocrine function are unlikely to occur. Patients seeking fatherhood should be offered sperm cryopreservation before chemotherapy, particularly if higher cisplatin doses are expected to be necessary. Thanks to advanced methods ofIVF, such as intracytoplasmic sperm injection, cryopreservation is no longer limited to sperm that meet certain quality criteria. Theoretically, a single viable sperm cell is sufficient for the purpose. Clinical experience has shown, however, that no more than 5% to 8% of patients opting for sperm cryopreservation later make use of the option (44). Although it has protected sperm cell production against the cytotoxic effects of chemotherapy in some animal experiments, hormonal treatment with GnRH analogues has not shown any protective effects in four clinical trials in humans (45). In conclusion, the severity and duration of chemotherapy-related long-term gonadal toxicity are determined by the extent of stem cell spermatogonial damage and correlate with the cumulative dose of
Pont and Albrecht Testis cancer: subsequent fertility
3
cisplatin in current chemotherapy regimens for germ cell cancer. At doses <400 mg/m", chemotherapy is unlikely to produce persistent infertility. Higher doses, by contrast, should be expected to cause longterm losses of exocrine and endocrine gonadal function. REFERENCES 1. Berthelsen JG. Testicular cancer and fertility. Int J Androl 1987; 10:371-80. 2. Fossa SD, Aass N, Molne K. Is routine pre-treatment cryopreservation of semen worthwhile in the management ofpatients with testicular cancer? Br J UrolI989;64:524-9. 3. Hansen SW, Berthelsen JG, van der Maase H. Long-term fertility and Leydig cell function in patients treated for germ cell cancer with cisplatin, vinblastine, and bleomycin versus surveillance. J Clin Oncol 1990;8:1695-8. 4. Hansen PV, Glavind K, Panduro J, Pedersen M. Paternity in patients with testicular germ cell cancer: pretreatment and post-treatment findings. Eur J Cancer 1991;27:1385-9. 5. Foster RS, Benett R, Bihrle R, Donohue JP. A preliminary report: postoperative fertility assessment in nerve-sparing RPLND patients. Eur UrolI993;23:165-8. 6. Pont J, Albrecht W, Postner G, Sellner F, Angel K, Holtl W. Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long term results of a prospective study. J Clin Oncol 1996; 14:441-8. 7. Liu DY, Baker HJ. Tests of human sperm function and fertilization in vitro. Fertil SterilI992;58:465-83. 8. Meistrich ML. Quantitative correlation between testicular stem cell survival, sperm production and fertility in the mouse after treatment with different cytotoxic agents. J Androl 1982;3:58-68. 9. Meistrich ML. Relationship between spermatogonal stem cell survival and testis function after cytotoxic therapy. Br J Cancer 1986;3(Suppl VII):89-101. 10. Viviani S, Ragni G, Santoro A, Perotti L, Caccomo E, Negretti E, et al. Testicular dysfunction in Hodgkin's disease before and after treatment. Eur J Cancer 1991;27:1389-92. 11. Meistrich ML, Wilson MS, Brown BW, Da Cunha MF, Lipshultz LI. Impact of cyclophosphamide on long term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer 1992;70: 2703-12. 12. Meistrich ML, Chawla SP, Da Cunha MF, Johnson SL, Plager C, Papadopoulos NE, et al, Recovery of sperm production after chemotherapy for osteosarcoma. Cancer 1989; 63:211523. 13. Scheiber K, Bartsch G. Exocrine and endocrine function in patients with testicular tumors. In: Khoury S, et al., eds. Testicular cancer. New York: Alan Liss, 1985:715-25. 14. Carroll PR, Whitmore WF, Jr, Herr HW. Endocrine and exocrine profiles of men with testicular tumors before orchiectomy. J Urol1987; 137:420-3. 15. Jewett MAS, Thachil JV, Harris JF. Exocrine function oftestis with germinal testicular tumor. Br Med J 1983;286:184953. 16. Fritz K, Weissbach 1. Sperm parameters and ejaculation before and after operative treatment of patients with germ cell testicular cancer. Fertil Steril 1985;43:451-5. 17. Horwich A, Nicholls EJ, Hendry WF. Seminal analysis after orchiectomy in stage I teratoma. Br J UrolI988;62:79-83. 18. Nijman JM, Schraffordt Koops H, Kremer J. Fertility and
