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Sperm count in Swedish clinical stage I testicular cancer patients following adjuvant treatment
Annals of Oncology 0: 1–8, 2019 doi:10.1093/annonc/mdz017
ORIGINAL ARTICLE
K. Weibring1,2*, C. Nord1,2, O. Sta˚hl3, J. Eberhard3, K. Sandberg1,2, H. Johansson1,2, S. Arver4,5, A. Giwercman6 & G. Cohn-Cedermark1,2 1 Department of Oncology-Pathology, Karolinska Institute, Stockholm; 2Department of Oncology, Karolinska University Hospital, Stockholm; 3Department of Oncology, Skane University Hospital, Lund; 4Department of Medicine/Huddinge, Karolinska Institute, Stockholm; 5Centre for Andrology and Sexual Medicine, Karolinska University Hospital, Stockholm; 6Department of Translational Medicine, Lund University, Malmo, Sweden
*Correspondence to: Dr Kristina Weibring, Tema Cancer, PO BES, A2:00, Karolinska University Hospital, 171 76 Stockholm, Sweden. Tel: þ 46-70-6050533; E-mail: [email protected]
Background: Little is known regarding sperm production following adjuvant treatment in testicular cancer (TC) clinical stage I (CS I) patients. Patients and methods: A total of 182 TC patients aged 18–50 years were prospectively included during 2001–2006 at any given time within 5 years of orchiectomy. Semen samples were delivered postorchiectomy but before further treatment, 6, 12, 24, 36 and 60 months (T0–T60) after completed therapy. Total sperm number (TSN) and sperm concentration (SC) were used as measurements of testicular function. Four groups according to treatment modality were identified; Radiotherapy; To a total dose of 25.2 Gy to the infradiaphragmal paraaortic and ipsilateral iliac lymph nodes (RT, N ¼ 70), one cycle of adjuvant BEP (bleomycin, etoposide, cisplatin, 5 day regimen) (BEP, N ¼ 62), one cycle of adjuvant carboplatin AUC 7 (Carbo, N ¼ 22), and patients managed by surveillance (SURV, N ¼ 28). Results: In the cross-sectional analysis, a significant but transient drop in mean TSN and mean SC (T0–T60) was seen at T6 after radiotherapy. Apart from a significant increase in mean SC at T12 compared with baseline, no significant differences were observed in the other treatment groups. In 119 patients delivering 3 or more samples, values in TSN and SC were rather stable over time. Azoospermic patients (N ¼ 11) were observed in most treatment groups except for in the BEP group. During followup, one azoospermic patient belonging to the Carbo group became normospermic. Conclusions: No clinically significant long-term effect on TSN or SC associated with adjuvant treatment in TC CSI patients was found. However, as patients may have low sperm counts before orchiectomy as well as after adjuvant treatment, we offer sperm banking before orchiectomy as assisted reproductive measures may be necessary regardless of treatment given. Key words: adjuvant treatment, sperm concentration, total sperm number, chemotherapy, testicular cancer
Introduction Testicular germ cell cancer (TC) is the most common cancer among young men, aged 15–40 years, with the highest incidence in white men in northern Europe [1–3]. There are two subgroups of TC, seminoma and non-seminoma [4]. Since the introduction of platinum-based combination chemotherapy in the 1970s, and due to the use of multimodality treatment, the overall survival rate is high, with more than 95% of the patients being cured [1, 5, 6]. As the incidence is still increasing in many countries [7–9] and the survival rates are high, efforts are made in order to reduce
long-term side-effects, by minimizing therapy without compromising outcome. This applies both for testicular cancer (TC) CS I patients as well as for patients with disseminated disease. After diagnosis, all TC patients undergo a unilateral orchiectomy of the tumorous testicle. Depending on tumor characteristics further treatment with adjuvant chemotherapy or irradiation could be added [4]. A well-known problem for men diagnosed with TC is impaired spermatogenesis. Testicular dysgenesis syndrome [10] may be a reason as well as local and systemic effects of the cancer, although the mechanisms are not totally clarified [11–13]. Cancer
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Sperm count in Swedish clinical stage I testicular cancer patients following adjuvant treatment
Original article
Patients and methods Population and study design A total of 459 TC patients, all tumor stages, age 18–50 years from the Department of Oncology, Skane University Hospital, Lund, and the Department of Oncology, Karolinska University Hospital, Stockholm were invited to participate in this study on testicular function. The inclusion periods were 2001–2006 (Lund) and 2003–2006 (Stockholm) at any given time point within 5 years postorchiectomy, which means a diagnosis at the earliest in 1996 in Lund and a diagnosis at the earliest in 1998 in Stockholm. All patients gave written informed consent and the study protocol was approved by the Ethical Review Boards of Lund University and the Karolinska Institute, Stockholm. Patients who moved, withdrew or relapsed during ongoing study, were included until that date. Out of 459 eligible patients, 75 patients declined and 58 patients were excluded due to mental co-morbidity, linguistic difficulties, physical disability or bilateral TC. Among the remaining 326 patients, 7 patients declined at a later time point and 137 patients did not fulfill the criteria for the cohort of interest due to metastatic disease, carcinoma in situ (CIS) in the contra lateral testicle, treatment with two or more cycles of chemotherapy, other chemotherapy than BEP or Carbo, development of CIS during ongoing followup, testosterone substitution before inclusion or before the first sperm sample was delivered, and patients having had a vasectomy carried out before treatment. This report includes the 182 of the 459 patients who fulfilled the following inclusion criteria; TC CS I, adjuvant treatment with radiotherapy 1.8 Gy 14 to a total dose of 25.2 Gy to the infradiaphragmal paraaortic and ipsilateral iliac lymph nodes (RT, N ¼ 70), one cycle of BEP (bleomycin, etoposide, cisplatin, 5-day regimen, N ¼ 62), one cycle of carboplatin AUC 7 (Carbo, N ¼ 22) or managed by surveillance (SURV, N ¼ 28). The patients were divided into four groups according to treatment modality. Semen samples were delivered at given time points; postorchiectomy but before further treatment (T0), 6 months (T6), 1 year (T12), 2 years (T24), 3 years (T36) and 5 years (T60) after completion of treatment. At least one sperm sample had to be delivered at any given time interval (T0– T60). Total number of delivered sperm samples per patient was dependent on at which time point after completed treatment the patient was
2 | Weibring et al.
recruited to the study, and how many sperm samples the patient chose to deliver. Preorchiectomy semen samples were too few to retrieve any statistics from, N ¼ 9 (5%) in the whole cohort. One hundred and five (58%) patients had seminoma and 77 (42%) patients had non-seminoma, with a median age of 34 and 28 years, respectively. Non-seminoma patients are generally younger (25–40 years of age) than seminoma patients (30–45 years of age) at time of diagnosis [23]. Nine (9%) of the seminoma patients and 13 (17%) of the nonseminoma patients were smokers at inclusion (Table 1). In accordance with the World Health Organization (WHO) laboratory manual for examination and processing of human semen, fifth edition, 2010, we focused on TSN and SC as measurements of testicular function [24]. Data from this study have partly been reported before [25, 26], but the cohort was smaller and included all TC stages, and therefore the results were less valid with regard to the specific subgroup of interest.
