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Treatment of testicular intraepithelial neoplasia (intratubular germ cell neoplasia unspecified) with local radiotherapy or with platinum-based chemotherapy: A survey of the German Testicular Cancer Study Group
original articles
Annals of Oncology Annals of Oncology 24: 1332–1337, 2013 doi:10.1093/annonc/mds628 Published online 4 January 2013
Treatment of testicular intraepithelial neoplasia (intratubular germ cell neoplasia unspecified) with local radiotherapy or with platinum-based chemotherapy: A survey of the German Testicular Cancer Study Group K.-P. Dieckmann1*, †, S. Wilken1,†, V. Loy2, C. Matthies3, K. Kleinschmidt4, J. Bedke5, A. Martinschek6, R. Souchon7, U. Pichlmeier8 & S. Kliesch9 1 Department of Urology, Albertinen-Krankenhaus, Hamburg; 2Department of Pathology, Vivantes MVZ Am Urban, Berlin; 3Department of Urology, Bundeswehrkrankenhaus Hamburg, Hamburg; 4Department of Urology, Dr. Horst Schmidt Kliniken, Wiesbaden; 5Department of Urology, Universitätsklinikum, Tuebingen; 6Department of Urology, Bundeswehrkrankenhaus, Ulm; 7Department of Radiooncology, Universitätsklinikum, Tuebingen; 8Institute of Medical Biometry and Epidemiology, Centre of experimental Medicine, Universitätsklinikum Eppendorf, Hamburg; 9Centre of Reproductive Medicine, Universitätsklinikum, Muenster, Germany
Background: The treatment of testicular intraepithelial neoplasia (TIN), the progenitor of testicular germ cell tumours (GCTs), is based on little data.
Patients and methods: Two hundred and twenty-eight GCT patients with contralateral TIN were retrospectively enrolled. Ten had surveillance, 122 radiotherapy to testis with 18–20 Gy, 30 cisplatin-based chemotherapy (two cycles), 51 chemotherapy (three cycles), and 15 carboplatin. The study end point was a malignant event (ME), defined as detection of TIN upon control biopsy or occurrence of a second GCT. The Secondary end point was hypogonadism during follow-up. Results: Numbers, proportions of ME, and median event-free survival (EFS) times were: radiotherapy N = 3, 2.5%, 11.08 years; chemotherapy (two cycles) N = 15, 50%, 3.0 years; chemotherapy (three cycles) N = 12, 23.5%, 9.83 years; carboplatin N = 10, 66%, 0.9 years; surveillance N = 5, 50%, 7.08 years. EFS is significantly different among the groups. Hypogonadism rates were in radiotherapy patients 30.8%, chemotherapy (two cycles) 13%, chemotherapy (three cycles) 17.8%, carboplatin 40%, surveillance 40%. Conclusions: Local radiotherapy is highly efficacious in curing TIN. Chemotherapy is significantly less effective and the cure rates are dose-dependent. Though hypogonadism occurs in one-third of patients, radiotherapy with 20 Gy remains the standard management of TIN. Key words: cisplatin, contralateral tumour, hypogonadism, radiotherapy, testicular biopsy, testicular neoplasms
introduction Adult testicular germ cell tumours (GCTs) are preceded by a common progenitor originally called ‘carcinoma in situ’ by Skakkebaek in 1972 [1,2]. Currently, other names are preferred, e.g. intratubular germ cell neoplasia unspecified [3] or testicular intraepithelial neoplasia (TIN) [4]. Throughout this report, the latter term will be used. Detection of TIN is accomplished by standardized immunohistochemical staining methods (Supplementary Figure S1, available at Annals of Oncology online) [3,5,6]. The lesion is found in ∼4%–8% of contralateral testes in patients *Correspondence to: Prof. K.-P. Dieckmann, Department of Urology, AlbertinenKrankenhaus, Suentelstr. 11a, D-22457 Hamburg, Germany. Tel: +49-40-55-88-22-53; Fax: +49-40-55-88-23-81; E-mail: [email protected] †
Contributed equally to this work.
with unilateral GCTs [7,8]. If left untreated, TIN will progress to invasive cancer in 50% of cases within 5 years and probably all of the cases will do so in the long term [9,10]. Treatment options encompass orchiectomy, local radiotherapy of the testis or surveillance according to European Consensus guidelines [11,12]. The rationale of radiotherapy is, first, to eradicate TIN cells and second, to preserve the Leydig cells for hormone production (Figure 1) as well as to preserve the external shape of the scrotum for the preservation of the masculine body image [13]. Irradiation with 16–20 Gy is effective in almost all of the cases [14]. However, impairment of testosterone production is an untoward effect in approximately one-quarter of these patients [15,16]. Cisplatinum-based chemotherapy is highly efficacious in curing metastatic GCT and it also has some activity in the intratesticular compartment [17]. Chemotherapy may render TIN cells apoptotic; however, it remains uncertain how
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Received 19 August 2012; revised 20 October 2012; accepted 2 November 2012
original articles
Annals of Oncology
complete and how durable this effect is and to what extent the chemotherapy dosage does influence this effect [18]. The present knowledge of treatment of TIN is based on few reports on small sample sizes only. The aim of the present study is to evaluate the effects of radiotherapy and chemotherapy on biopsy-proven TIN in a large cohort of patients.