4
Pont and Albrecht Testis cancer: subsequent fertility
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
hormonal function in patients with a non-seminomatous tumor of the testis. Arch Androl 1985; 14:239-43. Hansen PV, Trykker H, Andersen J. Germ cell function and hormonal status in patients with testicular cancer. Cancer 1989; 64:956-61. Drasga RE, Einhorn LH, Williams SD, ParteI DN, Stevens EE. Fertility after chemotherapy for testicular cancer. J Clin OncoI1983;1:179-83. Dearnaley DP, Horwich A, A'Hern R, Nicholls J, Jay G, Hendry WF, et a1. Combination chemotherapy with bleomycin, etoposide, and cisplatin (BEP) for metastatic testicular teratoma: long term follow-up. Eur J Cancer 1991;27:68491. Morrish D, Venner P, Siy 0, Barron G, Bhardwaj D, Outhet D. Mechanisms of endocrine dysfunction in patients with testicular cancer. J Natl Cancer Inst 1990;82:412-9. Calkins JH, Sigel MM, Nankin HR, Lin T. Interleukin 1 inhibits Leydig cell steroidogenesis in primary culture. Endocrinology 1988; 123:1605-9. Hong G, Calkins HJ, Sigel MM. Interleukin-2 is a potent inhibitor of Leydig cell steroidogenesis. Endocrinology 1990; 127:1234-9. Guazzeri S, Lembo A, Ferro G, Artibani W, Merlo F, Zachetta R, et a1. Sperm antibodies and infertility in patients with testicular cancer. Urology 1985;26:139-43. Hendry WF, Stedronska J, Jones CR, Blackmore CA, Barrett A, Peckham MJ. Semen analysis in testicular cancer and Hodgkin's disease: pre- and posttreatment findings and implications for cryopreservation. Br J Urol 1983; :769-72. Carroll PR, Morse MJ, Whitmore WF, Sogani PC, Klotz L, Herr HW, et al. Fertility status of patients with clinical stage I testis tumors on a surveillance protocol. J Urol 1987; 138:70-2. Fossa SD, Theodorsen L, Norman N, Abyholm T. Recovery of impaired pretreatment spermatogenesis in testicular cancer. Fertil SterilI990;54:493-6. Aass N, Fossa SD, Theodorsen L, Norman N. Prediction of long term gonadal toxicity after standard treatment for testicular cancer. Eur J Cancer 1991;27:1087 -91. Johnson DH, Hainsworth JD, Linde RB, Greco FA. Testicular function following combination chemotherapy with cisplatin, vinblastine and bleomycin. Med Pediatr Oncol 1984; 12:2338. Fossa SD, Ous S, Abyholm T, Norman N, Loeb M. Post-treatment fertility in patients with testicular cancer. II. Influence of cisplatin-based combination chemotherapy and of retroperitoneal surgery on hormone and sperm cell production. Br J UroI1985;57:210-4. Kreuser ED, Kurrle E, Hetzel WD, Heymer B, Porzsolt F, Hautmann R, et al. Reversible germ cell toxicity after aggressive chemotherapy in patients with testicular cancer: results of a prospective study. Klin Wochenschr 1989; 67:367-78. Leitner SP, Bosl GJ, Bajorounas D. Gonadal dysfunction in patients treated for metastatic germ cell tumors. J Clin Oncol 1986;4:1500-5. Petersen PM, Hansen SW, Giwerczman A, Rflrth M, Skakkebaek NE. Dose dependent impairment of testicular function in patients treated with cisplatin-based chemotherapy for germ cell cancer. Ann OncoI1991;5:355-8. Stephenson WT, Pairier SM, Rubin L, Einhorn LH. Evaluation of reproductive capacity in germ cell tumor patients following treatment with cisplatin, etoposide, and bleomycin. J Clin Oncol 1995; 13:2278-80. Schilsky RL. Infertility in patients with testicular cancer:
Fertility and Sterility"
37.
