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© 2002 American Society for Clinical Oncology Effect of Graded Testicular Doses of Radiotherapy in Patients Treated for Carcinoma-In-Situ in the TestisByFrom the Departments of Growth & Reproduction and Oncology, Finsencenter, Copenhagen University Hospital, Rigshospitalet, Copenhagen; Department of Biostatistics, University of Copenhagen; Department of Oncology, Herlev University Hospital, Herlev; and Department of Oncology, Aarhus University Hospital, Aarhus, Denmark. Address reprint requests to Peter Meidahl Petersen, MD, Department of Growth and Reproduction, Copenhagen University Hospital, Herlev, 9 Blegdamsvej, R54B1, Copenhagen 2730, Denmark; email: pmp{at}post11.tele.dk
PURPOSE: To determine the effect of radiotherapy in doses 14 to 20 Gy on eradication of carcinoma-in-situ (CIS) testis and on the Leydig cell function. PATIENTS AND METHODS: Forty-eight patients presented with unilateral testicular germ cell cancer and CIS of the contralateral testis. The CIS-bearing testis was treated with daily irradiation doses of 2 Gy, 5 days a week, to a cumulative dose of 20 Gy (21 patients), 18 Gy (three patients), 16 Gy (10 patients), and 14 Gy (14 patients). RESULTS: All patients treated at dose levels 20 Gy to 16 Gy achieved histologically verified complete remission without signs of recurrence of CIS after an observation period of more than 5 years. One of 14 patients treated at dose level 14 Gy had a relapse of CIS 20 months after irradiation. Leydig cell function was examined before and regularly after radiotherapy in 44 of 48 patients. The levels of testosterone were lower after radiotherapy than before. Testosterone showed a stable decrease for more than 5 years after treatment (3.6% per year) without dose dependency. The levels of luteinizing hormone and follicle-stimulating hormone were increased after radiotherapy. The need of androgen substitution therapy was similar at all dose levels. CONCLUSION: Testicular irradiation is a safe treatment at dose level 20 Gy (10 x 2 Gy). Decrease of dose to 14 Gy (7 x 2 Gy) might lead to risk of relapse of CIS. Impairment of hormone production without clinically significant dose dependency is seen in the dose range 14 to 20 Gy.
TESTICULAR GERM CELL cancer, which is the most common type of testicular cancer, is preceded by carcinoma-in-situ (CIS).1,2 CIS is found in the contralateral testis in 5% of the patients with testicular germ cell cancer.3,4,5 The management of CIS is important because the majority, if not all, cases of CIS will progress to invasive disease without treatment.4 In 1986, von der Maase6 et al showed that CIS could be eradicated by fractionated radiotherapy. Biopsies after irradiation revealed complete eradication of CIS cells and germ cells but preservation of Sertoli cells and Leydig cells in three patients treated with 10 doses of 2 Gy. These observations were confirmed in a subsequent study showing complete eradication of CIS and a moderate degree of impairment of Leydig cell function in 20 men treated with 10 doses of 2-Gy radiotherapy.7 The Leydig cell function is already impaired before treatment in patients with testicular cancer and CIS in the contralateral testis and is reduced further by radiotherapy.7 Lower doses of irradiation could cause a smaller degree of Leydig cell dysfunction. Our study was therefore initiated to evaluate the effect of radiotherapy in doses of 14 to 20 Gy on eradication of CIS and on the Leydig cell function.
Patients Forty-eight consecutive patients with unilateral testicular germ cell cancer and newly diagnosed CIS of the contralateral testis were investigated in the period from 1985 to 1998. The diagnosis of CIS was verified in all cases by histologic examination.