patients and methods In a multicentric survey conducted during 2006–2010, a total of 228 patients with unilateral GCTs and biopsy-proven contralateral TIN were retrospectively enrolled from 64 departments of urology in Germany and Austria (Supplementary Table S2, available at Annals of Oncology online). The study had been approved by an ethical committee. In Germany, contralateral biopsies are routinely carried out in about two-thirds of all GCT patients [19]. Eleven cases had been reported previously [20]. The following clinical parameters were registered using a commercially available database system (MS Access): histology of primary GCT (seminoma or nonseminoma), age at diagnosis, treatment in regard to contralateral TIN, duration of follow-up (months), and outcome regarding TIN. Treatment decisions were subject to local physicians according to the clinical stage of the primary tumour in agreement with current guide lines [12]. With regard to therapy of TIN, the following five options were registered: surveillance, radiotherapy to the testis with the standard dosage of 18–20 Gy, chemotherapy with two or less cycles of the PEB regimen (cisplatin, etoposide, bleomycin), chemotherapy with three or more cycles of PEB, or carboplatin monotherapy (dosage AUC 7; 1 to 2 courses). The median follow-up of all patients is 4 years (range 0.1–13.1 years). The primary end point of the study was the occurrence of a malignant event (ME) during follow-up, defined either by detection of TIN upon testicular control biopsy or by clinical detection of contralateral GCT upon follow-up visit. Decision to carry out a repeat biopsy was based on European guidelines in the chemotherapy patients [12] and on institutional guidelines in the others. A total of 107 patients (surveillance N = 6, radiotherapy N = 29, 2× PEB N = 23, ≥3 PEB N = 37, carboplatin N = 12) underwent control biopsy. The secondary end point was the occurrence of hypogonadism during follow-up. Although the measurements of serum testosterone levels would
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results Demographic details of the sample are summarized in Table 1. Of the 122 patients undergoing local radiotherapy, 33 (27%) had additional chemotherapy with carboplatin (N = 11), 2 courses of PEB (N = 12), and 3 courses of PEB (N = 10). Overall, 45 MEs were noted (19.7%), comprising 27 contralateral tumours presenting clinically and 18 cases with TIN detected upon re-biopsy (Table 2). The results with respect to carboplatin therapy have been briefly reported previously [22]. Noteworthily, nine chemotherapy patients developed ME, despite a TIN-negative control biopsy taken earlier during follow-up (Supplementary Table S3, available at Annals of Oncology online). The false-negative rate of biopsies in chemotherapy-treated patients is thus 12.5% (95% CI 5.88– 22.41). The EFS estimates regarding the five treatment modalities are given in Figure 2 and Table 2. Overall, there is a significant difference between treatment modalities with regard to EFS (log-rank test, P < 0.0001). In an exploratory post-hoc pair-wise comparison of treatment arms, radiotherapy imparted significantly longer EFS than chemotherapy with two or fewer cycles (P < 0.0001), three or more cycles chemotherapy (P < 0.0001), carboplatin (P < 0.0001) and surveillance (P = 0.0002), respectively. Of note, the three cycles regimen of chemotherapy conveyed significantly longer EFS than the two cycles regimen (P = 0.0336) and the carboplatin treatment (P = 0.0003), respectively. EFS in the group of two or fewer cycles PEB was not significantly different from that in the groups of carboplatin (P = 0.058) and surveillance (P = 0.123), respectively. The estimates of hazard ratios regarding the risk of ME in the various treatment modalities are listed in Table 3. Adjusting for clinical factors, i.e. patient’s age and histology of primary, did not alter the effects on the therapeutic outcome (P = 0.059, multivariate analysis, data not shown). Radiotherapy failed in three patients (details in Supplementary Table S4, available at Annals of Oncology online).
doi:10.1093/annonc/mds628 |
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Figure 1. Histological section of testicular biopsy specimen after radiotherapy: Sertoli cell only pattern. Note the absence of germ cells and TIN cells within tubules. Leydig cells in the interstitial spaces (arrow heads) appear normal, morphologically. Domagk-Elastika stain, Original ×15.
have been most appropriate to address this question, we had to simplify this evaluation for pragmatic reasons because of widely non-standardized follow-up examinations in this nationwide study. Thus, we restricted this analysis to the presence or absence of hypogonadism. Accordingly, hypogonadism was strictly defined by biochemical documentation of subnormal testosterone serum levels (if available) or by documented hormone supplementary medication. Clearly, some patients with existing androgen deficiency were missed by this rigid definition. Proportions of MEs and of hypogonadism, respectively, observed in the five treatment arms were evaluated statistically by calculating frequencies and percentages with regard to categorical data. Continuous data were summarized by using standard methods of descriptive analysis. Associated 95% Clopper–Pearson confidence intervals were derived. The Kaplan– Meier methods were applied for analyzing event-free survival (EFS). Analyses were stratified by treatment modalities and also by age groups and histology (seminoma versus nonseminoma). Log-rank tests were applied for comparison of groups. Cox proportional hazards models were applied to obtain point- and interval estimates of hazard ratios and to adjust treatment effects for potential prognostic factors. Statistical analysis was carried out with SAS software package version 9.2 (SAS Institute, Inc., Cary, NC) on Windows platform [21].
