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Originally published as JCO Early Release 10.1200/JCO.2006.10.2020 on May 21 2007 © 2007 American Society of Clinical Oncology. Gonadal Function in Males After Chemotherapy for Early-Stage Hodgkin's Lymphoma Treated in Four Subsequent Trials by the European Organisation for Research and Treatment of Cancer: EORTC Lymphoma Group and the Groupe d'Étude des Lymphomes de l'Adulte
From the Departments of Hematology and Gynecology, University Medical Centre Groningen, University of Groningen, Groningen; Department of Hematology, University Medical Centre Nijmegen, Nijmegen; Department of Radiotherapy, Leiden University Medical Centre, Leiden, the Netherlands; the Clinical Research Unit; Groupe Régional d'Etudes sur le Cancer (GRECAN 1772), University of Caen Basse-Normandie, Centre François Baclesse, Caen; Department of Hematology, Institut Bergonié, Bordeaux; the Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; and the Department of Oncology, UZ Gasthuisberg, Leuven, Belgium Address reprint requests to Hanneke C. Kluin-Nelemans, MD, PhD, Department of Hematology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB, PO Box 30.001, Groningen, the Netherlands; e-mail: j.c.kluin{at}int.umcg.nl
Purpose: To analyze fertility in male patients treated with various combinations of radiotherapy and chemotherapy, with or without alkylating agents, or with radiotherapy alone for Hodgkin's lymphoma. Patients and Methods: Follicle-stimulating hormone (FSH) levels were measured in patients with early-stage upper-diaphragmatic disease enrolled in four European Organisation for Research and Treatment of Cancer (EORTC) trials (H6-H9). Median follow-up after therapy was 32 months. Patients with FSH measurement at least 12 months after end of treatment (n = 355) were selected to assess post-treatment fertility. Patients with FSH measurement 0 to 9 months after therapy (n = 349) were selected to analyze fertility recovery; of these, patients with elevated FSH (> 10 U/L; n = 101) were followed until recovery. Factors predictive for therapy-related infertility were assessed by logistic regression. Results: The proportion of elevated FSH was 3% and 8% in patients treated with radiotherapy only or with nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD], epirubicin, bleomycin, vinblastine, prednisone [EBVP]); it was 60% (P < .001) after chemotherapy containing alkylating agents (mechlorethamine, vincristine, procarbazine, prednisone [MOPP], MOPP/doxorubicin, bleomycin, vinblastine [ABV], bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone [BEACOPP]). After a median time of 19 months, recovery of fertility occurred in 82% of patients treated without alkylating chemotherapy. This proportion was 30%, statistically (P < .001) lower in those treated with alkylating chemotherapy, and median time to recovery was 27 months. The post-treatment proportion of elevated FSH increased significantly (P < .001) with the dose of alkylating chemotherapy administered, and recovery was less frequent and slower after higher doses. Age more than 50 years and stage II disease also contributed to poor outcome. Conclusion: Fertility can be secured after nonalkylating chemotherapy for Hodgkin's lymphoma. In contrast, alkylating chemotherapy has a dismal effect, even after a limited number of cycles.
In Hodgkin's lymphoma (HL), the combination of high cure rates (80% to 90%) and increasing incidence in patients aged 20 to 44 years have led to a significant number of patients with a wish to start or complete a family after cure of HL.1-3 Male fertility after therapy for HL has been studied.4-6 However, most studies consisted of small series. The most informative results come from three publications in which a dose-dependent relationship between the number of cycles of MOPP (mechlorethamine, vincristine, procarbazine, prednisone) chemotherapy and toxicity was demonstrated.7-9 However, MOPP chemotherapy is no longer considered the best therapy for HL and has been replaced by newer regimens.10 Because most studies focused on MOPP-like chemotherapy regimens, pooling of data, larger series, and comparison with more recent and less toxic chemotherapy schedules is necessary. The European Organisation for Research and Treatment of Cancer (EORTC) had prospectively collected data on complications after treatment for HL since the start of the H6 trial in 1982. These data offered the opportunity for an analysis of male fertility after five combined chemoradiotherapy regimens applied between 1982 and 2004. Moreover, the size of the data set made possible analyses on the influence of various factors such as age, disease extension, presence of "B" symptoms, and treatment type on the preservation of gonadal function in males.