Treatment
Follow-Up The effect of irradiation on testicular hormone production was assessed by measurements of serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, estradiol, and sex hormone binding globulin before radiotherapy and 3, 12, 24, 36, 48, 60, and 120 months after radiotherapy. In three patients, data on hormone levels were missing either before or after testicular irradiation, and one patient received chemotherapy (cisplatin, etoposide, and bleomycin) for the disseminated germ cell cancer 3 years before inclusion in this study. Thus, 44 patients included on the hormone studies were examined both before and after testicular irradiation (median follow-up time, 39 months; range, 3 to 133 months). The characteristics of these 44 patients are listed in Table 1. Androgen substitution therapy was initiated if the patients had clinical symptoms of androgen insufficiency, increased levels of LH, and decreased levels of androgen.
Hormone Analyses In patients who received testosterone replacement therapy, the treatment, administered as intramuscular injections of testosterone enantate, was stopped at least 1 month before hormone investigations. A peroral treatment (testosterone endecanoate) was stopped at least 2 weeks before hormone investigations. Gonadotropins. Serum values of FSH and LH were measured using a radioimmunoassay kit (World Health Organization standard second IRP 78/549 for FSH and World Health Organization standard first IRP 68/40 for LH) until 1994 to 1995. Assays of gonadotropins were changed in 1994 to 1995 to time-resolved immuno-fluorometric assay (Delfia, Wallac, Finland). LH and FSH levels were expressed in international units per liter. Steroid hormones. Free serum testosterone, 4-androstene-dione, dihydrotestosterone, and dihydro-androstene-dione were measured by the same assay in all cases (radioimmunoassay, Statens Seruminstitut, Copenhagen, Denmark) in patients treated with doses of 16, 18, and 20 Gy. Testosterone and estradiol were measured by radioimmunoassay and expressed in nanomoles per liter and picomoles per liter (Statens Seruminstitut). The assays of these hormones were changed in 1995 to the Coat-a-Count radioimmunoassay kit (DPC, Los Angeles, CA) for testosterone and IDS (IDS Ltd, Boldon, United Kingdom) for estradiol. Human chorionic gonadotropin test. The human chorionic gonadotropin (hCG) test was made, as previously described, by intramuscular injection of 5,000 IU of hCG8 and the measurement of the testosterone level before and 72, and 96 hours after injection. LH-releasing hormone stimulation test. One hundred micrograms of LH-releasing hormone (LHRH) was injected intravenously. LH and FSH levels were determined before injection and 15, 30, 60, 90, 120, and 180 minutes after the administration of LHRH. The result of the test is expressed as the peak stimulated value. Inhibin B. Inhibin B was measured by immunometric assay as previously described by Illingworth et al9 and Anawalt et al.10 The lower detection limit of the inhibin B assay was 20 pg/mL, and the intra- and interassay variations were 12% and 17%, respectively. The reference interval was greater than 35 pg/mL.
Statistics The variation of hormone values over time after radiotherapy was described in a multivariate random coefficient model in which each individual was allowed a piecewise linear function in time. Also, the dose of irradiation and the assay used were entered into the model. In this way, information is extracted correctly from all patients regardless of whether or not the analysis of blood sample was done by one assay or another and regardless of the length of time each patient was followed up after radiotherapy. LH and LHRH-stimulated LH values and testosterone and hCG-stimulated testosterone values were logarithmically transformed to obtain variance stability and to normalize the data. The final models were subjected to standard checks of the residuals. The analyses were performed using the statistical package SAS (SAS Institute, Cary, NC).