original articles
Annals of Oncology
Table 1. Summary of demographic data
Number of patients Age (years) Mean (SD) Median (Q1, Q3) Min, max Histology Non-seminoma Seminoma
Surveillance
Radiotherapy
≤2 cycles PEB
>2 cycles PEB
Carboplatin
Total
10
122
30
51
15
228
31.0 (5.7) 30 (26, 34) 24, 44
31.3 (6.4) 31 (27, 35) 20, 54
30.29 (8.2) 29 (24, 36) 17, 47
27.9 (7.0) 28 (22, 33) 15, 42
34.0 (6.4) 35 (29, 37) 22, 48
30.5 (6.9) 30 (26, 35) 15, 54
2 8
42 80
29 1
43 8
0 15
116 112
Q1 25% quantile, Q3 75% quantile; SD, standard deviation; min, minimum; max, maximum. PEB, cisplatin, etoposide, bleomycin. Table 2. Synopsis of malignant events
(N)
TIN/tumour
ME (%)
95% CI
(years)
10 122 30 51 15 228
5 3 15 12 10 45
0/5 0/3 5/10 5/7 8/2 18/27
50 2.5 50 23.5 66.7 19.7
18.7–81.3 0.52–7.13 31.3–68.7 12.79–37.49 38.4–88.2 14.6–24.90
7.08 11.08 3.0 9.83 0.92 11.08
Median EFS 95% CI 0.92–n.a. 11.08–n.a. 2.17–6.83 3.83–15.92 0.67–n.a. 9.83–15.92
ME, malignant event; EFS event-free survival; n.a. not applicable.
Figure 2. Malignant event (ME)-free survival estimates of patients with contralateral TIN stratified by treatment.
Hypogonadism was noted in a total of 55 patients among 205 eligible patients (Table 4). Following radiotherapy, 36 patients (30.8%) developed this sequel, 8 of whom (22%) had received additional chemotherapy. Surprisingly, a high prevalence of hypogonadism of 40% was observed in both the surveillance and the carboplatin group. However, as these groups consisted of very few patients only, these results may represent chance findings. In an overall analysis,
| Dieckmann et al.
no statistically significant association was found between endocrine deficit and treatment modality (P = 0.147). Hypogonadism rates appear to be lower in the cisplatin chemotherapy groups than in the radiotherapy group (13% and 17.8%, respectively, versus 30.8%). Yet, pair-wise comparison of these proportions revealed non-significant differences (P = 0.083 and P = 0.096, respectively). If both chemotherapy groups are combined, the hypogonadism rate
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Surveillance Radiotherapy Two cycles PEB Three or more cycles PEB Carboplatin Total
Eligible (N)
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Annals of Oncology Table 3. Hazard ratios of developing malignant event (ME) according to treatment arms using radiotherapy as standard based on Cox proportional hazards model Treatment
Hazard ratio
95% CI
Radiotherapy Chemotherapy two or more cycles PEB Chemotherapy three or more cycles PEB Carboplatin Surveillance
1.0 29.1 11.5 63.6 12.3
8.41–100.85 3.15–42.30 17.21–235.11 2.88–52.35
Table 4. Synopsis of patients with hypogonadism in relation to treatment Hypogonadism (N) (%) 95% CI
10 117 23 45 10
4 36 3 8 4
40 30.8 13.0 17.8 40
12.16–73.76 22.41–39.13 2.78–33.59 8.0–32.05 12.16–73.76
in chemotherapy patients (16.2%) is significantly lower than in irradiated cases (P = 0.028). Endocrine deficit is associated with increasing age (P = 0.0186) in an overall analysis of all treatment modalities. The association is strongest (P = 0.0044) in irradiated patients (Supplementary Table S5, available at Annals of Oncology online).