38. 39.
40.
41.
testis, tumor, or treatment? J Natl Cancer Inst 1989; 81:1204-5. Hansen PV, Hansen SW. Gonadal function in men with testicular germ cell cancer: the influence of cisplatin-based chemotherapy. Eur UroI1993;23:153-6. Aass N, Fossa SD. Late side effects in patients treated for testicular cancer. Adv Biosciences 1994;91:337-43. Cullen MH, Stening SP, Parkinson MC, Fossa SD, Kaye SB, Horwich AH, et al. Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. J Clin Oncol 1996;14:1106-13. Roth BJ, Griest A, Kubilis PS, Williams SD, Einhorn LH. Cisplatin-based combination chemotherapy for disseminated germ cell tumors: long-term follow-up. J Clin OncoI1988;6:1239-47. Bisset D, Lunkeler L, Zwanenberg L, Paul J, Gray C, Swan
Vol. 68, No.1, July 1997
42.
43.
44.
45.
IRC, et al. Long-term sequelae of treatment for testicular germ cell tumors. Br J Cancer 1990;62:655-9. Senturia YD, Peckham CS. Children fathered by men treated with chemotherapy for testicular cancer. Eur J Cancer 1990;26:429-32. Mulvihill JJ, Myers MH, Connelley R, Byrne J, Austin DF, Brag K, et al. Cancer in offspring oflongterm survivors of childhood and adolescence cancer. Lancet 1987;11: 813. Fossa SD, Aass N, Molne K. Is routine pretreatment cryopreservation of semen worthwhile in the management of patients with testicular cancer? Br J UroI1989;64:524-9. Kreuser ED, Klingmuller D, Thiel E. The role of LhRH-analogues in protecting gonadal functions during chemotherapy and radiation. Eur UroI1993;23:157-64.
Pont and Albrecht Testis cancer: subsequent fertility
5
.0. ,
Vol. 68. No.1, July 1997
FERTILITY AND STERILITY® Copyright
0
1997 American Society for Reproductive Medicine
ociat Editor
Printed on acid-free paper in U. S. A.
Published by Elsevier Science Inc.
Fertility after chemotherapy for testicular germ cell cancer -Iorg Pont, M.D.*t Walter Albrecht, M.D.t Kaiser Franz Josef Spital and Rudolfstiftung, Vienna, Austria
Objective: To investigate the impact of cytostatic chemotherapy on long-term fertility in patients with testicular germ cell cancer. Background: Many patients with testicular germ cell cancer show impaired spermatogenesis before undergoing cytotoxic chemotherapy. The known infertility before treatment and the reversibility of the fertility problems observed in some of them after successful anticancer treatment so far have prevented an assessment of the true impact of chemotherapy on longterm fertility. The introduction of a wait-and-see strategy (surveillance) for patients with testicular cancer and recent prospective trials comparing patients with and without cytotoxic chemotherapy now have provided the means for estimating the extent to which chemotherapy itself affects long-term fertility. Result(s): Whether spermatogenesis is impaired irreversibly by chemotherapy is determined by the cumulative dose of cisplatin. At cumulative doses >400 mg/m'', irreversible impairment of gonadal function should be expected. Conclusion(s): At cumulative cisplatin doses <400 mg (equivalent to 4 courses of state-ofthe-art treatment), chemotherapy is unlikely to cause irreversible damage to fertility. (Fertil Steril'" 1997;68:1-5. © 1997 by American Society for Reproductive Medicine.) Key Words: Testicular cancer, chemotherapy, cisplatin, spermatogonial damage, fertility
As cytotoxic chemotherapy for malignant disease has improved the chances of long-term remission or cure in young patients who have not yet established a family, chemotherapy-induced impairment of fertility has gained increasing clinical importance. Although the time to conception and the rate of conception per unit time are the best measures of fertility in couples seeking parenthood (1), this approach is hardly helpful in the practical setting, because no more than one third of testicular cancer patients express a wish to father a child after completing treatment (2-6).