Patients A total of 2,362 male patients from 11 European countries were included in four consecutive randomized clinical trials between August 1982 and May 2004. Protocols and informed consent were submitted to and approved by local ethical committees. The studies were carried out in accordance with the Helsinki Declaration. Patients were aged 15 to 70 years and presented with histologically proven, previously untreated, classical, clinical stage I or II supradiaphragmatic HL with WHO performance status grade 0 to 2. Patients with concomitant or previous malignancies were excluded, as were patients with serious comorbidity, those with progressive disease during treatment, those who had received total nodal irradiation or more than one chemotherapy regimen, and patients for whom information about the treatment actually administered was missing. After exclusions, 2,064 male patients were suitable for analysis (Fig 1).
Study Design: Randomized H6-H9 Trials Patients in the H6 trial (1982-1988) received either mantle-field radiotherapy, mantle-field and para-aortic radiotherapy, 3x MOPP–mantle field radiotherapy–3x MOPP, or 3x ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)–mantle field radiotherapy–3x ABVD.11-14 Patients in the H7 trial (1988-1993) received either subtotal nodal irradiation (STNI) or six cycles of EBVP (epirubicin, bleomycin, vinblastine, prednisone) followed by involved-field radiotherapy (IF-RT) or six cycles of MOPP/ABV hybrid (mechlorethamine, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine) and IF-RT.15-17 The H8 trial (1993-1998) was a cooperative trial with the Groupe d'Étude des Lymphomes de l'Adulte (GELA). Patients received either STNI or three, four, or six cycles of MOPP/ABV hybrid and IF-RT or four cycles of MOPP/ABV and STNI.18 In the H9 trial (1998-2004), also in cooperation with the GELA, patients received either six cycles of EBVP with various doses of IF-RT or four to six cycles of ABVD and IF-RT or four cycles of BEACOPP baseline (cyclophosphamide, doxorubicin, vincristine, bleomycin, etoposide, procarbazine, prednisone) and IF-RT.19-22 Before start of treatment, data collected concerned patient characteristics, initial work-up for staging of the disease, and initial work-up for further evaluation of toxicity. After treatment, late toxicity measurements were performed at completion of initial treatment and at 1, 2, 3, and 5 years thereafter for the H6 trial; at completion of initial treatment and yearly thereafter for the H7 trial; and at completion of initial treatment, 2 and 5 years after completion of therapy, and every 5 years thereafter for the H8 and H9 trials. Additional toxicity evaluations could occur in particular during the first year after therapy. Late toxicity examinations for gonadal toxicity consisted of measurement of several hormonal parameters: follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. In a limited number of cases, a sperm-quality examination evaluating sperm count, motility, and morphology was also performed.
Analysis of Fertility FSH was considered elevated, and thus indicative of damage to fertility, at more than 10 U/L. Because data were issued from more than 60 laboratories from 11 countries within a time frame of more than 20 years, some safeguards were introduced. FSH values were dichotomized (normal/elevated): changes from one category to the other were checked blindly (without information on therapy) to state their significance. Small elevations crossing the upper level were ignored if the relative change was less than 20%. Dichotomized values were also evaluated in relation to normal FSH values for the laboratory (provided for 90% of the patients) and a conclusion made using the same approach. When no information on normal values was available, the relatively high (and safe) cutoff point of 10 U/L was used. Patients were selected provided that an FSH evaluation was available at least 1 year after the end of treatment. This selection enabled comparison with the results of published studies. An FSH evaluation before treatment was not available for all patients. To use these cases despite the lack of initial data, we first analyzed patients with pretreatment data and found elevated FSH levels in only 4% (11 of 294). Elevation ranged from 11.8 to 44 U/L with a median of 19.9 U/L (normal < 10 U/L). These cases were excluded from further analysis. Next, when analyzing the follow-up of these 11 patients, we observed that in all three patients who had received nonalkylating chemotherapy, FSH levels normalized after therapy, underlining the probable lack of clinical significance of pretreatment elevated FSH. Therefore, we argued that both the very low percentage of patients with spontaneously elevated FSH and its presumable lack of clinical impact justified that patients without pretreatment FSH levels were included. Consequently, all patients without FSH evaluation before treatment were also included in the study. Overall, 355 patients fulfilled those criteria (Fig 1, Selection A). In an attempt to study the change in FSH level with time after treatment, a second group was defined that included all patients with at least one FSH evaluation made during the 0- to 9-month period after treatment completion. The same assumption as above was applied to this group that consisted of 349 patients (Fig 1, Selection B). Of these, 203 had an FSH evaluation before treatment with a median value of 3.8 U/L (range, 0 to 10.1 U/L).