discussion There are two central results of this study. First, radiotherapy is highly efficacious in curing TIN but isolated failures occur. Second, cisplatinum-based chemotherapy is far less effective than radiotherapy and there is a clear dose–response relationship in regard to clearance of TIN. Low-dose localized radiotherapy was shown to cure TIN in 1986 [23], and its efficacy was repeatedly confirmed thereafter [24–26]. Accordingly, in a historical series of 1000 GCT patients receiving abdominal radiotherapy with inclusion of the remaining gonad in the radiation field, no case of contralateral GCT developed [27]. Testicular biopsies taken after radiotherapy usually reveal seminiferous tubules devoid of both TIN cells and germ cells but with preservation of Sertoli cells within the tubules and seemingly unaffected Leydig cells in the interstitial spaces (Figure 1). The present study fully confirmed the efficacy of radiotherapy, though three failures were noted (2.5%). Revision of the treatment protocols of the failing patients did not reveal any violations of radiotherapeutic treatment standards. Only three such cases had been documented previously [28,29]. Primary resistance of TIN to irradiation is the most probable reason for failure. The long intervals between radiotherapy and occurrence of second tumours would support this hypothesis. Accordingly, two of our failures occurred after long intervals (Supplementary Table S3, available at Annals of Oncology
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Surveillance Radiotherapy Two or fewer cycles PEB Three or more cycles PEB Carboplatin
Patients eligible (N)
online), but one presented after only 18 months. Technical problems may have accounted for this failure because the very small atrophic testicle of this patient probably caused targeting problems. The high cure rate of 97.5% reported here accords with the experience in more than 300 irradiated patients documented to date [13,16,25,26,28,30,31]. Chemotherapy is significantly less effective than local radiotherapy in eradicating TIN. In the 1980s, there was some suggestion of control of the lesion by chemotherapy [24]. However, that view contrasted with the experience of sequential bilateral GCTs occurring despite chemotherapy [32,33,34]. Also, two histopathological studies revealed the persistence of TIN after chemotherapy in >30% of cases [16,17], and in an observation study on 33 patients with TIN, a 10-year progression rate of 42% was reported [18]. Our results are in line with that experience demonstrating a high failure rate but obviously, there is evidence of at least some efficacy of chemotherapy. This contention is corroborated by a population-based study from Norway where contralateral tumours occurred less frequently in patients receiving systemic therapy [35]. The present study confirmed the importance of chemotherapy dosage in tackling TIN [20]. MEs occurred much more frequently in patients with low-dose chemotherapy (two cycles PEB or carboplatin) than in those with standard dose (50% and 66.6%, respectively, versus 23.5%). Accordingly, the median EFS was significantly higher in the standard-dose group (9.83 years) than in the groups with low-dose PEB (3.0 years) and carboplatin (0.92 years), respectively. The differences in EFS between the treatment modalities are very clear-cut; however, some caution is required with these results because the timing of control biopsies might influence the calculation of median EFS time. Although only 15 cases with carboplatin treatment were investigated, the unequivocally poor outcome with respect to control of TIN does not support the hypothesis of carboplatin being protective against second GCTs [36]. Importantly, a number of MEs occurred >5 years after chemotherapy (Figure 2). Probably, more events could have been registered if follow-up had been longer. This assumption is supported by the Norwegian study where bilateral tumours continued to occur in the chemotherapy group even after >20 years [35]. These observations endorse the view that TIN is temporarily suppressed or reduced in number rather than being completely eradicated by chemotherapy. Whether or not the blood–testis barrier [37] contributes to this effect or whether there is a primarily chemotherapy-resistant subfraction of TIN cells remains unsettled. Testicular biopsies may be inaccurate in pre-treated patients. In chemotherapy-naïve patients, false-negative biopsies are encountered in only 1% because usually most of the seminiferous tubules are populated by TIN cells [38]. Sensitivity of the biopsy is apparently inferior in pre-treated patients because TIN has been cleared from many tubules and is no more widely dispersed. Re-seeding of tubules with TIN takes time and if biopsy is done early after chemotherapy sampling errors may occur. Accordingly, a rate of false-negative biopsies of 12.5% was encountered in this study. Seven of the nine false-negative biopsies had been carried out within 1 year
original articles
| Dieckmann et al.
additional chemotherapy in about one-quarter of irradiated cases. Only 8 of 36 hypogonadal men after radiotherapy had received that dual therapy. Apparently, combining chemotherapy with radiotherapy does not result in a significantly further impairment of endocrinological function though minor deterioration cannot be ruled out. Although disputed by others [15], we found an association of hypogonadism with age in irradiated patients. As, radiotherapy patients had a somewhat higher median age than chemotherapy patients, it appears questionable whether the statistically significant advantage of chemotherapy over radiotherapy regarding endocrinological dysfunction is of clinical significance, likewise. Nonetheless, endeavours to reduce radiation dosage are undoubtedly mandatory. Two major studies yielded conflicting results [14,31]. Possibly, hyperfragmentation of irradiated dosage may afford both an efficacious and less toxic treatment of TIN [49]. Based on the present results, the 20 Gy regimen appears to be an appropriate standard until further data become available [12]. There are clearly limitations to this study. First, selection bias must be considered because cases have been enrolled retrospectively from 64 institutions. Second, there was no treatment protocol for radiotherapy nor were there any predefined quality standards regarding chemotherapy. Third, the median follow-up of 4 years is rather short particularly in light of late MEs occurring after chemotherapy. Fourth, follow-up was incomplete in many cases because aftercare was mostly done by office urologists not aware of the peculiarity of TIN. However, despite these drawbacks we believe that the results of this report deserve credit, because our study is by far the largest of its kind and the results are certainly sound. It is to be considered that contralateral TIN is an exceptionally rare entity and the final outcome of any treatment can only be assessed after very long observation periods. Thus, prospective controlled clinical trials based on the rules of evidence-based medicine will hardly ever be feasible. So, evidence for the efficacy of treatment modalities can only be obtained pragmatically by means of the classical skills of scholarly physicians, i.e. methodologically collecting cases, meticulous observation of patients, abstracting valuable information, analyzing data carefully and finally interpreting the results. In conclusion, local radiotherapy with 18–20 Gy eradicates TIN in ∼98%. Isolated failures may occur. Chemotherapy is less effective than radiotherapy, but there is evidence of some basic activity with regard to TIN. The effect of chemotherapy seems to be dose-dependent. Radiotherapy is inexorably associated with sterility. As the interval between diagnosis of TIN and clinical tumour manifestation is usually more than 1 year, further treatment may be deferred in patients with residual spermatogenesis for the purpose of achieving paternity. Hypogonadism must be expected in about one-third of patients irradiated with current standard doses. Refinement of the radiotherapeutic standard is mandatory.
disclosure The authors have declared no conflicts of interest.