Received February 10, 1997. * Department of Medical Oncology, Kaiser Franz Josef Spital. t Reprint requests: Jorg' Pont, M.D., 3. Medizinische Abteilung, Kaiser Franz Josef Spital, KundratstraBe 3, A-llOO Vienna, Austria (FAX 43-1-60191-2319). t Urological Department, Rudolfstiftung.
0015-0282/97/$17.00 PH S0015-0282(97)00061-7
In most studies, fertility was therefore evaluated on the basis of laboratory tests, i.e., sperm cell concentration and morphology in the ejaculate and/or FSH serum levels for exocrine gonadal function, as well as T and LH levels for endocrine function. However, these have limited value as predictors of'fertility (7). Most of the patients undergoing cytostatic chemotherapy become azoospermic approximately 7 to 8 weeks after beginning treatment. This is in keeping with the kinetics of human spermatogenesis, because the anticancer agents act mostly on the sperm cells during cell division and thus destroy mainly the rapidly proliferating type B spermatogonia. If all stem cell spermatogonia (type A spermatogonia) survive, spermatogenesis can be expected to recover 12 weeks after treatment. Partial or complete destruction of type A spermatogonia will, however, cause a sustained or irreversible loss of sperm cell
1
production. The severity and duration of cytotoxic agent-induced long-term impairment of spermatogenesis correlate with the numbers of type A spermatogonia that are destroyed (8, 9). Preclinical data and clinical trials in patients with lymphoma and sarcoma showed that busulfan and procarbazine hydrochloride caused stem cell damage and thus produced long-term impairment of spermatogenesis. However, these studies failed to provide information on the tolerated cumulative doses. Of the alkylating agents, chlorambucil, cyclophosphamide, and cisplatin were found to cause irreversible infertility at doses of 400 mg, 7,500 mg/m", and 600 mg/m", respectively (10-12). Antimetabolites, topoisomerase inhibitors, vinca alkaloids, dacarbazine, and bleomycin were not associated with a persistent reduction of sperm cell production at doses in the conventional dosage range. INFERTILITY IN PATIENTS WITH TESTICULAR CANCER: "TESTIS, TUMOR, OR TREATMENT?"
In patients with testicular germ cell cancer, studies of chemotherapy-induced long-term infertility are fraught with a number of problems. First, about half of all patients with testicular germ cell tumors show unequivocal evidence of impaired spermatogenesis before any treatment (13, 14) or after orchiectomy and before cytotoxic chemotherapy (2, 1321) (Table 1). Second, the mechanisms underlying the preexisting reduction in sperm cell production are still poorly understood. Likely candidates include disorders of urogenital development and/or primary endocrine dysfunction (22) as well as contralateral testicular pathology (atrophy and testicular intratubular neoplasia) (1), tumor-related factors (endocrine activity of ,B-hCG, tumor-mediated cytokine produc-
Table 1 Fertility of Patients With Testicular Cancer Before Cytotoxic Chemotherapy Elevated FSH
Elevated LH
First author
Oligospermia
Azoospermia
Fossa (2) Scheiber (13) Carroll (14) Jewett (15) Fritz (16) Horwich (17) Nijman (18) Hansen (19) Drasga (20) Dearnaley (21) Total*
102/147 32/42 9/15 23/86 6/36 47/97 18/25 51/97 32/41 38/75 358/661 (54)
25/147
9/60
15/60
1/15
1/15
5/15
30/60
10/72
40/135 (30)
30/147 (20)
11/97 7/41 4/75 48/375 (13)
* Values in parentheses are percentages.