Adjuvant TC treatment The adjuvant treatment was according to the SWENOTECA (Swedish and Norwegian Testicular Cancer Group) treatment protocols for seminoma and non-seminoma, respectively, in use during the time frame of the study [4].
Seminoma. During 2000 and 2004, CS I seminoma patients could choose between surveillance or adjuvant radiotherapy with 1.8 Gy 14 to a total dose of 25.2 Gy to the infradiaphragmal paraaortic and ipsilateral iliac lymph nodes. As results emerged from a randomized study in 2005, between radiotherapy and carboplatin, the recommendations changed in favor of carboplatin [27]. From 2006 and onward adjuvant treatment was recommended on the basis of emerging data related to risk of relapse. Risk factors for relapse in seminoma are tumor size >4 cm and invasion in the stromal rete testis [27, 28]. Patients with 0–1 risk factors were offered SURV but could also choose one course of adjuvant Carbo, whereas patients with two risk factors were recommended one course of adjuvant Carbo. Adjuvant RT is no longer used as standard treatment in Sweden, mainly due to the elevated risk of secondary malignancies [29]. Non-seminoma. The dominating risk factor for relapse for CS I nonseminoma patients is vascular invasion of tumor cells [30, 31]. Patients without vascular invasion could choose either SURV or one or two courses of adjuvant BEP (bleomycin 30 000 IU days 1, 5 and 15 to a maximum dose of 3 105 IU, etoposide 100 mg/m2 days 1–5, cisplatin 20 mg/ m2 per cycle days 1–5, given every third week). This study only included patients treated with one course of BEP since this is the currently recommended adjuvant treatment of CS I non-seminoma [4, 32].
Semen samples Fresh semen samples were delivered after a recommendation of 3 days of sexual abstinence. All sperm analyses from patients recruited in Lund were carried out at the Reproductive Medicine Centre (RMC), Skane University Hospital, Malmo, except 12 T0 ejaculates analyzed at the fertility laboratory, Lund University Hospital. For patients recruited in Stockholm, all sperm samples were analyzed at the Centre for Andrology and Sexual Medicine, Karolinska University Hospital, Stockholm. The laboratories in Malmo and Stockholm served as reference laboratories for the European Society of Human Reproduction and Embryology/Nordic Association for Andrology external quality control program. Lower reference values for these parameters are TSN >39 106 spermatozoa/ejaculate and SC >15106 spermatozoa/ml ejaculate. To assess TSN, the ejaculate volume had to be multiplied with the SC. Sperm samples were then classified depending on normal or pathological levels of spermatozoa in the ejaculate, i.e. normozoopermia (TSN or SC equal to or above lower reference limits), oligozoospermia (TSN or SC below
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treatment as well as orchiectomy also have negative impact on the reproductive function [13–15]. Previous studies have shown that infertile men are at higher risk of developing TC [16]. In recent years, there has been discussions on whether to treat in the adjuvant situation or to wait until relapse occurs [17, 18]. Those advocating against adjuvant treatment claim that little is known about long-term side-effects from adjuvant treatment, and that there is risk for overtreatment [18]. The negative effect of multiple cycles of chemotherapy has been studied and there is clear evidence of a dose response relationship with regard to several long-term side-effects [19, 20] and the detrimental effect on sperm recovery by multiple courses of chemotherapy is well known [21, 22]. Less is known about the effect on sperm recovery after adjuvant treatment in CS I disease. The aim of this prospective follow-up study was to describe testicular function described as total sperm number (TSN) and sperm concentration (SC) in a large cohort of TC CS I patients treated with adjuvant treatment such as one course of bleomycin, etoposide, cisplatin (BEP), one course of carboplatin (Carbo), radiotherapy to a total dose of 25.2 Gy (RT) or patients managed by surveillance, i.e. no further treatment after orchiectomy (SURV).
Annals of Oncology
Original article
Annals of Oncology Table 1. Patients’ characteristics BEP31
Carbo31
RT
Total
28 28 (19–42)
62 29.5 (15–49)
22 32.5 (26–46)
70 35 (20–48)
182 32 (15–49)
5 (18) 9 (32) 14 (50)
10 (16) 29 (47) 23 (37)
1 (5) 20 (91) 1 (5)
6 (9) 33 (47) 31 (44)
22 (12) 91 (50) 69 (38)
13 (46) 15 (54)
0 62 (100)
22 (100) 0
70 (100) 0
105 (58) 77 (42)
lower reference limit but above 0 spermatozoa) or azoospermia (no spermatozoa in the ejaculate) [24].
Abstinence time. One hundred and sixteen (64%) patients had an abstinence time of 3 days. The median abstinence time range in the different treatment groups were 2.5–5 days in the SURV group, 3–3.5 days in the Carbo group, 2–4 days in the RT group and 3 days in the BEP group (supplementary Table S1, available at Annals of Oncology online). Statistical methods. A paired t-test was used to test for changes within the treatment groups over time. Linear regression was used to estimate and test differences between the groups at 12 months. All results are presented as mean differences together with 95% confidence intervals. Age was adjusted for by including age as a continuous variable in the regression models. The significance level was set to 5%. Due to the exploratory nature of the analyses adjustment for multiple comparisons were not made.
Results A total of 119 (65%) patients in all treatment groups delivered sperm samples at three or more time points: SURV; N ¼ 17 (61%), Carbo; N ¼ 19 (86%), BEP; N ¼ 49 (79%) and RT; N ¼ 34 (49%). Both longitudinal and cross-sectional data were studied. The SURV group consists of both seminoma and non-seminoma patients. We found no significant difference in SC and TSN between the two groups at any time point over 5 years.
Mean TSN and mean SC Cross-sectional and longitudinal analysis of mean TSN and mean SC showed an increase over time (T0–T60) in all groups except the RT group where a distinct decrease in both mean TSN and mean SC at 6 months post-treatment compared with the other treatment groups was seen. However, after T6 both mean TSN and mean SC recovered and increased in the RT group. The Carbo group showed a decline in mean TSN and mean SC at T60 (Figures 1 and 2).
Within group comparison at baseline and at 12 months post-treatment; mean TSN and mean SC Mean TSN. No significant changes were seen at 12 months posttreatment compared with baseline. However, an increase, close to the level of statistical significance (P ¼ 0.065, P ¼ 0.057, P ¼ 0.059) in the SURV, BEP and Carbo treatment groups was
seen. In the RT group a nonsignificant (P ¼ 0.62) decrease was noted (Table 2).
Mean SC. There was a significant increase in the SURV, BEP and Carbo treatment groups (P ¼ 0.016, P ¼ 0.02 and P ¼ 0.04) at 12 months post-treatment compared with baseline. In the RT group, there was a nonsignificant decrease (P ¼ 0.19) (Table 2).
Between group comparison at 12 months; mean TSN and mean SC There were no significant differences between the treatment groups BEP, Carbo or RT overall, in mean TSN or mean SC at 12 months compared with the SURV group (P ¼ 0.11 and P ¼ 0.28). However, a significant decrease in mean SC between the RT group alone compared with the SURV group was seen (Table 2).
