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Fertility after testicular cancer treatments
Results of a large multicenter study
Article first published online: 9 JAN 2004
Copyright © 2004 American Cancer Society
Volume 100, Issue 4, pages 732–737, 15 February 2004
How to Cite
Huyghe, E., Matsuda, T., Daudin, M., Chevreau, C., Bachaud, J.-M., Plante, P., Bujan, L. and Thonneau, P. (2004), Fertility after testicular cancer treatments. Cancer, 100: 732–737. doi: 10.1002/cncr.11950
- Issue published online: 3 FEB 2004
- Article first published online: 9 JAN 2004
- Manuscript Revised: 6 NOV 2003
- Manuscript Accepted: 6 NOV 2003
- Manuscript Received: 9 JUL 2003
- French National Institute of Health and Medical Research
- Fondation pour la Recherche Medicale
- CECOS Midi-Pyrénées
- testicular cancer;
Patients with testicular cancer have an excellent survival rate, and fertility is one of the main concerns of survivors. The authors investigated fertility status after treatment for testis cancer in long-term survivors.
Four hundred fifty-one consecutive patients with testicular cancer (1979–1999) from health facilities in the French Midi-Pyrenees region were enrolled. Testis tumors were classified according to the Royal Marsden Hospital Classification. Fertility status was assessed by means of a mailed, standardized questionnaire focused on reproductive events that occurred before and after treatment. Of 451 patients with germ-cell tumors, information concerning fertility was obtained in 446 patients (98.9%). The follow-up was at least 3 years.
Before they were diagnosed with testicular cancer, 91.2% of patients who had tried to get their partners pregnant had succeeded, compared with 67.1% of patients after treatment. Radiotherapy had a much more deleterious effect on fertility compared with chemotherapy alone. Furthermore, cumulative conception rates (log-rank test) for patients who received radiotherapy were significantly lower compared with the rates for patients who received chemotherapy.
The outcome of this study, which included the largest series reported to date, showed that fertility in patients with testicular cancer decreased by 30% after treatments and that radiotherapy seemed to have the most deleterious effect on fertility. Cancer 2004;100:732–7. © 2004 American Cancer Society.
Testicular cancer (TC) is the most common malignancy in men ages 20–34 years, and several recent publications have reported a major increase in the incidence of TC in industrialized countries in recent decades.1 Patients with TC now have an excellent survival rate due to recent advances in chemotherapy and radiotherapy treatments.2 These young patients often have not yet attempted to father children, and fertility is certainly one of the main concerns of survivors.
Conflicting results have been published concerning fertility in long-term survivors of TC.3 Arai et al. analyzed the impact of TC treatment on fertility in 85 Japanese patients and observed that infertility was one of the major persistent side effects after treatment.4 Similarly, Hansen et al. noted that infertility remained a problem 5 years after the end of treatment in 53% of 177 Danish patients with unilateral testicular germ cell tumors.5
Nevertheless, other authors have reported no significant deleterious effect on fertility after TC treatment. In a follow-up study of 104 patients with clinical Stage I nonseminomatous germ cell tumors (NSGCT) performed in the U.S., Herr et al. found that a majority of patients achieved a successful pregnancy with their partners.6 Böhlen et al. observed that two cycles of cisplatin-based, adjuvant chemotherapy did not affect fertility adversely in patients with Stage I NSGCT.7 We investigated fertility status after treatment for TC by conducting a large, retrospective study in consecutive patients diagnosed with TC.
MATERIALS AND METHODS
In 1999, we enrolled 488 consecutive patients with testicular tumors who registered from 1979 to 1999 at health facilities of the French Midi-Pyrenees region (all private and public urologic units and the single regional reference oncology facility, the Claudius Regaud Institute). Of the 488 patients, we excluded 17 patients who had a diagnosis of testicular lymphoma, 17 patients who had Leydig cell tumors, 1 patient who had a Sertoli cell tumor, and 2 patients for whom histologic type or treatment was not recorded.