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after completion of therapy. So, the efficacy of chemotherapy to treat TIN may be overestimated if the analysis mainly relies on control biopsies, methodologically. To obtain a safe control of TIN, it thus appears useful to apply additional radiotherapy in those patients who only require low-dose chemotherapy according to the clinical stage of the primary. In those receiving more than two cycles, definitive treatment of TIN should be postponed until rebiopsy has evidenced persistence of the lesion. Measurement of serum levels of follicle-stimulating hormone might aid in the detection of persisting TIN [39]; however, the sensitivity and specificity of this test are probably low. Ten patients underwent surveillance for TIN. Expectedly, half of them progressed to invasive cancer within a median time of 7 years. Though based on a very small number, this figure is entirely corresponding to previous data [9,40]. Treatment of TIN is not without adverse effects. The exocrine function of the testis was not addressed in this study. Radiotherapy of the testis inevitably results in sterility because germ cells are extremely vulnerable to ionizing impact [41]. Accordingly, the disappearance of germ cells secondary to radiotherapy was confirmed histologically (Figure 1). However, the clinical significance of sterility resulting from radiotherapy must be valued with caution. TIN is part of the testicular dysgenesis syndrome [42] and thus, various forms of spermatogenic arrest are typical, histologically [43]. Hence, infertility is a common clinical feature in TIN patients [7,44,45]. In all, the additional burden of sterility resulting from irradiation is probably modest. Further, the high cure rate needs to be balanced against a 30% rate of hypogonadism [13,16,41]. Evidently, this functional loss secondary to radiotherapy is dose dependent [41,15], and it develops despite grossly unchanged morphology of Leydig cells [24,16]. Moreover, a primary testicular dysfunction with subnormal endocrinological function must be considered in patients with TIN [45] as also observed in the present surveillance group. Moreover, testosterone deficiency may even develop in GCT patients with healthy contralateral gonad in up to one-quarter of cases in the long run as a consequence of a presumed primary Leydig cell dysfunction in GCT patients [46,47]. Thus, the hypogonadism rate observed subsequent to local radiotherapy must be weighted against the bottom-line of a pre-existing endocrine dysfunction in GCT patients. Cisplatin-based chemotherapy produced hypogonadism rates around 16% in TIN patients. Chemotherapy-related reduction of Leydig cell function is well documented [46,48], and evidently, there is a graded response to chemotherapy dosage. Accordingly, hypogonadism rates are slightly but not significantly different between the two PEB regimens (13% versus 18%). Moreover, these frequencies accord with hypogonadism rates generally found in GCT patients during the late course [47]. Radiotherapy appears to cause a higher rate of hypogonadism than the PEB regimens (30.8% versus 16.2%, P = 0.0028). However, this result requires caution because statistical significance was only obtained when the chemotherapy patients were taken together. Methodologically, comparison of the treatment modalities is confounded by
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1. Skakkebaek NE. Possible carcinoma in situ of the testis. Lancet 1972; ii: 516–517. 2. Dieckmann KP, Skakkebaek NE. Carcinoma in situ of the testis: a review of biological and clinical features. Int J Cancer 1999; 83: 815–822. 3. Emerson RE, Ulbright TM. Intratubular germ cell neoplasia of the testis and its associated cancers: the use of novel biomarkers. Pathology 2010; 42: 344–355. 4. Loy V, Dieckmann K-P. Carcinoma in situ of the testis: Intratubular germ cell neoplasia or testicular intraepithelial neoplasia? Hum Pathol 1990; 21: 457. 5. Looijenga LH. Human testicular (non)seminomatous germ cell tumours: the clinical implications of recent pathobiological insights. J Pathol 2009; 218: 146–162. 6. Hoei-Hansen CE, Olesen IA, Jorgensen N et al. Current approaches for detection of carcinoma in situ testis. Int. J. Androl. 2007; 30: 398–405. 