Sperm number category No clinically significant difference was detected between the sperm samples delivered postorchiectomy and those delivered 6 and 12 months after completed treatment in all treatment groups, except for in the RT group where a distinct decrease was seen, especially at 6 months. From 24 months and onwards all treatment groups showed normozoospermia in 70%–90% of the patients, except for in the Carbo group where at 5 years, N ¼ 9 (56%) of the patients were normospermic (Figure 3). In the BEP group, 32 (84%) patients were normospermic at 12 months and none of the patients were azospermic throughout the whole study period. In the other treatment groups, 11 (6%) patients were azospermic at some time point. One patient treated with carboplatin became normospermic after having been primarily azospermic (Figure 3).
Individual longitudinal values; TSN and SC All 119 patients included in the longitudinal analyses delivered three or more sperm samples. Sperm analyses of nine randomly selected patients in each treatment group showed rather stable values in TSN and SC over time (supplementary Figures S1 and S2, available at Annals of Oncology online).
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Number of patients (N) Age, years, median (range) Smoker at inclusion (N, %) Yes No Unknown Histology (N, %) Seminoma Nonseminoma
Surveillance
Original article
Annals of Oncology
175 150 125 100 75 50 25 0 0
6
12
24
36
60
Month SURV
CARBO
RT
BEP
Time point 0
6
12
24
36
60
SURV (N) 3
14
12
18
19
17
CARBO (N)
18
20
15
13
9
Treatment
18
RT (N)
38
21
30
34
37
47
BEP (N)
40
31
37
40
46
40
24
36
60
Figure 1. Mean total sperm number, all treatment groups.
Mean number of spermatozoa per ml
100 90 80 70 60 50 40 30 20 10 0 0
6
12
Month SURV
CARBO
RT
BEP
Time point 0
6
12
24
36
60
Treatment SURV (N) 3
14
12
18
21
17
CARBO (N) 18
19
20
15
13
9
RT (N)
38
22
31
34
37
48
BEP (N)
40
31
38
42
46
42
Figure 2. Mean sperm concentration, all treatment groups.
4 | Weibring et al.
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Mean number of spermatozoa per ejaculate
200
Original article
Annals of Oncology Table 2. Within and between group comparison at baseline and at 12 months Treatment
12 months versus baseline Mean (SD) Baseline
11 16 18 25
31 (16) 24 (25) 29 (28) 24 (27)
11 16 17 25
117 (95) 91 (96) 91 (110) 84 (92)
Within group comparison 12 months
Between group comparisonc
Difference (95% CI)
P-value
N
Mean (SD)
Difference (95% CI)
45 (29) 35 (34) 18 (27) 32 (30)
14 (3 to 25) 10 (1 to 20) 11 (29 to 6) 8 (1 to 15)
0.016 0.040 0.19 0.020
12 20 31 38
43 (29) 33 (33) 19 (26) 31 (28)
Ref 10 (29 to 12) 22 (42 to 3) 13 (32 to 6)
148 (103) 124 (117) 77 (156) 126 (129)
31 (2 to 65) 33 (2 to 67) 14 (72 to 44) 43 (1 to 87)
0.065 0.059 0.62 0.057
12 20 30 37
140 (101) 137 (140) 73 (127) 128 (121)
Ref 0 (91 to 92) 62 (148 to 25) 15 (99 to 68)
P-value
0.11
0.28
a
Baseline values correspond to the 6 month assessment as BL is lacking for most patients (SURV). Paired t-test. c Linear regression controlling for age, using all available data at the 12-month assessment. b
Discussion Affected spermatogenesis in TC patients is well known. Since TC patients are young men often wanting to father children at some point, the question of testicular function is utterly important. To our knowledge our study is the largest study carried out on TSN and SC after adjuvant treatment in TC CS I patients, also including patients managed by surveillance only. Both crosssectional and longitudinal data were analyzed, with 119 (65%) patients delivering three or more sperm samples during the study period. Some of the patients delivered sperm samples as long as 5 years after treatment. Also, the sperm production before treatment was known, making it possible to compare pretreatment sperm values with posttreatment sperm values. We chose not to split the SURV group into seminoma and non-seminoma in our study (Table 2) since there was no significant difference between the two groups in SC or TSN at any time point over 5 years. We found no clinically significant detrimental long-term effect in either TSN or SC irrespective of adjuvant TC treatment modality. This finding is important when discussing pros and cons of adjuvant treatment with the patient with regard to longterm side-effects on sperm parameters. SC was included in our semen analysis since it is recommended by the WHO to report this as it is related to fertilization and pregnancy rates. Previous studies from Sta˚hl et al. [26], also showed no detrimental effect on sperm DNA fragmentation index from adjuvant therapy, another way to study the side-effects of adjuvant treatment on fertility. Sperm motility is another parameter that can be used for assessing testicular function, however, we decided not to analyze sperm motility because the criteria for assessing motility are more subjective than the analysis of sperm number [33]. Thus, in a longitudinal study, any time-related variation in motility parameters
might be due to changes in methodology rather than related to biological events. In this context SC and TSN are more robust parameters for assessment of testicular function. Previous studies [11, 21, 34, 35] all support our results, showing no negative effect on sperm parameters in TC CS I patients after adjuvant BEP. Many of the patients in those studies received two courses of chemotherapy, which means exposure to even more toxicity than our patients who only received BEP x1. Ghezzi et al. [36] investigated the effect of one cycle of carboplatin, and in accordance with our study, no negative effect on spermatogenesis was seen. The observed decrease in TSN and SC 5 years after adjuvant Carbo in Figures 1 and 2 cannot be considered reliable due to the small number of patients delivering sperm samples at that time point and is a shortcoming of the study. Bujan et al. [11] also investigated the effect of adjuvant RT showing recovery of sperm parameters to pretreatment values 2– 5 years after treatment, which is in accordance with our results. The sharp decline in both TSN and SC at 6 months posttreatment in the RT group (Figures 1 and 2) is most likely due to the negative effect of scattered doses of radiation to the remaining testicle, and is confirmed by other studies [37–39]. Radiotherapy is, however, no longer recommended as preferred adjuvant treatment in many guidelines, and is not used as standard treatment in Sweden any more [4, 40]. The results of our study are therefore most important with regard to adjuvant chemotherapy and surveillance. Different factors can affect the testicular function negatively. As older men in general have decreased sperm quality compared with younger men [41], age was adjusted for in the regression model. Time since last ejaculation, the abstinence time, is another factor potentially affecting sperm parameters. In our study the abstinence time did not differ between the different treatment groups and time points in any major way, and was therefore not adjusted for (supplementary Table S1, available at Annals of
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Sperm concentration; spermatozoa/ml Surveillancea Carboplatin RT BEP Total sperm number; spermatozoa/ejaculate Surveillancea Carboplatin RT BEP
N
At 12 months b
Original article
Annals of Oncology
0 6 12 24 36 60
CARBO: Sperm number category by follow-up month
100 93
7
Month
Month
SURV: Sperm number category by follow-up month
100 89 86
11 10 5
76
10 20 30 40 50 60 70 80 90 100 Percent Normo
Oligo
48 76 71
0
18 45 6
71
21
9
16
8
23 6
10 20 30 40 50 60 70 80 90 100 Percent Normo
Oligo
27
69
31
56
44
10 20 30 40 50 60 70 80 90 100 Percent Oligo
Azo
BEP: Sperm number category by follow-up month
26 5 68
25
73
Normo
Month
Month
68
21 5
75
Azo
14
22 6
74
0
RT: Sperm number category by follow-up month 0 6 12 24 36 60
72
0 6 12 24 36 60
61
39 68
32 84 88 85 83
0
16 12 15 17
10 20 30 40 50 60 70 80 90 100 Percent
Azo
Oligo
Normo Treatment group
SURV (N)
CARBO (N)
RT (N)
BEP (N)
Time point 0
3
18
38
40
6
14
19
22
31
12
12
20
31
38
24
18
15
34
42
36
21
13
37
46
60
17
9
48
42
Figure 3. Sperm number category. Cross-sectional data per treatment group and time point.