2
Pont and Albrecht Testis cancer: subsequent fertility
Table 2 Fertility Data >2 Years After Chemotherapy: Comparison of Patients with Testicular Cancer Treated with and Without Cytotoxic Chemotherapy First author
No. of courses
Pont (6) Aass (29) Nijman (18) Aass (29) Hansen (37) Hansen (3)
2x PEB* 3-4x PEBIPVBt 4x PVB >4x PEBIPVB sx PVB sx PVB
% Sperm cell Azoospermia concentration FSH
NS* NS NS Sign
NS NS
NS NS NS Sign§ Sign Sign
LH NS NS NS NS Sign Sign
* PEB, cisplatin, etoposide, and bleomycin. t PVB, cisplatin, vinblastine, and bleomycin. :1: NS, not significant. § Sign, significant; P < 0.05.
tion, and antisperm autoantibodies) (23-25), and emotional stress. Third, in some patients, improvement or recovery of sperm cell production was reported after the removal and/or other successful treatment of germ cell cancers (26-28). Aass et al. (29) found that the impairment of gonadal function 3 years after treatment for germ cell cancer correlated with the fertility parameters before treatment rather than with the type of treatment. A significant correlation with the type of treatment was seen only in patients who received more than four courses of cisplatin-based chemotherapy and/or adjuvant radiotherapy. The numerous published fertility data 2 years after completing cisplatin-based combination chemotherapy (3, 18-21, 29, 30-36) thus have failed to provide an answer to the question Schilsky posed in the title of an editorial: "Infertility in Patients with Testicular Cancer: Testis, Tumor, or Treatment?" (36). COMPARATIVE STUDIES OF CHEMOTHERAPY· TREATED TESTIS CANCER VERSUS TESTIS CANCER WITHOUT CYTOTOXIC TREATMENT
To evaluate the long-term impairment of gonadal function caused by cytotoxic chemotherapy in patients with germ cell cancer, comparative studies are needed using (age-matched) patients with testicular cancer who went into or stayed in remission without chemotherapy, i.e., patients treated by surgery alone or enrolled in a surveillance program. The outcome of such studies is shown in Table 2 (3, 6, 18, 29, 37). They clearly document that 2 years after chemotherapy with up to four cisplatin-based combination chemotherapy courses at a cumulative cisplatin dose of 400 mg/m'', the sperm concentration, rate of azoospermia, and FSH and LH levels did not differ significantly from those of such patients treated
Fertility and Sterility"
without chemotherapy. After more than four courses of chemotherapy, however, spermatogenesis and endocrine gonadal function were significantly altered in the chemotherapy versus the nonchemotherapy group. It is true that patients who receive more than four courses of chemotherapy have more advanced disease and possibly higher hCG levels and are less healthy than those patients who receive lower dosages. In theory, these may well be confounding variables for fertility assessment during active disease. However, they are not likely to playa role in patients 2 years after chemotherapy, who have long been in complete remission, as were the patients in the studies quoted. The time it takes for spermatogenesis to recover after chemotherapy, i.e., the time at which the elevated FSH levels return to normal, also correlates with the cumulative cisplatin dose (32). If the azoospermia caused by extremely high cumulative cytotoxic doses persists for more than 3 years, sperm cell production is unlikely to return to normal (12). When administered at conventional doses, vinblastine, etoposide, bleomycin, and ifosfamide do not appear to affect long-term fertility. For vinblastine, etoposide, and bleomycin, there is no reported evidence of type A spermatogonial toxicity. The only report (Hartlapp JM, Brensing KM, Voss R, Deitenbeck R, Mumperow E, abstract) suggesting that platinum, etoposide, and bleomycin were more toxic for long-term gonadal function