Effect of Treatment on CIS 20-Gy dose level. All 21 patients at 20 Gy showed complete remission with the Sertoli cell only pattern (ie, complete eradication of CIS cells and germ cells but the presence of Sertoli cells in the seminiferous tubules and Leydig cells in the intertubular space). There was no evidence of relapse of CIS after a median observation period of 125 months (range, 26 to 188 months). 16- to 18-Gy dose level. The same histologic pattern with Sertoli cells only in the seminiferous tubules and Leydig cells in the intertubular space was seen in the three patients treated with 18 Gy and in the 10 patients treated with 16 Gy. No patients showed evidence of relapse of CIS during the median observation period of 74 months (range, 61 to 124 months). 14-Gy dose level. Thirteen of 14 patients treated with 14 Gy achieved complete remission without signs of recurrence of CIS of the testis after a median observation period of 44 months (range, 25 to 52 months). One patient treated at dose level 14 Gy had a relapse of CIS, which was verified by biopsy 20 months after irradiation. This patient was initially treated with right-sided orchidectomy, followed by standard-dose chemotherapy (cisplatin, etoposide, and bleomycin) for advanced nonseminoma. Biopsy specimens from the left testis showed CIS before chemotherapy. Biopsy specimens obtained 26 months after chemotherapy showed CIS, and radiotherapy was initiated. Twenty months after radiotherapy, new biopsy specimens showed CIS cells in a few tubules, and left-sided orchidectomy was performed. Histologic investigation of the left testis confirmed the results from the histologic investigation of the biopsy specimens: a few tubules with CIS cells, no germ cells, and presence of Leydig cells. A careful review of the radiotherapy in this patient did not reveal any signs of technical problems or errors.
Reproductive Hormones
Dose dependency of the acute effect of radiotherapy. Table 3 lists the differences between pre- and posttreatment hormone levels. The only hormone that showed dose-dependent changes after testicular irradiation was estradiol. Estradiol levels increased at the first follow-up after testicular irradiation with 14 Gy as compared with the pretreatment level (P = .03). The levels were unchanged after testicular irradiation with 16 to 18 Gy (P = .20), whereas the levels showed borderline significant decreased levels after a dose of 20 Gy (P = .06). Moreover, the differences between pretreatment hormone levels and hormone levels 2 to 3 years after radiotherapy in patients treated with 18 to 20 Gy and patients treated with lower doses (14 to 16 Gy) were tested (Mann-Whitney U test). The only statistically significant difference between these two groups was a larger LH increase in the high-dose group (P = .046).
Hormone levels after radiotherapy. Table 4 lists the trends of testosterone and LH after radiotherapy. Testosterone showed a stable decrease (3.6% per year) without statistically significant dose dependency after treatment (dose level 20 Gy v 14 Gy; P = .33). The decrease of testosterone levels continued at the same rate for more than 5 years. Stimulated testosterone showed a significant decrease at dose level 20 Gy (P = .002) but not at dose level 14 Gy (P = .63) or 18 Gy (P = .81). No significant difference was seen when the trends of 14 Gy and 20 Gy were compared (P = .42). Stimulated testosterone showed a significant decrease the first 5 years after irradiation (8% per year, P = .00005), whereas no further change was seen during the subsequent 5 years (2% per year, P = .23). As listed in Table 4, no significant changes were seen in LH levels after irradiation. However, the difference between patients treated at dose levels 18 and 20 Gy, who showed a slight increase in LH levels, and patients treated at dose levels 14 and 16 Gy, who had a minor decrease in LH levels, reached borderline statistical significance (P = .05).
Overall, 18 of 42 men for whom the data on testosterone treatment were available received androgen substitution therapy because of symptoms of androgen insufficiency. Ten of 18 in the 20-Gy group, two of three in the 18-Gy group, three of nine in the 16-Gy group, and five of 13 in the 14-Gy group received androgen replacement therapy. The treatment was initiated after a median period of 33 months (range, 0 to 164 months).