7. Dieckmann KP, Kulejewski M, Pichlmeier U et al. Diagnosis of contralateral testicular intraepithelial neoplasia (TIN) in patients with testicular germ cell cancer: systematic two-site biopsies are more sensitive than a single random biopsy. Eur Urol 2007; 51: 175–185. 8. Kliesch S, Thomaidis T, Schütte B et al. Update on the diagnostic safety for detection of testicular intraepithelial neoplasia (TIN). APMIS 2003; 111: 70–74. 9. Rorth M, Rajpert-De Meyts E, Andersson L et al. Carcinoma in situ in the testis. Scand J Urol Nephrol 2000; 205(suppl.): 166–186. 10. Hoei-Hansen CE, Rajpert-De Meyts E, Daugaard G et al. Carcinoma in situ testis, the progenitor of testicular germ cell tumours: a clinical review. Ann Oncol 2005; 16: 863–868. 11. Albers P, Albrecht W, Algaba F et al. EAU guidelines on testicular cancer: 2011 update. Eur Urol 2011; 60: 304–319. 12. Krege S, Beyer J, Souchon R et al. European Consensus Conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus group (EGCCCG). Part I Eur Urol 2008; 53: 478–496. 13. Mortensen MS, Gundgaard MG, Daugaard G. Treatment options for carcinoma in situ testis. Int J Androl 2011; 34: e32–e36. 14. Classen J, Dieckmann K, Bamberg M et al. Radiotherapy with 16 Gy may fail to eradicate testicular intraepithelial neoplasia: preliminary communication of a dose-reduction trial of the German Testicular Cancer Study Group. Br. J. Cancer 2003; 88: 828–831. 15. Bang AK, Petersen JH, Petersen PM et al. Testosterone production is better preserved after 16 than 20 Gray irradiation treatment against testicular carcinoma in situ cells. Int J Radiat Oncol Biol Phys 2009; 75: 672–676. 16. Dieckmann KP, Loy V. The value of the biopsy of the contralateral testis in patients with testicular germ cell cancer: the recent German experience. APMIS 1998; 106: 13–20. 17. Bottomley D, Fisher C, Hendry WF et al. Persistent carcinoma in situ of the testis after chemotherapy for advanced testicular germ cell tumours. Br J Urol 1990; 66: 420–424. 18. Christensen TB, Daugaard G, Geertsen PF et al. Effect of chemotherapy on carcinoma in situ of the testis. Ann Oncol 1998; 9: 657–660. 19. Dieckmann KP, Classen J, Loy V. Diagnosis and management of testicular intraepithelial neoplasia (carcinoma in situ)-surgical aspects. APMIS 2003; 111: 64–68. 20. Kleinschmidt K, Dieckmann KP, Georgiew A et al. Chemotherapy is of limited efficacy in the control of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell cancer. Oncology 2009; 77: 33–39. 21. Armitage P, Berry G, Matthews JNS. Statistical Methods in Medical Research (4th edition). Oxford: Blackwell Scientific 2001. 22. Dieckmann KP, Matthies C, Kliesch S. Carboplatin does not prevent contralateral testicular tumors in patients with seminoma. J Clin Oncol 2011; 29: 2944–2945. 23. von der Maase H, Giwercman A, Skakkebaek NE. Radiation treatment of carcinoma-in-situ of testis [letter]. Lancet 1986; 1: 624–625. 24. von der Maase H, Giwercman A, Müller J et al. Management of carcinoma-insitu of the testis. Int J Androl 1987; 10: 209–220. 25. Dieckmann KP, Besserer A, Loy V. Low-dose radiation therapy of testicular intraepithelial neoplasia. J Cancer Res Clin Oncol 1993; 119: 355–359.
original articles
Annals of Oncology Annals of Oncology 24: 1332–1337, 2013 doi:10.1093/annonc/mds628 Published online 4 January 2013
Treatment of testicular intraepithelial neoplasia (intratubular germ cell neoplasia unspecified) with local radiotherapy or with platinum-based chemotherapy: A survey of the German Testicular Cancer Study Group K.-P. Dieckmann1*, †, S. Wilken1,†, V. Loy2, C. Matthies3, K. Kleinschmidt4, J. Bedke5, A. Martinschek6, R. Souchon7, U. Pichlmeier8 & S. Kliesch9 1 Department of Urology, Albertinen-Krankenhaus, Hamburg; 2Department of Pathology, Vivantes MVZ Am Urban, Berlin; 3Department of Urology, Bundeswehrkrankenhaus Hamburg, Hamburg; 4Department of Urology, Dr. Horst Schmidt Kliniken, Wiesbaden; 5Department of Urology, Universitätsklinikum, Tuebingen; 6Department of Urology, Bundeswehrkrankenhaus, Ulm; 7Department of Radiooncology, Universitätsklinikum, Tuebingen; 8Institute of Medical Biometry and Epidemiology, Centre of experimental Medicine, Universitätsklinikum Eppendorf, Hamburg; 9Centre of Reproductive Medicine, Universitätsklinikum, Muenster, Germany
Background: The treatment of testicular intraepithelial neoplasia (TIN), the progenitor of testicular germ cell tumours (GCTs), is based on little data.