All 451 germ cell tumors that were included were classified according to the Royal Marsden Hospital Classification. Distribution of the tumors by tumor type, disease stage (Royal Marsden Hospital Staging System), and treatment is summarized in Table 1. Two homogeneous treatment groups were defined.
|Tumor type||Orchiectomy and surveillance or retroperitoneal lymph node dissection (n = 21 patients)||Orchiectomy and cisplatin-based chemotherapy (n = 143 patients)||Orchiectomy and radiotherapy (n = 171 patients)||Orchiectomy and chemotherapy with or without radiotherapy or surgical resection of residual retroperitoneal tumor masses (n = 116 patients)|
|Seminoma (n = 216 patients)|
|Stage I, IIA, IIB||1||—||171b||—|
|Stage IIC and III||—||18||—||26|
|NSGCT (n = 235 patients)|
|Stage I, IIA, IIB||20||125c||—||—|
|Stage IIC, III||—||—||—||90|
Group 1 (n = 125 patients) included patients with Stage I, Stage IIA, and Stage IIB NSGCT who underwent inguinal orchiectomy and received cisplatin-based, standard chemotherapy regimens. Twenty-three patients received cisplatin, vinblastine, and prednisone (3 or 4 cycles); 91 patients received bleomycin, etoposide, and cisplatin (2–4 cycles); 11 patients received etoposide and cisplatin (3 or 4 cycles).
Group 2 (n = 171 patients) included patients with Stage I, Stage IIA, and Stage IIB seminoma who underwent inguinal orchiectomy and received subdiaphragmatic radiotherapy, which was comprised of paraaortic and ipsilateral iliac irradiation with 25–35 grays (Gy) (median, 28 Gy), with a median daily fractionation of 0.2 Gy. Before 1988, radiotherapy was administered using a cobaltotherapy unit and, after 1988, a 25-megaelectron volt linear accelerator was used. In all patients, testicular shielding was used.
We assessed fertility status by means of a questionnaire (Table 2). To obtain a high response rate, we used a limited number of clear, simple questions. The items focused on all reproductive events (number of children, pregnancies achieved naturally or through in vitro fertilization methods) that occurred before and after treatment. We also included specific questions concerning the time required by the couple to achieve conception (i.e., the time between the end of contraceptive use and the beginning of pregnancy [time to pregnancy (TTP)]).8 First, we pretested the questionnaire for 1 month. Analysis showed that all items were understood well; and, after minor changes, we printed the final version of the questionnaire, which was mailed with a cover letter to all 451 patients.
|The global aim of the study was presented briefly, with an explanation of how to fill out the questions and where to return the questionnaire. A telephone number (a direct, confidential line) with names of the scientists in charge of the study also was provided.|
|The questionnaire comprised several clearly identified sections relating to various domains: reproductive events, sociodemographic characteristics, progress of main treatments, cryopreservation, and other main issues after treatment.|
|The Reproductive Events section was divided into two parts, with questions formulated in the same way: Section 1 included reproductive events hat occurred before the start of treatments for testicular cancer, and Section 2 included reproductive events that occurred after the start of treatments for testicular cancer.|
|Have you ever tried to have children?|
|If not (I never tried to have children), can you give the main reasons why?|
|I was living alone without a partner|
|I personally did not want to have a child|
|My wife did not want to have a child|
|If yes (I tried to have children), did you succeed?|
|No, I did not succeed|
|If you did not succeed in having a child, for how many months did you try?|
|If you did not succeed in having a child, did your wife have a miscarriage?|
|If you did not succeed in having a child, did you use in vitro fertilization techniques, sperm donors, or any other treatments (please specify)?|
|Yes, I did succeed|
|If you did succeed, how many children do you have?|
|Would you please indicate for each child:|
|The date of the beginning of pregnancy and the date of delivery|
|Whether pregnancy occurred naturally or through in vitro fertilization techniques (please specify)|
|How many months your wife had taken to start the pregnancy, i.e., the time from the moment you decided to have a child and the beginning of pregnancy|
|If your wife stopped using contraception to have the child, indicate which contraceptive method was used and the date when it was discontinued|
Finally, after checking patients' addresses carefully and sending 2 follow-up letters to patients who did not respond, we obtained the participation of 446 of 451 patients (98.9%) for the study of fertility status before and after they were treated for TC.
We used STATA® software (Stata Corp., Tulsa, OK) with a significance level of 0.05. The chi-square test was used for comparison of subgroups. Univariate and multivariate regression analyses were performed to compare various infertility risk factors (estimated odds ratio values are given with 95% confidence limits). In couples for whom TTP data were available, Kaplan–Meier estimates were used to calculate the cumulative probability of conception, and comparisons were performed by the log-rank test.