Our study confirmed the previous observation that testicular irradiation with a total dose of 20 Gy (10 doses of 2 Gy) is an effective and safe treatment of CIS in the contralateral testis in patients with unilateral testicular germ cell cancer.6,7 We followed up 21 patients treated with 20 Gy and three patients treated with 18 Gy for a median period of 10 years after radiotherapy. Biopsy specimens obtained 1 year after treatment showed complete eradication of CIS. The same finding was seen in one study of four patients investigated more than 18 months after radiotherapy (18 Gy to 20 Gy), and another study showed complete eradication of CIS in biopsy specimens from 23 patients investigated 3 months after testicular irradiation with 18 to 20 Gy.11,12 Thus, complete eradication of CIS cells has been reported in 51 patients treated with testicular irradiation with a dose level of nine to 10 doses of 2 Gy. Twenty-four of these 51 patients were observed for more than 18 months after treatment, and none of these had any signs of relapse in the testis. However, in a recent publication, a case of testicular relapse of CIS and development of invasive seminoma was seen 6 years after testicular radiotherapy with nine doses of 2 Gy.13 In the present study, testicular irradiation with the lower dose level (eight doses of 2 Gy) eradicated CIS, whereas one of 14 patients had a relapse of CIS when the dose was lowered to seven doses of 2 Gy. Failure of treatment could theoretically be caused by errors or technical failures of the irradiation. In our case, a careful review of the treatment files did not reveal any indications of problems or errors during the treatment. The duration of follow-up in patients treated with 16 Gy and 14 Gy was shorter than in patients treated with higher doses. Therefore, we cannot yet exclude further late relapses of CIS in patients treated with 16 Gy and 14 Gy. The eradication of germ cells is in line with the finding that a single dose of irradiation causes irreversible azoospermia in healthy men when the dose exceeds 6 to 8 Gy.14 In the present study, the patients were treated with radiotherapy given in fractionated schedules, which is suggested to be even more toxic to the germ cells than single doses. However, recovery of spermatogenesis was reported in few patients treated with total-body irradiation of 15.75 Gy (seven doses of 2.25 Gy) for leukemia.15,16 It is possible that the patients with germ cell neoplasia might be more vulnerable to the effects of irradiation because spermatogenetic function is subnormal already before irradiation. The present study confirmed the data from the preliminary study: that Leydig cell function is impaired after testicular irradiation with 20 Gy (10 doses of 2 Gy) for CIS.7 This impairment is apparent from the increased LH levels and decreased testosterone levels after radiotherapy as compared with pretreatment levels (Fig 1). The acute effect of radiotherapy (ie, the hormone levels at first follow-up examination after radiotherapy as compared with the pretreatment levels) on the levels of reproductive hormones was only dose dependent for estradiol. None of the other reproductive hormones showed dose dependency in the given range of 14 Gy to 20 Gy. This might indicate a minor degree of dose-dependent gonadal toxicity because estradiol levels previously have been shown to be a quite sensitive marker of changes in Leydig cell function.17,18 During long-term follow-up, only weak indications of dose dependency were seen. The minor but statistically significant decline in LH seen after the initial increase at first follow-up after irradiation in patients treated with 14 and 16 Gy may indicate some degree of regeneration. The minor and statistically insignificant increase of LH, seen after radiotherapy in patients treated with the dose levels 18 and 20 Gy, may indicate persisting damage to the Leydig cells. However, these suggestions were not reflected by the changes in testosterone levels. Testosterone showed a continuous decrease more than 5 years after testicular irradiation without any differences between the different dose levels. The differences between pretreatment hormone levels and levels 2 to 3 years after treatment did not show any dose dependency. The lack of an obvious dose dependency was also reflected by the fact that an equal proportion of patients at the dose levels 20 Gy, 18 Gy, 16 Gy, and 14 Gy required androgen substitution therapy. Thus, we could only see vague and probably clinically insignificant signs of dose dependency of testicular irradiation in the 14- to 20-Gy range. The present findings are in line with the existing sparse data on the effect of testicular irradiation on Leydig cell function in men, which indicates dose-dependent impairment of Leydig cell function with increased LH values but unchanged testosterone values in patients who received a testicular dose above 0.5 Gy. The increase in LH values was permanent in patients who had received a dose higher than 20 Gy but normalized at 30 months in patients treated with lower doses.19 Data in patients with testicular