Oncology online). Smoking also has a negative effect on sperm quality and sperm count [42, 43]. Unfortunately, we only had information about the patients smoking habits at the inclusion of the study, and thus smoking was not adjusted for in the study. TC patients are, however, an otherwise healthy patient group and show no higher sick leave than other people without TC [44]. Potentially, our results can be affected by the fact that some patients only delivered one sperm sample throughout the study period. Nonetheless, the large number of patients in the cohort gives enough data for statistical analysis. As baseline, we used the postorchiectomy time point. Patients in the SURV group, however, were included later on in the study which resulted in very few collected sperm samples postorchiectomy, therefore the 6 month baseline for this group. The different baselines are not considered to affect the results in any major way thanks to the long study period of 5 years postorchiectomy. Sperm production after chemotherapy usually recovers in 1–4 years [45], and is why we chose to compare sperm values at 12 months with sperm values at baseline (Table 2). In similarity with Petersen [13], our study could confirm that TC patients have spermatogenic dysfunction before orchiectomy. This supports inviting the patients to bank sperm before the orchiectomy and not after, in order to maximize the
6 | Weibring et al.
chances of in vitro fertilization if post-treatment azoospermia would occur [11, 15, 46]. Another reason to offer patients to bank sperm before orchiectomy is that neither stage or further treatment is known, nor is the function of the remaining testicle. The optimal treatment strategy for TC CS I patients is frequently debated and controversy still exists. It is well known that when a relapse occurs, the patient will often need three or more courses of chemotherapy, which can induce long-term sideeffects, such as heart toxicity, neurotoxicity and permanent damage in regard to fertility [6, 47]. For relapsing non-seminoma patients, retroperitoneal lymph node dissection may also be necessary, including the risk of retrograde ejaculation making these patients infertile [48]. Patient autonomy should be respected and in order to help the patients, it is necessary to give patients information on different short and long-term risks with adjuvant treatment versus full chemotherapy, in case of relapse. Treating in the adjuvant situation decreases the risk of relapse significantly [29, 49] and hence reduces the risk of side-effects caused by multiple courses of chemotherapy needed in case of metastatic disease. With the results of this study we can now inform our patients that adjuvant chemotherapy does not seem to affect the testicular function.
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0
24
0 6 12 24 36 60
Annals of Oncology Discussion Conclusion
Funding This work was supported by grants from the Swedish Government Funding for Clinical Research, the Swedish Cancer Society, Gunnar Nilsson’s Cancer Fund, Malmo University Hospital Foundation for Cancer Research and Foundation for Urological Research and King Gustaf V’s Jubilee Fund for Cancer Research, Stockholm, Sweden (no grant numbers apply).
Disclosure The authors have declared no conflicts of interest.
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12. Agarwal A, Allamaneni SS. Disruption of spermatogenesis by the cancer disease process. J Natl Cancer Inst Monogr 2005; 2005(34): 9–12. 13. Petersen PM, Skakkebaek NE, Giwercman A. Gonadal function in men with testicular cancer: biological and clinical aspects. APMIS 1998; 106(1–6): 24–34; discussion 34–36. 14. Brydoy M, Fossa SD, Dahl O et al. Gonadal dysfunction and fertility problems in cancer survivors. Acta Oncol 2007; 46(4): 480–489. 15. Petersen PM, Skakkebaek NE, Rorth M et al. Semen quality and reproductive hormones before and after orchiectomy in men with testicular cancer. J Urol 1999; 161(3): 822–826. 16. Walsh TJ, Croughan MS, Schembri M et al. Increased risk of testicular germ cell cancer among infertile men. Arch Intern Med 2009; 169(4): 351–356. 17. de Wit R, Bosl GJ. Optimal management of clinical stage I testis cancer: one size does not fit all. J Clin Oncol 2013; 31(28): 3477–3479. 18. Nichols CR, Roth B, Albers P et al. Active surveillance is the preferred approach to clinical stage I testicular cancer. JCO 2013; 31(28): 3490–3493. 19. Hjelle LV, Bremnes RM, Gundersen PO et al. Associations between longterm serum platinum and neurotoxicity and ototoxicity, endocrine gonadal function, and cardiovascular disease in testicular cancer survivors. Urol Oncol 2016; 34(11): 487.e13–487.e20. 20. Oldenburg J, Fossa˚ SD, Nuver J et al. Testicular seminoma and nonseminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi125–vi132. 21. Eberhard J, Stahl O, Giwercman Y et al. Impact of therapy and androgen receptor polymorphism on sperm concentration in men treated for testicular germ cell cancer: a longitudinal study. Hum Reprod 2004; 19(6): 1418–1425. 22. Petersen PM, Hansen SW, Giwercman A et al. Dose-dependent impairment of testicular function in patients treated with cisplatinbased chemotherapy for germ cell cancer. Ann Oncol 1994; 5(4): 355–358. 23. https://www.cancercentrum.se/stockholm-gotland/cancerdiagnoser/testi kel/, 2017 (29 January 2019, date last accessed). 24. World Health Organization DoRHaR: WHO laboratory manual for the Examination and processing of human semen FIFTH EDITION, World Health Organisation, 2010. https://apps.who.int/iris/bitstream/handle/ 10665/44261/9789241547789_eng.pdf?sequence=1 (29 January 2019, date last accessed). 25. Isaksson S, Eberhard J, Stahl O et al. Inhibin B concentration is predictive for long-term azoospermia in men treated for testicular cancer. Andrology 2014; 2(2): 252–258. 26. Sta˚hl O, Eberhard J, Jepson K et al. Sperm DNA integrity in testicular cancer patients. Hum Reprod 2006; 21(12): 3199–3205. 27. Oliver RT, Mason MD, Mead GM et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet 2005; 366(9482): 293–300. 28. Warde P, Specht L, Horwich A et al. Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. JCO 2002; 20(22): 4448–4452. 29. Tandstad T, Smaaland R, Solberg A et al. Management of seminomatous testicular cancer: a binational prospective population-based study from the Swedish Norwegian Testicular Cancer Study Group. JCO 2011; 29(6): 719–725. 30. Oldenburg J, Haugnes HS, Dahl O et al. [Treatment for stage I-testicular cancer should be assessed individually]. Tidsskr nor Laegeforen 2015; 135(15): 1340–1341. 31. Maroto P, del Muro XG, Aparicio J et al. Multicentre risk-adapted management for stage I non-seminomatous germ cell tumours. Ann Oncol 2005; 16(12): 1915–1920. 32. Tandstad T, Sta˚hl O, Ha˚kansson U et al. One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group. Ann Oncol 2014; 25(11): 2167–2172. 33. Jorgensen N, Auger J, Giwercman A et al. Semen analysis performed by different laboratory teams: an intervariation study. Int J Androl 1997; 20(4): 201–208.