Age distribution of the 451 participating patients was bimodal, with a median age of 27 years (range, 14–64 years) in patients with NSGCT and 34 years (range, 15–73 years) in patients with seminoma. Fifty-six patients (12.4%) reported a history of cryptorchidism.
Histologic Types, Treatment, and Survival
Seminoma accounted for 48% of tumors (n = 216 patients) and NSGCT accounted for 52% of tumors (n = 235 patients), including 4.4% teratomas, 30.9% embryonic cancers, 2.4% choriocancers, 1.6% yolk sac tumors, and 60.7% mixed tumors. Table 1 provides a breakdown of the various treatments according to histologic type.
Sixty-two patients developed recurrent disease. We recorded 35 deaths that were linked to TC, for an overall TC mortality rate of 7.8%, with a mean follow-up of 101 months (range, 36–318 months).
Before they were diagnosed with TC, 228 patients had attempted to achieve pregnancy with their partners, and 208 patients (91.2%) had succeeded. After they were treated for TC, 164 men attempted to achieve pregnancy with their partners, and 110 succeeded (Fig. 1).
The mean time between the end of TC treatment and the birth of the first child was 4.8 years (± 3.0 years). Of 55 patients who attempted unsuccessfully to achieve pregnancy with their partners, 7 fathered a child using their cryopreserved semen.
In the 164 patients who attempted to achieve pregnancy with their partners after treatments for TC, we performed a logistic regression analysis to assess various infertility risk factors. We found that a history of cryptorchidism was a significant infertility risk factor. Furthermore, we observed that radiotherapy had much more deleterious effects on fertility compared with chemotherapy (Table 3).
|History/treatment||Fecundability ratio (95% CI)||P value|
|No history of cryptorchidism||1.00||—|
|History of cryptorchidism||0.17 (0.044–0.627)||0.008|
|Chemotherapy (Group 1)||1.00||—|
|Radiotherapy (Group 2)||0.35 (0.146–0.825)||0.017|
We were able to calculate the TTP for 73.6% of patients who attempted to achieve pregnancy with their partners. The cumulative conception rates for patients who were treated with radiotherapy were significantly lower compared with the rates for patients who were treated with chemotherapy (log-rank test), confirming the more deleterious effect of radiotherapy compared with chemotherapy (Fig. 2)
The major finding of the current study was the low fertility rate observed for couples in which the male partner was treated for TC: Only two-thirds of couples who attempted a pregnancy after treatment for TC were successful. The results of the current study are similar to those obtained by Fossä and Kravdal in a population-based study (using the Norwegian Cancer Registry, the Norwegian Population Register, and the Population Census), in which fertility rates in patients with TC were approximately 30% lower compared with the rates in the normal population.9 Similar trends have also been observed in clinical studies. In Germany, Hartmann et al. evaluated the fertility of 98 patients with germ cell tumors (80% with NSGCT) between 1970–1993. Twenty-one of 40 patients (53%) in that study who expressed a desire to father children achieved this goal in a median of 54 months (range, 3–108 months). The lowest fertility rate was observed among patients who were treated with chemotherapy followed by secondary resection of residual retroperitoneal tumor masses, which we also observed in our sample.10 In Switzerland, Böhlen et al. reported a fertility rate of 69% after chemotherapy in 49 patients with Stage I NSGCT and no risk factor, with a follow-up of at least 32 months.7 In the U.S. (Memorial Sloan-Kettering Cancer Center, New York, NY), Herr et al. studied long-term paternity in men who were diagnosed with Stage I NSGCT who underwent orchiectomy alone. Forty one of 63 patients (65%) who attempted to achieve pregnancy with their partners succeeded, most within the first 5 years.6
Nevertheless, other authors have reported infertility rates after treatment for TC that were lower than the rates reported here (67%). In Denmark, Hansen et al. studied the paternity of patients with a diagnosis of unilateral testicular germ cell tumor from 1977 to 1986. Forty-one of 158 patients in that study attempted to father children, and only 16 patients (39%) succeeded. Those results must be balanced by the finding that 47% of patients would have fathered children within 5 years of the end of treatment (according to Kaplan–Meier estimates).5 In Japan, Arai et al. assessed fertility in 85 long-term survivors of TC. Very low fertility rates were observed in patients who were treated with chemotherapy and underwent retroperitoneal lymph node dissection (2 of 19 patients) and in patients who were treated with radiotherapy (4 of 42 patients). The highest fertility rate was recorded for four of nine patients who underwent orchiectomy and surveillance. Unfortunately, the follow-up for those patients ranged from 1–22 years, and the number of patients who suffered from erectile dysfunction was high (25% of the sample).4