Statistical Analysis
Patient characteristics for all eligible patients (N = 2,064) and those included in the two selected groups (Selection A, n = 355; Selection B, n = 349) are listed in Table 1. Overall, 174 patients (33%) were selected in both groups for a total of 530 patients studied. Patients selected were more often issued from H7 and H8 trials in which toxicity evaluation was mandatory according to protocol. Age, clinical stage, and B-symptoms distributions were similar in the three groups. Treatments actually administered are indicated in Table 2. Radiotherapy alone was administered in one sixth of the patients, combined chemoradiotherapy without alkylating agents in one third, and a combination of radiotherapy and alkylating agents in more than one half.
Effect of Therapy on Fertility (Selection A) In this group, time between end of treatment and FSH evaluation ranged from 12 to 135 months, with a median of 32 months. According to treatment groups, median time was 30 months for patients treated with alkylating chemotherapy, 35 months for those treated with chemotherapy without alkylators, and 31 months for patients with radiotherapy only. FSH was elevated in 35% of patients (126 of 355). This proportion was 3% (two of 62; 95% CI, 0% to 11%) in patients who received radiotherapy only, 8% (eight of 101; 95% CI, 3% to 15%) in patients treated with chemotherapy without alkylators, and 60% (116 of 192; 95% CI, 53% to 67%) in patients treated with alkylating chemotherapy (P < .001). The proportion of patients with post-treatment elevated FSH was also influenced by age (P < .001), clinical stage (P = .012), and the presence of B symptoms (P = .003; Table 3).
The amount of alkylating agents administered was estimated using the number of cycles administered and expressed in MOPP equivalents, counting one cycle of MOPP/ABV or BEACOPP as 0.5 MOPP equivalents. Forty-three patients received 1.5 MOPP equivalents, 67 patients 2.0 or 2.5 MOPP equivalents and 82 patients three (n = 64) or six (n = 18) MOPP equivalents. The proportions of patients with post-treatment elevated FSH were 33% (95% CI, 19% to 49%), 60% (95% CI, 47% to 72%), 75% (95% CI, 63% to 85%), and 78% (95% CI, 52% to 94%), respectively (P < .001). According to the EORTC protocols, all patients older than 50 years were considered unfavorable and received alkylating chemotherapy and radiotherapy. Therefore, age might not be an independent risk factor. A stepwise logistic regression analysis was made in which age, B symptoms, clinical stage, and type of treatment were included as explanatory variables. Two analyses were made. In the first one, the treatment actually received was categorized as radiotherapy only, chemoradiotherapy not including alkylating agents, and chemoradiotherapy including alkylating agents. In the second analysis, the amount of MOPP equivalents was introduced in the regression model. The first model showed that age over 50 years (odds ratio [OR] = 3.66; 95% CI, 1.42 to 9.47; P = .007), stage II disease (OR = 2.32; 95% CI, 1.28 to 4.19; P = .005), and the administration of alkylating chemotherapy (OR = 22.59; 95% CI, 11.12 to 45.89; P < .001) were independent factors predicting for post-treatment elevated FSH. When the number of MOPP-equivalent cycles of alkylating chemotherapy was introduced in the model, age over 50 years (OR = 4.37; 95% CI, 1.83 to 10.46; P = .001), 2.0 or 2.5 MOPP equivalents (OR = 3.49; 95% CI, 1.93 to 6.30; P < .001) and three to six MOPP equivalents (OR = 10.85; 95% CI, 3.44 to 34.19; P < .001) remained statistically significant, supporting the assumption that age did have an independent influence on FSH values and chances of recovery.