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This study has shown that there is no clinically significant detrimental long-term effect on TSN or SC associated to adjuvant treatment with BEP 1, Carbo1 or RT to the infradiaphragmal paraaortic and ipsilateral iliac lymph nodes, in TC CS I patients. However, we offer patients sperm banking before orchiectomy as a number of patients may have low sperm counts before orchiectomy and remain so also after adjuvant treatment. Type of TC and further treatment postorchiectomy are also often unknown factors, adding further importance to sperm banking before orchiectomy. Assisted reproductive measures may be necessary for these patients regardless of any treatment given.
Original article
Original article
8 | Weibring et al.
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Taiwan. J Environ Sci Health A Tox Hazard Subst Environ Eng 2014; 49(3): 262–268. Mostafa RM, Nasrallah YS, Hassan MM et al. The effect of cigarette smoking on human seminal parameters, sperm chromatin structure and condensation. Andrologia 2018; 50(3). doi: 10.1111/and.12910. Nord C, Olofsson S-E, Glimelius I et al. Sick leave and disability pension among Swedish testicular cancer survivors according to clinical stage and treatment. Acta Oncol 2015; 54(10): 1770–1780. Staff AMCaN: How Cancer Treatments Can Effect Fertility in Men, 2017. https://www.cancer.org/treatment/treatments-and-side-effects/physical-sideeffects/fertility-and-sexual-side-effects/fertility-and-men-with-cancer/how-can cer-treatments-affect-fertility.html (29 January 2019, date last accessed). Depalo R, Falagario D, Masciandaro P et al. Fertility preservation in males with cancer: 16-year monocentric experience of sperm banking and post-thaw reproductive outcomes. Ther Adv Med Oncol 2016; 8(6): 412–420. O’Flaherty C, Hales BF, Chan P et al. Impact of chemotherapeutics and advanced testicular cancer or Hodgkin lymphoma on sperm deoxyribonucleic acid integrity. Fertil Steril 2010; 94(4): 1374–1379. Crestani A, Esperto F, Rossanese M et al. Andrological complications following retroperitoneal lymph node dissection for testicular cancer. Minerva Urol Nefrol 2017; 69(3): 209–219. Gumus M, Bilici A, Odabas H et al. Outcomes of surveillance versus adjuvant chemotherapy for patients with stage IA and IB nonseminomatous testicular germ cell tumors. World J Urol 2016; 35: 1103–1110.
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34. Pont J, Albrecht W, Postner G et al. Adjuvant chemotherapy for highrisk clinical stage I nonseminomatous testicular germ cell cancer: longterm results of a prospective trial. JCO 1996; 14(2): 441–448. 35. Cullen MH, Stenning SP, Parkinson MC et al. Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. JCO 1996; 14(4): 1106–1113. 36. Ghezzi M, Berretta M, Bottacin A et al. Impact of Bep or carboplatin chemotherapy on testicular function and sperm nucleus of subjects with testicular germ cell tumor. Front Pharmacol 2016; 7: 122. 37. Gordon WJr, Siegmund K, Stanisic TH et al. A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711). Int J Radiat Oncol Biol Phys 1997; 38(1): 83–94. 38. Gandini L, Sgro` P, Lombardo F et al. Effect of chemo- or radiotherapy on sperm parameters of testicular cancer patients. Hum Reprod 2006; 21(11): 2882–2889. 39. Berthelsen JG. Sperm counts and serum follicle-stimulating hormone levels before and after radiotherapy and chemotherapy in men with testicular germ cell cancer. Fertil Steril 1984; 41(2): 281–286. 40. EAUs guidelines on Testicular Cancer 2017. https://uroweb.org/wp-con tent/uploads/11-Testicular-Cancer_2017_web.pdf (29 January 2019, date last accessed). 41. Eskenazi B, Wyrobek AJ, Sloter E et al. The association of age and semen quality in healthy men. Hum Reprod 2003; 18(2): 447–454. 42. Jeng HA, Chen YL, Kantaria KN. Association of cigarette smoking with reproductive hormone levels and semen quality in healthy adult men in
Annals of Oncology
ORIGINAL ARTICLE
K. Weibring1,2*, C. Nord1,2, O. Sta˚hl3, J. Eberhard3, K. Sandberg1,2, H. Johansson1,2, S. Arver4,5, A. Giwercman6 & G. Cohn-Cedermark1,2 1 Department of Oncology-Pathology, Karolinska Institute, Stockholm; 2Department of Oncology, Karolinska University Hospital, Stockholm; 3Department of Oncology, Skane University Hospital, Lund; 4Department of Medicine/Huddinge, Karolinska Institute, Stockholm; 5Centre for Andrology and Sexual Medicine, Karolinska University Hospital, Stockholm; 6Department of Translational Medicine, Lund University, Malmo, Sweden
*Correspondence to: Dr Kristina Weibring, Tema Cancer, PO BES, A2:00, Karolinska University Hospital, 171 76 Stockholm, Sweden. Tel: þ 46-70-6050533; E-mail: [email protected]
Background: Little is known regarding sperm production following adjuvant treatment in testicular cancer (TC) clinical stage I (CS I) patients. Patients and methods: A total of 182 TC patients aged 18–50 years were prospectively included during 2001–2006 at any given time within 5 years of orchiectomy. Semen samples were delivered postorchiectomy but before further treatment, 6, 12, 24, 36 and 60 months (T0–T60) after completed therapy. Total sperm number (TSN) and sperm concentration (SC) were used as measurements of testicular function. Four groups according to treatment modality were identified; Radiotherapy; To a total dose of 25.2 Gy to the infradiaphragmal paraaortic and ipsilateral iliac lymph nodes (RT, N ¼ 70), one cycle of adjuvant BEP (bleomycin, etoposide, cisplatin, 5 day regimen) (BEP, N ¼ 62), one cycle of adjuvant carboplatin AUC 7 (Carbo, N ¼ 22), and patients managed by surveillance (SURV, N ¼ 28). Results: In the cross-sectional analysis, a significant but transient drop in mean TSN and mean SC (T0–T60) was seen at T6 after radiotherapy. Apart from a significant increase in mean SC at T12 compared with baseline, no significant differences were observed in the other treatment groups. In 119 patients delivering 3 or more samples, values in TSN and SC were rather stable over time. Azoospermic patients (N ¼ 11) were observed in most treatment groups except for in the BEP group. During followup, one azoospermic patient belonging to the Carbo group became normospermic. Conclusions: No clinically significant long-term effect on TSN or SC associated with adjuvant treatment in TC CSI patients was found. However, as patients may have low sperm counts before orchiectomy as well as after adjuvant treatment, we offer sperm banking before orchiectomy as assisted reproductive measures may be necessary regardless of treatment given. Key words: adjuvant treatment, sperm concentration, total sperm number, chemotherapy, testicular cancer
Introduction Testicular germ cell cancer (TC) is the most common cancer among young men, aged 15–40 years, with the highest incidence in white men in northern Europe [1–3]. There are two subgroups of TC, seminoma and non-seminoma [4]. Since the introduction of platinum-based combination chemotherapy in the 1970s, and due to the use of multimodality treatment, the overall survival rate is high, with more than 95% of the patients being cured [1, 5, 6]. As the incidence is still increasing in many countries [7–9] and the survival rates are high, efforts are made in order to reduce
long-term side-effects, by minimizing therapy without compromising outcome. This applies both for testicular cancer (TC) CS I patients as well as for patients with disseminated disease. After diagnosis, all TC patients undergo a unilateral orchiectomy of the tumorous testicle. Depending on tumor characteristics further treatment with adjuvant chemotherapy or irradiation could be added [4]. A well-known problem for men diagnosed with TC is impaired spermatogenesis. Testicular dysgenesis syndrome [10] may be a reason as well as local and systemic effects of the cancer, although the mechanisms are not totally clarified [11–13]. Cancer