cancer who were treated with a testicular dose of 30 Gy showed marked Leydig cell dysfunction.20 The large proportion of patients who needed androgen replacement therapy in this study was not surprising when seen in the light of the poor pretreatment Leydig cell function in men with CIS in the contralateral testis after unilateral orchidectomy.17 From the reference values of testosterone in our own laboratory, and from cross-sectional studies comparing testosterone levels in younger and older men, we would not expect a decline in testosterone with increasing age in this group of patients.21 A recent study indicated a slight decrease in serum testosterone levels and in free testosterone indexes with increasing age.22 This decrease was in the magnitude of 0.5% per year, whereas the decrease in serum testosterone in the present study was 3.6% per year. Thus, we cannot exclude that a part of the observed decrease in serum testosterone levels during follow-up is due to an age-related decrease. However, we believe that a decrease of serum testosterone of 3.6% per year cannot be explained solely by aging. However, the interpretation of the relationship between age and hormone levels is hampered by the lack of longitudinal studies of hormone levels in patients with testicular cancer with or without CIS in the contralateral testis. Two strategies are possible in the treatment of contralateral CIS in men with testicular cancer: (1) radiotherapy, with a dose level that eradicates germ cells and CIS cells but at least partly allows preservation of Leydig cells,7 and (2) surveillance, followed by orchidectomy if a second invasive testicular cancer evolves. The rationale for the last strategy is to preserve fertility until development of a second testicular cancer might occur. However, patients with CIS already have poor semen quality before radiotherapy,17 and only few patients are expected to induce pregnancy without assisted fertilization.23 The majority, if not all, cases of CIS will progress to invasive disease without treatment.4 Thus, the consequence, if this strategy is followed, is permanent androgen insufficiency after bilateral orchidectomy in all patients. Some of the patients with contralateral CIS are initially treated with chemotherapy because of advanced disease. Chemotherapy leads to the disappearance of CIS cells, but this is only temporary because the cumulative risk of relapse of CIS 5 and 10 years after chemotherapy in these patients has been estimated to 21% and 42%, respectively.24 Thus, treatment with chemotherapy implies that surveillance with biopsies is similar to the surveillance in testicular cancer patients with contralateral CIS treated with unilateral orchidectomy alone. It is not documented that fertility is preserved after chemotherapy in this group of patients. Thus, in our opinion, the optimal treatment seems to be local radiotherapy of the testis with CIS to preserve at least a part of the Leydig cell function. The present study was initiated to find the optimal dose level that eradicates CIS but preserves Leydig cell function. In light of the cases with relapse after 14 Gy (seven dose of 2 Gy) and 18 Gy (nine doses of 2 Gy),13 the present finding of equal effect on androgen production at the dose levels of 20 Gy, 18 Gy, 16 Gy, and 14 Gy indicates that testicular irradiation with a dose of 20 Gy (10 doses of 2 Gy) is the optimal treatment. However, investigation of more patients treated with 14 Gy and 16 Gy and a longer follow-up of patients are required to make more definitive conclusions. In conclusion, (1) testicular irradiation is a safe treatment at the 20-Gy dose level given as fractionated irradiation (10 doses of 2 Gy), (2) testicular irradiation at the 16-Gy dose level (eight doses of 2 Gy) seems to eradicate testicular CIS, (3) a decrease of dose to 14 Gy (seven doses of 2 Gy) might lead to a risk of relapse of CIS, (4) impairment of hormone production is seen in the dose range of irradiation (14 to 20 Gy), and (5) only minor dose dependency is seen in the impairment of Leydig cell function after irradiation with doses between 14 and 20 Gy.
Supported by the Danish Cancer Society, Copenhagen, Denmark.
1. Skakkebæk NE: Possible carcinoma-in-situ of the testis. Lancet 2: 516-517, 1972[Medline] 2. Skakkebæk NE, Berthelsen JG, Giwercman A, et al: Carcinoma-in-situ of the testis: Possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int J Androl 10: 19-28, 1987[Medline] 3. Berthelsen JG, Skakkebæk NE, von der Maase H, et al: Screening for carcinoma in situ of the contralateral testis in patients with germinal testicular cancer. Br Med J 285: 1683-1686, 1982 4. von der Maase H, Rørth M, Walbom-Jørgensen S, et al: Carcinoma in situ of contralateral testis in patients with testicular germ cell cancer: Study of 27 cases in 500 patients. Br Med J 293: 1398-1401, 1986 5. Dieckmann K-P, Loy V: Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms. J Clin Oncol 14: 3121-3125, 1996[Abstract] 6. von der Maase H, Giwercman A, Skakkebæk NE: Radiation treatment of carcinoma-in-situ of testis. Lancet 1: 624-625, 1986
7.