Recovery of Fertility (Selection B) At first evaluation (median time, 3 months after end of treatment), 55% of patients (191 of 349) had elevated FSH. Recovery occurred in 42% (42 of 101) at a median time of 23 months (range, 10 to 67 months) after end of treatment (Fig 2). It was 24 months (range, 14 to 67 months) for patients treated with alkylating chemotherapy, 16 months (range, 10 to 39 months) for those treated with chemotherapy without alkylators, and 18 months (range, 10 to 34 months) for patients with radiotherapy only (P < .001). The cumulative probability of gonadal function recovery by treatment type is illustrated in Figure 3A, where a statistically significant (P < .001) trend was noticed. Besides treatment, no factors influenced recovery.
The influence of the amount of MOPP equivalents was also studied. Among the 79 patients treated with alkylating chemotherapy, 20 received 1.5 MOPP equivalents, 24 received two MOPP equivalents, 23 received three MOPP equivalents and 12 patients received six MOPP equivalents. The cumulative probability of gonadal function recovery by treatment intensity is illustrated in Figure 3B, in which patients (n = 22) treated without alkylators, as well as patients (n = 20) who received one or 1.5 MOPP equivalents and those (n = 59) who received two to six MOPP-equivalent cycles, were grouped. The three curves differed significantly (P < .001). No other factors were associated with recovery.
In a large cohort of patients with early-stage HL participating in the EORTC (H6-H7) and combined EORTC-GELA trials H8-H9 in whom FSH values were prospectively collected, we confirm that alkylating chemotherapy has a marked effect on male fertility. Persistent damage was found four times more often than with other treatments. Recovery, when occurring, also took longer. Besides treatment with alkylating agents, factors increasing susceptibility to treatment-related fertility damage were clinical stage II and age over 50 years at start of therapy. The number of cycles of alkylating chemotherapy had a large impact on the outcome of FSH when elevated after treatment in limiting the chances and speed of recovery. Our results are consistent with those of Viviani et al, Marmor and Duyck, and Specht et al, who mainly studied MOPP chemotherapy.24-26 Although the ABVD regimen—among others—was developed because of its fertility-sparing capacity (which we confirm hereby), the MOPP-ABV regimen and especially the newer BEACOPP regimen appear to represent a step back in this regard. Our data provide additional information on recovery of fertility and time before recovery. Using a subset of patients with FSH evaluations both during the 0 to 9 month period after treatment completion and later on, we show that immediately after alkylating chemotherapy, FSH was elevated in a large majority of patients, irrespectively of the number of MOPP-equivalent cycles administered. However, time to recovery, if any, was proportional to the number of cycles of alkylating chemotherapy. These results are consistent with data obtained by Da Cunha et al.7 Radiotherapy also has an influence on fertility.27 Patients included in this study have received either mantle-field irradiation, IF-RT (always supradiaphragmatic) or subtotal nodal irradiation, the latter extending to the level of the fourth lumbar vertebra. Scatter irradiation from subdiaphragmatic radiotherapy can possibly cause gonadal damage.4 However, scatter irradiation from the para-aortic fields is estimated to be around 1%.28 In our study, STNI had a small effect on FSH: Patients made a fast and complete recovery, and at a median time of 31 months after treatment, only 3% maintained an elevated FSH. These results are in agreement with those of Shapiro et al29 and Kinsella et al.30 Our results are based on a large group of patients with clinical stage I or II HL representative of those included in the last four trials conducted by the EORTC Lymphoma Group and the GELA. Furthermore, they concern data on recent chemotherapy schedules. They highlight the risk of infertility experienced by male patients treated with BEACOPP if this chemotherapy is preferred to ABVD as standard treatment. One can also hypothesize that with escalated BEACOPP, damage to fertility will be even higher. However, intensive chemotherapy regimens such as escalated BEACOPP could be the preferable treatment in patients with an unfavorable risk profile, such as patients with early positron emission tomography positivity or patients with three or more adverse factors.31 For them, the balance between avoidance of toxic therapy and the risk of relapse—inevitably followed by much more toxic salvage therapy—clearly points to the selection of the most effective initial therapy even if fertility cannot be spared. In this study, potential sources of bias can have occurred. Firstly, fertility could have been evaluated more often in patients at risk (ie, in those treated with alkylating chemotherapy). However, the proportions of patients included in this study were distributed equally among the various treatment groups (Table 1). Secondly, the number of post-treatment FSH evaluations and the time interval could have been larger in patients with earlier abnormal FSH values. Again, this is not the case because the occurrence and the number of evaluations appeared independent of pretreatment FSH values. In conclusion, we demonstrate in the largest series studied so far that male fertility can be secured after chemotherapy for HL if alkylating agents are excluded. Even if an elevated FSH is observed within the first months after the end of such chemotherapy, recovery is frequently seen. In contrast, full-dose alkylating chemotherapy is associated with dismal prognosis for the majority of patients. Even if only a limited number of cycles are administered, recovery is incomplete in many patients. Finally, age above 50 years and stage II disease contribute to a poor outcome as far as fertility and recovery are concerned.