than platinum, vinblastine, and bleomycin was not confirmed by two other studies (21, 38). Evidence from clinical trials indicated that ifosfamide was less toxic for type A spermatogonia than was cyclophosphamide. Whereas cyclophosphamide was found to cause irreversible infertility at a dose of 7.5 g/m" (11), the median FSH levels in 15 of 16 patients receiving 15 to 30 g/m" ifosfamide returned to normal (33). Except for cyclophosphamide, data on the effects on long-term gonadal toxicity of cytotoxic doses, such as those used for high-dose regimens, are not yet available. Data also are lacking for the taxanes, which will have a future place in the treatment of germ cell tumors. Studies on the effects of adjuvant chemotherapy on the long-term fertility of patients with germ cell cancer are of special interest because about half of them are, in essence, overtreated by adjuvant regimens. To date, three research teams have compared fertility after treatment in a total of 58 patients after two adjuvant cisplatin-based combination chemotherapy courses with a cumulative cisplatin dose of
Vol. 68, No.1, July 1997
200 mg/m'', These studies have assessed either pretreatment fertility (33, 39) or fertility in agematched patients during surveillance (6). These patients did not show any significant losses of gonadal function 9 to >24 months after chemotherapy. In 12 long-term follow-up studies of patients with testicular cancer treated with different cumulative cisplatin doses (3, 4, 6, 18, 20, 21, 29, 32, 34, 35, 40, 41), 145 ofthe total of 680 patients (21%) achieved paternity. However, the number of patients actually seeking fatherhood after completing treatment was not reported. The reported data (2-6) suggest that one third of all patients seek paternity after treatment, and more than half of them apparently achieve it. There is no evidence of an elevated relative risk of malformations in children fathered by patients with germ cell cancer after chemotherapy (42), just as there is no evidence of an increased risk of malignancies in these children (43). WHAT CAN BE DONE TO MINIMIZE THE POTENTIAL CHEMOTHERAPY-INDUCED IMPAIRMENT OF GONADAL FUNCTION IN PATIENTS TREATED FOR GERM CELL CANCER?
Although it is most toxic for type A spermatogonia, cisplatin currently is irreplaceable in the treatment of germ cell cancer. Therefore, the cumulative doses used should be adapted carefully to the risks: At doses below 400 mg/m", long-term effects on sperm cell production and endocrine function are unlikely to occur. Patients seeking fatherhood should be offered sperm cryopreservation before chemotherapy, particularly if higher cisplatin doses are expected to be necessary. Thanks to advanced methods ofIVF, such as intracytoplasmic sperm injection, cryopreservation is no longer limited to sperm that meet certain quality criteria. Theoretically, a single viable sperm cell is sufficient for the purpose. Clinical experience has shown, however, that no more than 5% to 8% of patients opting for sperm cryopreservation later make use of the option (44). Although it has protected sperm cell production against the cytotoxic effects of chemotherapy in some animal experiments, hormonal treatment with GnRH analogues has not shown any protective effects in four clinical trials in humans (45). In conclusion, the severity and duration of chemotherapy-related long-term gonadal toxicity are determined by the extent of stem cell spermatogonial damage and correlate with the cumulative dose of
Pont and Albrecht Testis cancer: subsequent fertility
3