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Sperm count in Swedish clinical stage I testicular cancer patients following adjuvant treatment
Original article
Patients and methods Population and study design A total of 459 TC patients, all tumor stages, age 18–50 years from the Department of Oncology, Skane University Hospital, Lund, and the Department of Oncology, Karolinska University Hospital, Stockholm were invited to participate in this study on testicular function. The inclusion periods were 2001–2006 (Lund) and 2003–2006 (Stockholm) at any given time point within 5 years postorchiectomy, which means a diagnosis at the earliest in 1996 in Lund and a diagnosis at the earliest in 1998 in Stockholm. All patients gave written informed consent and the study protocol was approved by the Ethical Review Boards of Lund University and the Karolinska Institute, Stockholm. Patients who moved, withdrew or relapsed during ongoing study, were included until that date. Out of 459 eligible patients, 75 patients declined and 58 patients were excluded due to mental co-morbidity, linguistic difficulties, physical disability or bilateral TC. Among the remaining 326 patients, 7 patients declined at a later time point and 137 patients did not fulfill the criteria for the cohort of interest due to metastatic disease, carcinoma in situ (CIS) in the contra lateral testicle, treatment with two or more cycles of chemotherapy, other chemotherapy than BEP or Carbo, development of CIS during ongoing followup, testosterone substitution before inclusion or before the first sperm sample was delivered, and patients having had a vasectomy carried out before treatment. This report includes the 182 of the 459 patients who fulfilled the following inclusion criteria; TC CS I, adjuvant treatment with radiotherapy 1.8 Gy 14 to a total dose of 25.2 Gy to the infradiaphragmal paraaortic and ipsilateral iliac lymph nodes (RT, N ¼ 70), one cycle of BEP (bleomycin, etoposide, cisplatin, 5-day regimen, N ¼ 62), one cycle of carboplatin AUC 7 (Carbo, N ¼ 22) or managed by surveillance (SURV, N ¼ 28). The patients were divided into four groups according to treatment modality. Semen samples were delivered at given time points; postorchiectomy but before further treatment (T0), 6 months (T6), 1 year (T12), 2 years (T24), 3 years (T36) and 5 years (T60) after completion of treatment. At least one sperm sample had to be delivered at any given time interval (T0– T60). Total number of delivered sperm samples per patient was dependent on at which time point after completed treatment the patient was
2 | Weibring et al.
recruited to the study, and how many sperm samples the patient chose to deliver. Preorchiectomy semen samples were too few to retrieve any statistics from, N ¼ 9 (5%) in the whole cohort. One hundred and five (58%) patients had seminoma and 77 (42%) patients had non-seminoma, with a median age of 34 and 28 years, respectively. Non-seminoma patients are generally younger (25–40 years of age) than seminoma patients (30–45 years of age) at time of diagnosis [23]. Nine (9%) of the seminoma patients and 13 (17%) of the nonseminoma patients were smokers at inclusion (Table 1). In accordance with the World Health Organization (WHO) laboratory manual for examination and processing of human semen, fifth edition, 2010, we focused on TSN and SC as measurements of testicular function [24]. Data from this study have partly been reported before [25, 26], but the cohort was smaller and included all TC stages, and therefore the results were less valid with regard to the specific subgroup of interest.
Adjuvant TC treatment The adjuvant treatment was according to the SWENOTECA (Swedish and Norwegian Testicular Cancer Group) treatment protocols for seminoma and non-seminoma, respectively, in use during the time frame of the study [4].
Seminoma. During 2000 and 2004, CS I seminoma patients could choose between surveillance or adjuvant radiotherapy with 1.8 Gy 14 to a total dose of 25.2 Gy to the infradiaphragmal paraaortic and ipsilateral iliac lymph nodes. As results emerged from a randomized study in 2005, between radiotherapy and carboplatin, the recommendations changed in favor of carboplatin [27]. From 2006 and onward adjuvant treatment was recommended on the basis of emerging data related to risk of relapse. Risk factors for relapse in seminoma are tumor size >4 cm and invasion in the stromal rete testis [27, 28]. Patients with 0–1 risk factors were offered SURV but could also choose one course of adjuvant Carbo, whereas patients with two risk factors were recommended one course of adjuvant Carbo. Adjuvant RT is no longer used as standard treatment in Sweden, mainly due to the elevated risk of secondary malignancies [29]. Non-seminoma. The dominating risk factor for relapse for CS I nonseminoma patients is vascular invasion of tumor cells [30, 31]. Patients without vascular invasion could choose either SURV or one or two courses of adjuvant BEP (bleomycin 30 000 IU days 1, 5 and 15 to a maximum dose of 3 105 IU, etoposide 100 mg/m2 days 1–5, cisplatin 20 mg/ m2 per cycle days 1–5, given every third week). This study only included patients treated with one course of BEP since this is the currently recommended adjuvant treatment of CS I non-seminoma [4, 32].
Semen samples Fresh semen samples were delivered after a recommendation of 3 days of sexual abstinence. All sperm analyses from patients recruited in Lund were carried out at the Reproductive Medicine Centre (RMC), Skane University Hospital, Malmo, except 12 T0 ejaculates analyzed at the fertility laboratory, Lund University Hospital. For patients recruited in Stockholm, all sperm samples were analyzed at the Centre for Andrology and Sexual Medicine, Karolinska University Hospital, Stockholm. The laboratories in Malmo and Stockholm served as reference laboratories for the European Society of Human Reproduction and Embryology/Nordic Association for Andrology external quality control program. Lower reference values for these parameters are TSN >39 106 spermatozoa/ejaculate and SC >15106 spermatozoa/ml ejaculate. To assess TSN, the ejaculate volume had to be multiplied with the SC. Sperm samples were then classified depending on normal or pathological levels of spermatozoa in the ejaculate, i.e. normozoopermia (TSN or SC equal to or above lower reference limits), oligozoospermia (TSN or SC below
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treatment as well as orchiectomy also have negative impact on the reproductive function [13–15]. Previous studies have shown that infertile men are at higher risk of developing TC [16]. In recent years, there has been discussions on whether to treat in the adjuvant situation or to wait until relapse occurs [17, 18]. Those advocating against adjuvant treatment claim that little is known about long-term side-effects from adjuvant treatment, and that there is risk for overtreatment [18]. The negative effect of multiple cycles of chemotherapy has been studied and there is clear evidence of a dose response relationship with regard to several long-term side-effects [19, 20] and the detrimental effect on sperm recovery by multiple courses of chemotherapy is well known [21, 22]. Less is known about the effect on sperm recovery after adjuvant treatment in CS I disease. The aim of this prospective follow-up study was to describe testicular function described as total sperm number (TSN) and sperm concentration (SC) in a large cohort of TC CS I patients treated with adjuvant treatment such as one course of bleomycin, etoposide, cisplatin (BEP), one course of carboplatin (Carbo), radiotherapy to a total dose of 25.2 Gy (RT) or patients managed by surveillance, i.e. no further treatment after orchiectomy (SURV).