Patients and methods: Two hundred and twenty-eight GCT patients with contralateral TIN were retrospectively enrolled. Ten had surveillance, 122 radiotherapy to testis with 18–20 Gy, 30 cisplatin-based chemotherapy (two cycles), 51 chemotherapy (three cycles), and 15 carboplatin. The study end point was a malignant event (ME), defined as detection of TIN upon control biopsy or occurrence of a second GCT. The Secondary end point was hypogonadism during follow-up. Results: Numbers, proportions of ME, and median event-free survival (EFS) times were: radiotherapy N = 3, 2.5%, 11.08 years; chemotherapy (two cycles) N = 15, 50%, 3.0 years; chemotherapy (three cycles) N = 12, 23.5%, 9.83 years; carboplatin N = 10, 66%, 0.9 years; surveillance N = 5, 50%, 7.08 years. EFS is significantly different among the groups. Hypogonadism rates were in radiotherapy patients 30.8%, chemotherapy (two cycles) 13%, chemotherapy (three cycles) 17.8%, carboplatin 40%, surveillance 40%. Conclusions: Local radiotherapy is highly efficacious in curing TIN. Chemotherapy is significantly less effective and the cure rates are dose-dependent. Though hypogonadism occurs in one-third of patients, radiotherapy with 20 Gy remains the standard management of TIN. Key words: cisplatin, contralateral tumour, hypogonadism, radiotherapy, testicular biopsy, testicular neoplasms
introduction Adult testicular germ cell tumours (GCTs) are preceded by a common progenitor originally called ‘carcinoma in situ’ by Skakkebaek in 1972 [1,2]. Currently, other names are preferred, e.g. intratubular germ cell neoplasia unspecified [3] or testicular intraepithelial neoplasia (TIN) [4]. Throughout this report, the latter term will be used. Detection of TIN is accomplished by standardized immunohistochemical staining methods (Supplementary Figure S1, available at Annals of Oncology online) [3,5,6]. The lesion is found in ∼4%–8% of contralateral testes in patients *Correspondence to: Prof. K.-P. Dieckmann, Department of Urology, AlbertinenKrankenhaus, Suentelstr. 11a, D-22457 Hamburg, Germany. Tel: +49-40-55-88-22-53; Fax: +49-40-55-88-23-81; E-mail: [email protected] †
Contributed equally to this work.
with unilateral GCTs [7,8]. If left untreated, TIN will progress to invasive cancer in 50% of cases within 5 years and probably all of the cases will do so in the long term [9,10]. Treatment options encompass orchiectomy, local radiotherapy of the testis or surveillance according to European Consensus guidelines [11,12]. The rationale of radiotherapy is, first, to eradicate TIN cells and second, to preserve the Leydig cells for hormone production (Figure 1) as well as to preserve the external shape of the scrotum for the preservation of the masculine body image [13]. Irradiation with 16–20 Gy is effective in almost all of the cases [14]. However, impairment of testosterone production is an untoward effect in approximately one-quarter of these patients [15,16]. Cisplatinum-based chemotherapy is highly efficacious in curing metastatic GCT and it also has some activity in the intratesticular compartment [17]. Chemotherapy may render TIN cells apoptotic; however, it remains uncertain how
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Received 19 August 2012; revised 20 October 2012; accepted 2 November 2012
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Annals of Oncology
complete and how durable this effect is and to what extent the chemotherapy dosage does influence this effect [18]. The present knowledge of treatment of TIN is based on few reports on small sample sizes only. The aim of the present study is to evaluate the effects of radiotherapy and chemotherapy on biopsy-proven TIN in a large cohort of patients.
patients and methods In a multicentric survey conducted during 2006–2010, a total of 228 patients with unilateral GCTs and biopsy-proven contralateral TIN were retrospectively enrolled from 64 departments of urology in Germany and Austria (Supplementary Table S2, available at Annals of Oncology online). The study had been approved by an ethical committee. In Germany, contralateral biopsies are routinely carried out in about two-thirds of all GCT patients [19]. Eleven cases had been reported previously [20]. The following clinical parameters were registered using a commercially available database system (MS Access): histology of primary GCT (seminoma or nonseminoma), age at diagnosis, treatment in regard to contralateral TIN, duration of follow-up (months), and outcome regarding TIN. Treatment decisions were subject to local physicians according to the clinical stage of the primary tumour in agreement with current guide lines [12]. With regard to therapy of TIN, the following five options were registered: surveillance, radiotherapy to the testis with the standard dosage of 18–20 Gy, chemotherapy with two or less cycles of the PEB regimen (cisplatin, etoposide, bleomycin), chemotherapy with three or more cycles of PEB, or carboplatin monotherapy (dosage AUC 7; 1 to 2 courses). The median follow-up of all patients is 4 years (range 0.1–13.1 years). The primary end point of the study was the occurrence of a malignant event (ME) during follow-up, defined either by detection of TIN upon testicular control biopsy or by clinical detection of contralateral GCT upon follow-up visit. Decision to carry out a repeat biopsy was based on European guidelines in the chemotherapy patients [12] and on institutional guidelines in the others. A total of 107 patients (surveillance N = 6, radiotherapy N = 29, 2× PEB N = 23, ≥3 PEB N = 37, carboplatin N = 12) underwent control biopsy. The secondary end point was the occurrence of hypogonadism during follow-up. Although the measurements of serum testosterone levels would
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results Demographic details of the sample are summarized in Table 1. Of the 122 patients undergoing local radiotherapy, 33 (27%) had additional chemotherapy with carboplatin (N = 11), 2 courses of PEB (N = 12), and 3 courses of PEB (N = 10). Overall, 45 MEs were noted (19.7%), comprising 27 contralateral tumours presenting clinically and 18 cases with TIN detected upon re-biopsy (Table 2). The results with respect to carboplatin therapy have been briefly reported previously [22]. Noteworthily, nine chemotherapy patients developed ME, despite a TIN-negative control biopsy taken earlier during follow-up (Supplementary Table S3, available at Annals of Oncology online). The false-negative rate of biopsies in chemotherapy-treated patients is thus 12.5% (95% CI 5.88– 22.41). The EFS estimates regarding the five treatment modalities are given in Figure 2 and Table 2. Overall, there is a significant difference between treatment modalities with regard to EFS (log-rank test, P < 0.0001). In an exploratory post-hoc pair-wise comparison of treatment arms, radiotherapy imparted significantly longer EFS than chemotherapy with two or fewer cycles (P < 0.0001), three or more cycles chemotherapy (P < 0.0001), carboplatin (P < 0.0001) and surveillance (P = 0.0002), respectively. Of note, the three cycles regimen of chemotherapy conveyed significantly longer EFS than the two cycles regimen (P = 0.0336) and the carboplatin treatment (P = 0.0003), respectively. EFS in the group of two or fewer cycles PEB was not significantly different from that in the groups of carboplatin (P = 0.058) and surveillance (P = 0.123), respectively. The estimates of hazard ratios regarding the risk of ME in the various treatment modalities are listed in Table 3. Adjusting for clinical factors, i.e. patient’s age and histology of primary, did not alter the effects on the therapeutic outcome (P = 0.059, multivariate analysis, data not shown). Radiotherapy failed in three patients (details in Supplementary Table S4, available at Annals of Oncology online).