cisplatin in current chemotherapy regimens for germ cell cancer. At doses <400 mg/m", chemotherapy is unlikely to produce persistent infertility. Higher doses, by contrast, should be expected to cause longterm losses of exocrine and endocrine gonadal function. REFERENCES 1. Berthelsen JG. Testicular cancer and fertility. Int J Androl 1987; 10:371-80. 2. Fossa SD, Aass N, Molne K. Is routine pre-treatment cryopreservation of semen worthwhile in the management ofpatients with testicular cancer? Br J UrolI989;64:524-9. 3. Hansen SW, Berthelsen JG, van der Maase H. Long-term fertility and Leydig cell function in patients treated for germ cell cancer with cisplatin, vinblastine, and bleomycin versus surveillance. J Clin Oncol 1990;8:1695-8. 4. Hansen PV, Glavind K, Panduro J, Pedersen M. Paternity in patients with testicular germ cell cancer: pretreatment and post-treatment findings. Eur J Cancer 1991;27:1385-9. 5. Foster RS, Benett R, Bihrle R, Donohue JP. A preliminary report: postoperative fertility assessment in nerve-sparing RPLND patients. Eur UrolI993;23:165-8. 6. Pont J, Albrecht W, Postner G, Sellner F, Angel K, Holtl W. Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long term results of a prospective study. J Clin Oncol 1996; 14:441-8. 7. Liu DY, Baker HJ. Tests of human sperm function and fertilization in vitro. Fertil SterilI992;58:465-83. 8. Meistrich ML. Quantitative correlation between testicular stem cell survival, sperm production and fertility in the mouse after treatment with different cytotoxic agents. J Androl 1982;3:58-68. 9. Meistrich ML. Relationship between spermatogonal stem cell survival and testis function after cytotoxic therapy. Br J Cancer 1986;3(Suppl VII):89-101. 10. Viviani S, Ragni G, Santoro A, Perotti L, Caccomo E, Negretti E, et al. Testicular dysfunction in Hodgkin's disease before and after treatment. Eur J Cancer 1991;27:1389-92. 11. Meistrich ML, Wilson MS, Brown BW, Da Cunha MF, Lipshultz LI. Impact of cyclophosphamide on long term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer 1992;70: 2703-12. 12. Meistrich ML, Chawla SP, Da Cunha MF, Johnson SL, Plager C, Papadopoulos NE, et al, Recovery of sperm production after chemotherapy for osteosarcoma. Cancer 1989; 63:211523. 13. Scheiber K, Bartsch G. Exocrine and endocrine function in patients with testicular tumors. In: Khoury S, et al., eds. Testicular cancer. New York: Alan Liss, 1985:715-25. 14. Carroll PR, Whitmore WF, Jr, Herr HW. Endocrine and exocrine profiles of men with testicular tumors before orchiectomy. J Urol1987; 137:420-3. 15. Jewett MAS, Thachil JV, Harris JF. Exocrine function oftestis with germinal testicular tumor. Br Med J 1983;286:184953. 16. Fritz K, Weissbach 1. Sperm parameters and ejaculation before and after operative treatment of patients with germ cell testicular cancer. Fertil Steril 1985;43:451-5. 17. Horwich A, Nicholls EJ, Hendry WF. Seminal analysis after orchiectomy in stage I teratoma. Br J UrolI988;62:79-83. 18. Nijman JM, Schraffordt Koops H, Kremer J. Fertility and
4
Pont and Albrecht Testis cancer: subsequent fertility
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
hormonal function in patients with a non-seminomatous tumor of the testis. Arch Androl 1985; 14:239-43. Hansen PV, Trykker H, Andersen J. Germ cell function and hormonal status in patients with testicular cancer. Cancer 1989; 64:956-61. Drasga RE, Einhorn LH, Williams SD, ParteI DN, Stevens EE. Fertility after chemotherapy for testicular cancer. J Clin OncoI1983;1:179-83. Dearnaley DP, Horwich A, A'Hern R, Nicholls J, Jay G, Hendry WF, et a1. Combination chemotherapy with bleomycin, etoposide, and cisplatin (BEP) for metastatic testicular teratoma: long term follow-up. Eur J Cancer 1991;27:68491. Morrish D, Venner P, Siy 0, Barron G, Bhardwaj D, Outhet D. Mechanisms of endocrine dysfunction in patients with testicular cancer. J Natl Cancer Inst 1990;82:412-9. Calkins JH, Sigel MM, Nankin HR, Lin T. Interleukin 1 inhibits Leydig cell steroidogenesis in primary culture. Endocrinology 1988; 123:1605-9. Hong G, Calkins HJ, Sigel MM. Interleukin-2 