Annals of Oncology
Original article
Annals of Oncology Table 1. Patients’ characteristics BEP31
Carbo31
RT
Total
28 28 (19–42)
62 29.5 (15–49)
22 32.5 (26–46)
70 35 (20–48)
182 32 (15–49)
5 (18) 9 (32) 14 (50)
10 (16) 29 (47) 23 (37)
1 (5) 20 (91) 1 (5)
6 (9) 33 (47) 31 (44)
22 (12) 91 (50) 69 (38)
13 (46) 15 (54)
0 62 (100)
22 (100) 0
70 (100) 0
105 (58) 77 (42)
lower reference limit but above 0 spermatozoa) or azoospermia (no spermatozoa in the ejaculate) [24].
Abstinence time. One hundred and sixteen (64%) patients had an abstinence time of 3 days. The median abstinence time range in the different treatment groups were 2.5–5 days in the SURV group, 3–3.5 days in the Carbo group, 2–4 days in the RT group and 3 days in the BEP group (supplementary Table S1, available at Annals of Oncology online). Statistical methods. A paired t-test was used to test for changes within the treatment groups over time. Linear regression was used to estimate and test differences between the groups at 12 months. All results are presented as mean differences together with 95% confidence intervals. Age was adjusted for by including age as a continuous variable in the regression models. The significance level was set to 5%. Due to the exploratory nature of the analyses adjustment for multiple comparisons were not made.
Results A total of 119 (65%) patients in all treatment groups delivered sperm samples at three or more time points: SURV; N ¼ 17 (61%), Carbo; N ¼ 19 (86%), BEP; N ¼ 49 (79%) and RT; N ¼ 34 (49%). Both longitudinal and cross-sectional data were studied. The SURV group consists of both seminoma and non-seminoma patients. We found no significant difference in SC and TSN between the two groups at any time point over 5 years.
Mean TSN and mean SC Cross-sectional and longitudinal analysis of mean TSN and mean SC showed an increase over time (T0–T60) in all groups except the RT group where a distinct decrease in both mean TSN and mean SC at 6 months post-treatment compared with the other treatment groups was seen. However, after T6 both mean TSN and mean SC recovered and increased in the RT group. The Carbo group showed a decline in mean TSN and mean SC at T60 (Figures 1 and 2).
Within group comparison at baseline and at 12 months post-treatment; mean TSN and mean SC Mean TSN. No significant changes were seen at 12 months posttreatment compared with baseline. However, an increase, close to the level of statistical significance (P ¼ 0.065, P ¼ 0.057, P ¼ 0.059) in the SURV, BEP and Carbo treatment groups was
seen. In the RT group a nonsignificant (P ¼ 0.62) decrease was noted (Table 2).
Mean SC. There was a significant increase in the SURV, BEP and Carbo treatment groups (P ¼ 0.016, P ¼ 0.02 and P ¼ 0.04) at 12 months post-treatment compared with baseline. In the RT group, there was a nonsignificant decrease (P ¼ 0.19) (Table 2).
Between group comparison at 12 months; mean TSN and mean SC There were no significant differences between the treatment groups BEP, Carbo or RT overall, in mean TSN or mean SC at 12 months compared with the SURV group (P ¼ 0.11 and P ¼ 0.28). However, a significant decrease in mean SC between the RT group alone compared with the SURV group was seen (Table 2).
Sperm number category No clinically significant difference was detected between the sperm samples delivered postorchiectomy and those delivered 6 and 12 months after completed treatment in all treatment groups, except for in the RT group where a distinct decrease was seen, especially at 6 months. From 24 months and onwards all treatment groups showed normozoospermia in 70%–90% of the patients, except for in the Carbo group where at 5 years, N ¼ 9 (56%) of the patients were normospermic (Figure 3). In the BEP group, 32 (84%) patients were normospermic at 12 months and none of the patients were azospermic throughout the whole study period. In the other treatment groups, 11 (6%) patients were azospermic at some time point. One patient treated with carboplatin became normospermic after having been primarily azospermic (Figure 3).
Individual longitudinal values; TSN and SC All 119 patients included in the longitudinal analyses delivered three or more sperm samples. Sperm analyses of nine randomly selected patients in each treatment group showed rather stable values in TSN and SC over time (supplementary Figures S1 and S2, available at Annals of Oncology online).
doi:10.1093/annonc/mdz017 | 3
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Number of patients (N) Age, years, median (range) Smoker at inclusion (N, %) Yes No Unknown Histology (N, %) Seminoma Nonseminoma
Surveillance
Original article
Annals of Oncology
175 150 125 100 75 50 25 0 0
6
12
24
36
60
Month SURV
CARBO
RT
BEP
Time point 0
6
12
24
36
60
SURV (N) 3
14
12
18
19
17
CARBO (N)
18
20
15
13
9
Treatment
18
RT (N)
38
21
30
34
37
47
BEP (N)
40
31
37
40
46
40
24
36
60
Figure 1. Mean total sperm number, all treatment groups.
Mean number of spermatozoa per ml
100 90 80 70 60 50 40 30 20 10 0 0
6
12
Month SURV
CARBO
RT
BEP
Time point 0
6
12
24
36
60
Treatment SURV (N) 3
14
12
18
21
17
CARBO (N) 18
19
20
15
13
9
RT (N)
38
22
31
34
37
48
BEP (N)
40
31
38
42
46
42
Figure 2. Mean sperm concentration, all treatment groups.
4 | Weibring et al.