The differences between these studies may be accounted for largely by 1) the inclusion of patients with testicular tumors at different histologic stages and receiving a wide range of treatments, 2) by the frequent lack of information regarding the number of patients who attempted unsuccessfully to achieve pregnancy with their partners, and 3) by the vast diversity of methods used to obtain information concerning the fertility of the couple (face-to-face interview, telephone interview, self-reported questionnaire). The current study, we were able, for what to our knowledge is the first time, to record and analyze the TTP in a population of men who were treated for TC. Logistic regression analysis and cumulative conception rates indicate that a decrease in fertility after TC may be attributed largely to treatment-induced damage to the gonads, especially after radiotherapy (Fig. 2) (Table 3). It is well known that the testis is one of the most radiosensitive tissues and that low doses of irradiation may have deleterious effects on testis function in healthy men.11–13 Several studies have confirmed that subdiaphragmatic irradiation may cause profound, dose dependent impairment of spermatogenesis due to radiation reaching the testis.14, 15 In 1981, at Mount Sinai Hospital in New York, Hahn et al. found that sperm production recovered within 30–80 weeks of radiation therapy (0.32 Gy).15 Centola et al. found that no recovery of spermatogenesis was observed in patients who received radiation doses of 1.4–2.6 Gy (this dose represents a threshold for permanent testicular damage) but that partial recovery could occur with lower doses of radiation.16 Meistrich pointed out that the timing of recovery of sperm production and fertility may depend on the extent of stem cell (spermatogonium) killing and on the total dose of radiation received by the testis.17
With regard to chemotherapy for patients with TC, several authors have stressed that this treatment may impair subsequent fertility, with transitory, reversible, and dose dependent effects.18–20 However, Böhlen et al. recently concluded that chemotherapy did not seem to have an adverse effect on fertility in an analysis of 59 patients who were treated with 2 cycles of cisplatin-based, adjuvant chemotherapy (for Stage I NSGCT).7
This study was not a regional, population-based study; thus, we cannot exclude the possibility that some patients with a diagnosis of TC between 1979 and 1999 were not included in the current study sample. Nevertheless, the participation of all of the urologic units and of the only reference oncologic institute in the Midi-Pyrenees region, together with the very high response rate to the questionnaire inquiry (98.9%), certainly limited this possibility. The use of a simple questionnaire that was easy to fill out may explain the very high rate of patient participation, even by patients with disease that dated back more than 15 years. Furthermore, reminders through two follow-up letters enabled us to recontact some undecided patients. Table 2 presents the main items that were included in our questionnaire.
Another potential limitation was the small number of patients in each of the various treatment categories, which limited the impact of our results for some patients. Although the current study included what to our knowledge is the largest number of individuals ever followed for fertility after TC treatment, the group of patients who underwent orchiectomy as their only treatment (without chemotherapy or radiotherapy) was too small to constitute an appropriate reference group (21 patients, only 4 of whom had attempted to achieve pregnancy with their partners). Similarly, regression analysis could not be used in patients who developed recurrent disease and who received very different complementary treatments (intensive chemotherapy, radiotherapy, or both), limiting comparisons with radiotherapy versus chemotherapy. Because our objective is to assess treatment impact on the whole population of patients with TC, currently, we are extending our study to national and European levels.
The current study of what to our knowledge is the largest series published to date reported a high response rate (98.9%) and showed that the fertility rate in patients with TC decreased by roughly 30% after treatment and that radiotherapy appeared to have the most deleterious effects on fertility. Consequently, and to preserve future fertility, semen cryopreservation and sperm banking before treatment must be recommended strongly for men who are diagnosed with TC.21
- 1Cancer incidence in five continents. Edition 143, Vol VII. Lyon: IARC Scientific Publications, 1997., , , , .