Giwercman A, von der Maase H, Berthelsen JG, et al: Localized irradiation of testes with carcinoma in situ: Effects on Leydig cell function and eradication of malignant germ cells in 20 patients. J Clin Endocrinol Metab 73: 596-603, 1991 8. Forest MG: How should we perform the human chorionic gonadotrophin (hCG) stimulation test? Int J Androl 6: 1-4, 1983[Medline] 9. Illingworth PJ, Groome NP, Bryd W, et al: Inhibin-B: A likely candidate for the physiologically important form of inhibin in man. J Clin Endocrinol Metab 81: 1321-1325, 1996[Abstract] 10. Anawalt BD, Bebb RA, Matsumoto AM, et al: Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab 81: 3341-3345, 1996[Abstract] 11. Dieckmann K-P, Besserer A, Loy V: Low-dose radiation therapy for testicular intraepithelial neoplasia. J Cancer Res Clin Oncol 119: 355-359, 1993[CrossRef][Medline] 12. Dieckmann KP, Loy V: The value of the biopsy of the contralateral testis in patients with testicular germ cell cancer: The recent German experience. APMIS 106: 13-20, 1998[Medline] 13. Dotsch M, Brauers A, Buttner R, et al: Malignant germ cell tumor of the contralateral testis after radiotherapy for testicular intraepithelial neoplasia. J Urol 164: 452-453, 2000[CrossRef][Medline] 14. Rowley MJ, Leach DR, Warner GA, et al: Effect of graded doses of ionizing radiation on the human testis. Radiat Res 59: 665-678, 1974[CrossRef][Medline] 15. Sanders JE, Buckner CD, Leonard JM, et al: Late effects on gonadal function of cyclophosphamide, total-body irradiation, and marrow transplantation. Transplantation 36: 252-255, 1983[Medline]
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Sanders JE, Pritchard S, Mahoney P, et al: Growth and development following marrow transplantation for leukemia. Blood 68: 1129-1135, 1986
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Petersen PM, Giwercman A, Hansen SW, et al: Impaired testicular function in patients with carcinoma in situ of the testis. J Clin Oncol 17: 173-179, 1999 18. Petersen PM, Skakkebæk NE, Rørth M, et al: Semen quality and reproductive hormones before and after orchiectomy in men with testicular cancer. J Urol 161: 822-826, 1999[CrossRef][Medline]
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Shapiro E, Kinsella TJ, Makuch RW, et al: Effects of fractionated irradiation on endocrine aspects of testicular function. J Clin Oncol 3: 1232-1239, 1985
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Shalet SM, Tsatsoulis A, Whitehead E, et al: Vulnerability of the human Leydig cell to radiation damage is dependent upon age. J Endocrinol 120: 161-165, 1989 21. Vermeulen A: Environment, human reproduction, menopause and andropause. Environ Health Perspect 101: 91-100, 1993 (suppl 2)
22.
Harman SM, Metter EJ, Tobin JD, et al: Longitudinal effects of aging on serum total and free testosterone levels in healthy men: Baltimore longitudinal study of aging. J Clin Endocrinol Metab 86: 724-731, 2001 23. Fordham MVP, Mason MD, Blackmore C, et al: Management of the contralateral testis in patients with testicular germ cell cancer. Br J Urol 65: 290-293, 1990[Medline]
24.
Christensen TB, Daugaard G, Geertsen PF, et al: Effect of chemotherapy on carcinoma in situ of the testis. Ann Oncol 9: 657-660, 1998 Submitted March 14, 2001; accepted December 5, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