is a potent inhibitor of Leydig cell steroidogenesis. Endocrinology 1990; 127:1234-9. Guazzeri S, Lembo A, Ferro G, Artibani W, Merlo F, Zachetta R, et a1. Sperm antibodies and infertility in patients with testicular cancer. Urology 1985;26:139-43. Hendry WF, Stedronska J, Jones CR, Blackmore CA, Barrett A, Peckham MJ. Semen analysis in testicular cancer and Hodgkin's disease: pre- and posttreatment findings and implications for cryopreservation. Br J Urol 1983; :769-72. Carroll PR, Morse MJ, Whitmore WF, Sogani PC, Klotz L, Herr HW, et al. Fertility status of patients with clinical stage I testis tumors on a surveillance protocol. J Urol 1987; 138:70-2. Fossa SD, Theodorsen L, Norman N, Abyholm T. Recovery of impaired pretreatment spermatogenesis in testicular cancer. Fertil SterilI990;54:493-6. Aass N, Fossa SD, Theodorsen L, Norman N. Prediction of long term gonadal toxicity after standard treatment for testicular cancer. Eur J Cancer 1991;27:1087 -91. Johnson DH, Hainsworth JD, Linde RB, Greco FA. Testicular function following combination chemotherapy with cisplatin, vinblastine and bleomycin. Med Pediatr Oncol 1984; 12:2338. Fossa SD, Ous S, Abyholm T, Norman N, Loeb M. Post-treatment fertility in patients with testicular cancer. II. Influence of cisplatin-based combination chemotherapy and of retroperitoneal surgery on hormone and sperm cell production. Br J UroI1985;57:210-4. Kreuser ED, Kurrle E, Hetzel WD, Heymer B, Porzsolt F, Hautmann R, et al. Reversible germ cell toxicity after aggressive chemotherapy in patients with testicular cancer: results of a prospective study. Klin Wochenschr 1989; 67:367-78. Leitner SP, Bosl GJ, Bajorounas D. Gonadal dysfunction in patients treated for metastatic germ cell tumors. J Clin Oncol 1986;4:1500-5. Petersen PM, Hansen SW, Giwerczman A, Rflrth M, Skakkebaek NE. Dose dependent impairment of testicular function in patients treated with cisplatin-based chemotherapy for germ cell cancer. Ann OncoI1991;5:355-8. Stephenson WT, Pairier SM, Rubin L, Einhorn LH. Evaluation of reproductive capacity in germ cell tumor patients following treatment with cisplatin, etoposide, and bleomycin. J Clin Oncol 1995; 13:2278-80. Schilsky RL. Infertility in patients with testicular cancer:
Fertility and Sterility"
37.
38. 39.
40.
41.
testis, tumor, or treatment? J Natl Cancer Inst 1989; 81:1204-5. Hansen PV, Hansen SW. Gonadal function in men with testicular germ cell cancer: the influence of cisplatin-based chemotherapy. Eur UroI1993;23:153-6. Aass N, Fossa SD. Late side effects in patients treated for testicular cancer. Adv Biosciences 1994;91:337-43. Cullen MH, Stening SP, Parkinson MC, Fossa SD, Kaye SB, Horwich AH, et al. Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. J Clin Oncol 1996;14:1106-13. Roth BJ, Griest A, Kubilis PS, Williams SD, Einhorn LH. Cisplatin-based combination chemotherapy for disseminated germ cell tumors: long-term follow-up. J Clin OncoI1988;6:1239-47. Bisset D, Lunkeler L, Zwanenberg L, Paul J, Gray C, Swan
Vol. 68, No.1, July 1997
42.
43.
44.
45.
IRC, et al. Long-term sequelae of treatment for testicular germ cell tumors. Br J Cancer 1990;62:655-9. Senturia YD, Peckham CS. Children fathered by men treated with chemotherapy for testicular cancer. Eur J Cancer 1990;26:429-32. Mulvihill JJ, Myers MH, Connelley R, Byrne J, Austin DF, Brag K, et al. Cancer in offspring oflongterm survivors of childhood and adolescence cancer. Lancet 1987;11: 813. Fossa SD, Aass N, Molne K. Is routine pretreatment cryopreservation of semen worthwhile in the management of patients with testicular cancer? Br J UroI1989;64:524-9. Kreuser ED, Klingmuller D, Thiel E. The role of LhRH-analogues in protecting gonadal functions during chemotherapy and radiation. Eur UroI1993;23:157-64.
Pont and Albrecht Testis cancer: subsequent fertility
5