The author(s) indicated no potential conflicts of interest.
Conception and design: Marleen A.E. van der Kaaij, John M.M. Raemaekers, Hanneke C. Kluin-Nelemans, Michel Henry-Amar Financial support: John M.M. Raemaekers, Hanneke C. Kluin-Nelemans, Michel Henry-Amar Administrative support: Hanneke C. Kluin-Nelemans, Michel Henry-Amar Provision of study materials or patients: John M.M. Raemaekers, Patrice Carde, Evert M. Noordijk, Christophe Fermé, José Thomas, Houchingue Eghbali, Hanneke C. Kluin-Nelemans, Michel Henry-Amar Collection and assembly of data: Marleen A.E. van der Kaaij, Nolwenn Le Stang, Michel Henry-Amar Data analysis and interpretation: Marleen A.E. van der Kaaij, Natacha Heutte, Arnold H.M. Simons, Hanneke C. Kluin-Nelemans, Michel Henry-Amar Manuscript writing: Marleen A.E. van der Kaaij, John M.M. Raemaekers, Arnold H.M. Simons, Houchingue Eghbali, Hanneke C. Kluin-Nelemans, Michel Henry-Amar Final approval of manuscript: Marleen A.E. van der Kaaij, Natacha Heutte, Nolwenn Le Stang, John M.M. Raemaekers, Arnold H.M. Simons, Patrice Carde, Evert M. Noordijk, Christophe Fermé, José Thomas, Houchingue Eghbali, Hanneke C. Kluin-Nelemans, Michel Henry-Amar
published online ahead of print at www.jco.org on May 21, 2007. Supported by research grants from the Lance Armstrong Foundation. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Sieber M, Rueffer U, Josting A, et al: Treatment of Hodgkin's disease: Current strategies of the German Hodgkin's Lymphoma Study Group. Ann Oncol 10:23-29, 1999 (suppl 6)[Medline] 2. Raemaekers J, Kluin-Nelemans H, Teodorovic I, et al: The achievements of the EORTC Lymphoma Group: European Organisation for Research and Treatment of Cancer. Eur J Cancer 38:S107-S113, 2002 (suppl 4)[Medline] 3. Chen YT, Zheng T, Chou MC, et al: The increase of Hodgkin's disease incidence among young adults: Experience in Connecticut, 1935-1992. Cancer 79:2209-2218, 1997[CrossRef][Medline] 4. Howell SJ, Shalet SM: Spermatogenesis after cancer treatment: Damage and recovery. J Natl Cancer Inst Monogr 12-17, 2005 5. Grigg A: The impact of conventional and high-dose therapy for lymphoma on fertility. Clin Lymphoma 5:84-88, 2004[Medline] 6. Blumenfeld Z, Dann E, Avivi I, et al: Fertility after treatment for Hodgkin's disease. Ann Oncol 13:138-147, 2002 (suppl 1)[Abstract] 7. da Cunha MF, Meistrich ML, Fuller LM, et al: Recovery of spermatogenesis after treatment for Hodgkin's disease: Limiting dose of MOPP chemotherapy. J Clin Oncol 2:571-577, 1984[Abstract] 8. Anselmo AP, Cartoni C, Bellantuono P, et al: Risk of infertility in patients with Hodgkin's disease treated with ABVD vs MOPP vs ABVD/MOPP. Haematologica 75:155-158, 1990[Medline] 9. Viviani S, Ragni G, Santoro A, et al: Testicular dysfunction in Hodgkin's disease before and after treatment. Eur J Cancer 27:1389-1392, 1991[Medline] 10. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478-1484, 1992[Abstract] 11. Carde P, Hagenbeek A, Hayat M, et al: Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: The H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 11:2258-2272, 1993 12. DeVita VT Jr, Serpick AA, Carbone PP: Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann Intern Med 73:881-895, 1970[Medline] 13. Bonadonna G, Zucali R, Monfardini S, et al: Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 36:252-259, 1975[CrossRef][Medline] 14. Santoro A, Bonfante V, Bonadonna G: Salvage chemotherapy with ABVD in MOPP-resistant Hodgkin's disease. Ann Intern Med 96:139-143, 1982[CrossRef][Medline] 15. Noordijk EM, Carde P, Dupouy