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Mean number of spermatozoa per ejaculate
200
Original article
Annals of Oncology Table 2. Within and between group comparison at baseline and at 12 months Treatment
12 months versus baseline Mean (SD) Baseline
11 16 18 25
31 (16) 24 (25) 29 (28) 24 (27)
11 16 17 25
117 (95) 91 (96) 91 (110) 84 (92)
Within group comparison 12 months
Between group comparisonc
Difference (95% CI)
P-value
N
Mean (SD)
Difference (95% CI)
45 (29) 35 (34) 18 (27) 32 (30)
14 (3 to 25) 10 (1 to 20) 11 (29 to 6) 8 (1 to 15)
0.016 0.040 0.19 0.020
12 20 31 38
43 (29) 33 (33) 19 (26) 31 (28)
Ref 10 (29 to 12) 22 (42 to 3) 13 (32 to 6)
148 (103) 124 (117) 77 (156) 126 (129)
31 (2 to 65) 33 (2 to 67) 14 (72 to 44) 43 (1 to 87)
0.065 0.059 0.62 0.057
12 20 30 37
140 (101) 137 (140) 73 (127) 128 (121)
Ref 0 (91 to 92) 62 (148 to 25) 15 (99 to 68)
P-value
0.11
0.28
a
Baseline values correspond to the 6 month assessment as BL is lacking for most patients (SURV). Paired t-test. c Linear regression controlling for age, using all available data at the 12-month assessment. b
Discussion Affected spermatogenesis in TC patients is well known. Since TC patients are young men often wanting to father children at some point, the question of testicular function is utterly important. To our knowledge our study is the largest study carried out on TSN and SC after adjuvant treatment in TC CS I patients, also including patients managed by surveillance only. Both crosssectional and longitudinal data were analyzed, with 119 (65%) patients delivering three or more sperm samples during the study period. Some of the patients delivered sperm samples as long as 5 years after treatment. Also, the sperm production before treatment was known, making it possible to compare pretreatment sperm values with posttreatment sperm values. We chose not to split the SURV group into seminoma and non-seminoma in our study (Table 2) since there was no significant difference between the two groups in SC or TSN at any time point over 5 years. We found no clinically significant detrimental long-term effect in either TSN or SC irrespective of adjuvant TC treatment modality. This finding is important when discussing pros and cons of adjuvant treatment with the patient with regard to longterm side-effects on sperm parameters. SC was included in our semen analysis since it is recommended by the WHO to report this as it is related to fertilization and pregnancy rates. Previous studies from Sta˚hl et al. [26], also showed no detrimental effect on sperm DNA fragmentation index from adjuvant therapy, another way to study the side-effects of adjuvant treatment on fertility. Sperm motility is another parameter that can be used for assessing testicular function, however, we decided not to analyze sperm motility because the criteria for assessing motility are more subjective than the analysis of sperm number [33]. Thus, in a longitudinal study, any time-related variation in motility parameters
might be due to changes in methodology rather than related to biological events. In this context SC and TSN are more robust parameters for assessment of testicular function. Previous studies [11, 21, 34, 35] all support our results, showing no negative effect on sperm parameters in TC CS I patients after adjuvant BEP. Many of the patients in those studies received two courses of chemotherapy, which means exposure to even more toxicity than our patients who only received BEP x1. Ghezzi et al. [36] investigated the effect of one cycle of carboplatin, and in accordance with our study, no negative effect on spermatogenesis was seen. The observed decrease in TSN and SC 5 years after adjuvant Carbo in Figures 1 and 2 cannot be considered reliable due to the small number of patients delivering sperm samples at that time point and is a shortcoming of the study. Bujan et al. [11] also investigated the effect of adjuvant RT showing recovery of sperm parameters to pretreatment values 2– 5 years after treatment, which is in accordance with our results. The sharp decline in both TSN and SC at 6 months posttreatment in the RT group (Figures 1 and 2) is most likely due to the negative effect of scattered doses of radiation to the remaining testicle, and is confirmed by other studies [37–39]. Radiotherapy is, however, no longer recommended as preferred adjuvant treatment in many guidelines, and is not used as standard treatment in Sweden any more [4, 40]. The results of our study are therefore most important with regard to adjuvant chemotherapy and surveillance. Different factors can affect the testicular function negatively. As older men in general have decreased sperm quality compared with younger men [41], age was adjusted for in the regression model. Time since last ejaculation, the abstinence time, is another factor potentially affecting sperm parameters. In our study the abstinence time did not differ between the different treatment groups and time points in any major way, and was therefore not adjusted for (supplementary Table S1, available at Annals of
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Sperm concentration; spermatozoa/ml Surveillancea Carboplatin RT BEP Total sperm number; spermatozoa/ejaculate Surveillancea Carboplatin RT BEP
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CARBO: Sperm number category by follow-up month
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Figure 3. Sperm number category. Cross-sectional data per treatment group and time point.
Oncology online). Smoking also has a negative effect on sperm quality and sperm count [42, 43]. Unfortunately, we only had information about the patients smoking habits at the inclusion of the study, and thus smoking was not adjusted for in the study. TC patients are, however, an otherwise healthy patient group and show no higher sick leave than other people without TC [44]. Potentially, our results can be affected by the fact that some patients only delivered one sperm sample throughout the study period. Nonetheless, the large number of patients in the cohort gives enough data for statistical analysis. As baseline, we used the postorchiectomy time point. Patients in the SURV group, however, were included later on in the study which resulted in very few collected sperm samples postorchiectomy, therefore the 6 month baseline for this group. The different baselines are not considered to affect the results in any major way thanks to the long study period of 5 years postorchiectomy. Sperm production after chemotherapy usually recovers in 1–4 years [45], and is why we chose to compare sperm values at 12 months with sperm values at baseline (Table 2). In similarity with Petersen [13], our study could confirm that TC patients have spermatogenic dysfunction before orchiectomy. This supports inviting the patients to bank sperm before the orchiectomy and not after, in order to maximize the
6 | Weibring et al.
chances of in vitro fertilization if post-treatment azoospermia would occur [11, 15, 46]. Another reason to offer patients to bank sperm before orchiectomy is that neither stage or further treatment is known, nor is the function of the remaining testicle. The optimal treatment strategy for TC CS I patients is frequently debated and controversy still exists. It is well known that when a relapse occurs, the patient will often need three or more courses of chemotherapy, which can induce long-term sideeffects, such as heart toxicity, neurotoxicity and permanent damage in regard to fertility [6, 47]. For relapsing non-seminoma patients, retroperitoneal lymph node dissection may also be necessary, including the risk of retrograde ejaculation making these patients infertile [48]. Patient autonomy should be respected and in order to help the patients, it is necessary to give patients information on different short and long-term risks with adjuvant treatment versus full chemotherapy, in case of relapse. Treating in the adjuvant situation decreases the risk of relapse significantly [29, 49] and hence reduces the risk of side-effects caused by multiple courses of chemotherapy needed in case of metastatic disease. With the results of this study we can now inform our patients that adjuvant chemotherapy does not seem to affect the testicular function.
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0
24
0 6 12 24 36 60
Annals of Oncology Discussion Conclusion
Funding This work was supported by grants from the Swedish Government Funding for Clinical Research, the Swedish Cancer Society, Gunnar Nilsson’s Cancer Fund, Malmo University Hospital Foundation for Cancer Research and Foundation for Urological Research and King Gustaf V’s Jubilee Fund for Cancer Research, Stockholm, Sweden (no grant numbers apply).
Disclosure The authors have declared no conflicts of interest.
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This study has shown that there is no clinically significant detrimental long-term effect on TSN or SC associated to adjuvant treatment with BEP 1, Carbo1 or RT to the infradiaphragmal paraaortic and ipsilateral iliac lymph nodes, in TC CS I patients. However, we offer patients sperm banking before orchiectomy as a number of patients may have low sperm counts before orchiectomy and remain so also after adjuvant treatment. Type of TC and further treatment postorchiectomy are also often unknown factors, adding further importance to sperm banking before orchiectomy. Assisted reproductive measures may be necessary for these patients regardless of any treatment given.
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