N, et al: Combined modality therapy for all patients with clinical stage I-II Hodgkin's lymphoma. Long term results of the EORTC H7 randomized controlled trials (1988-1993). J Clin Oncol 24:3128-3135, 2006 16. Zittoun R, Eghbali H, Audebert A, et al: The combination of epirubicin, bleomycin, vinblastine and prednisone (EBVP) before radiotherapy in localized stages of Hodgkin's disease. Phase II trials [French]. Bull Cancer 74:151-157, 1987[Medline] 17. Klimo P, Connors JM: MOPP/ABV hybrid program: Combination chemotherapy based on early introduction of seven effective drugs for advanced Hodgkin's disease. J Clin Oncol 3:1174-1182, 1985 18. Ferme C, Eghbali H, Meerwaldt JH, et al: Combined Modality Treatment for Early Stages Hodgkin's Lymphoma Based on Prognostic Factors. Results of the EORTC-GELA H8 Trial. N Engl J Med (in press) 19. Noordijk EM, Thomas J, Ferme C, et al: First results of the EORTC-GELA H9 randomized trials: The H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stage Hodgkin's lymphoma (HL). J Clin Oncol 23:561s, 2005 (suppl; abstr 6505) 20. Ferme C, Divine M, Vranovsky A, et al: Four ABVD and involved-field radiotherapy in unfavorable supradiaphragmatic clinical stages (CS) I-II Hodgkin's lymphoma (HL): Preliminary results of the EORTC-GELA H9-U trial. Proc Am Soc Hematol 106:813, 2005 (abstr) 21. Eghbali H, Brice P, Creemers GY, et al: Comparison of three radiation dose levels after EBVP regimen in favorable supradiaphragmatic clinical stages (CS) I-II Hodgkin's lymphoma (HL): Preliminary results of the EORTC-GELA H9-F trial. Proc Am Soc Hematol 106:814, 2005 (abstr) 22. Diehl V, Sieber M, Ruffer U, et al: BEACOPP: An intensified chemotherapy regimen in advanced Hodgkin's disease: The German Hodgkin's Lymphoma Study Group. Ann Oncol 8:143-148, 1997 23. Rothman K, Boice J: Epidemiologic Analysis With a Programmable Calculator. Boston, MA, Epidemiology Resources Inc, 1982 24. Viviani S, Santoro A, Ragni G, et al: Gonadal toxicity after combination chemotherapy for Hodgkin's disease: Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 21:601-605, 1985[CrossRef][Medline] 25. Marmor D, Duyck F: Male reproductive potential after MOPP therapy for Hodgkin's disease: A long-term survey. Andrologia 27:99-106, 1995[Medline] 26. Specht L, Geisler C, Hansen MM, et al: Testicular function in young men in long-term remission after treatment for the early stages of Hodgkin's disease. Scand J Haematol 33:356-362, 1984[Medline] 27. 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] 28. Fraass BA, van de Geÿn J: Peripheral dose from megavolt beams. Med Phys 10:809-818, 1983[CrossRef][Medline] 29. Shapiro E, Kinsella TJ, Makuch RW, et al: Effects of fractionated irradiation of endocrine aspects of testicular function. J Clin Oncol 3:1232-1239, 1985 30. Kinsella TJ, Trivette G, Rowland J, et al: Long-term follow-up of testicular function following radiation therapy for early-stage Hodgkin's disease. J Clin Oncol 7:718-724, 1989[Abstract] 31. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin's disease: International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 339:1506-1514, 1998 Submitted December 1, 2006; accepted April 4, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50), stage (I v II), and systemic (B) symptoms (absent v present). Probability of fertility recovery was estimated according to the Kaplan-Meier method, and the rates between groups were compared with use of the log-rank test. Ninety-five percent CI for the rates were estimated using the method of Rothman and Boice.