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Figure 1. Histological section of testicular biopsy specimen after radiotherapy: Sertoli cell only pattern. Note the absence of germ cells and TIN cells within tubules. Leydig cells in the interstitial spaces (arrow heads) appear normal, morphologically. Domagk-Elastika stain, Original ×15.
have been most appropriate to address this question, we had to simplify this evaluation for pragmatic reasons because of widely non-standardized follow-up examinations in this nationwide study. Thus, we restricted this analysis to the presence or absence of hypogonadism. Accordingly, hypogonadism was strictly defined by biochemical documentation of subnormal testosterone serum levels (if available) or by documented hormone supplementary medication. Clearly, some patients with existing androgen deficiency were missed by this rigid definition. Proportions of MEs and of hypogonadism, respectively, observed in the five treatment arms were evaluated statistically by calculating frequencies and percentages with regard to categorical data. Continuous data were summarized by using standard methods of descriptive analysis. Associated 95% Clopper–Pearson confidence intervals were derived. The Kaplan– Meier methods were applied for analyzing event-free survival (EFS). Analyses were stratified by treatment modalities and also by age groups and histology (seminoma versus nonseminoma). Log-rank tests were applied for comparison of groups. Cox proportional hazards models were applied to obtain point- and interval estimates of hazard ratios and to adjust treatment effects for potential prognostic factors. Statistical analysis was carried out with SAS software package version 9.2 (SAS Institute, Inc., Cary, NC) on Windows platform [21].
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Annals of Oncology
Table 1. Summary of demographic data
Number of patients Age (years) Mean (SD) Median (Q1, Q3) Min, max Histology Non-seminoma Seminoma
Surveillance
Radiotherapy
≤2 cycles PEB
>2 cycles PEB
Carboplatin
Total
10
122
30
51
15
228
31.0 (5.7) 30 (26, 34) 24, 44
31.3 (6.4) 31 (27, 35) 20, 54
30.29 (8.2) 29 (24, 36) 17, 47
27.9 (7.0) 28 (22, 33) 15, 42
34.0 (6.4) 35 (29, 37) 22, 48
30.5 (6.9) 30 (26, 35) 15, 54
2 8
42 80
29 1
43 8
0 15
116 112
Q1 25% quantile, Q3 75% quantile; SD, standard deviation; min, minimum; max, maximum. PEB, cisplatin, etoposide, bleomycin. Table 2. Synopsis of malignant events
(N)
TIN/tumour
ME (%)
95% CI
(years)
10 122 30 51 15 228
5 3 15 12 10 45
0/5 0/3 5/10 5/7 8/2 18/27
50 2.5 50 23.5 66.7 19.7
18.7–81.3 0.52–7.13 31.3–68.7 12.79–37.49 38.4–88.2 14.6–24.90
7.08 11.08 3.0 9.83 0.92 11.08
Median EFS 95% CI 0.92–n.a. 11.08–n.a. 2.17–6.83 3.83–15.92 0.67–n.a. 9.83–15.92
ME, malignant event; EFS event-free survival; n.a. not applicable.
Figure 2. Malignant event (ME)-free survival estimates of patients with contralateral TIN stratified by treatment.
Hypogonadism was noted in a total of 55 patients among 205 eligible patients (Table 4). Following radiotherapy, 36 patients (30.8%) developed this sequel, 8 of whom (22%) had received additional chemotherapy. Surprisingly, a high prevalence of hypogonadism of 40% was observed in both the surveillance and the carboplatin group. However, as these groups consisted of very few patients only, these results may represent chance findings. In an overall analysis,
| Dieckmann et al.
no statistically significant association was found between endocrine deficit and treatment modality (P = 0.147). Hypogonadism rates appear to be lower in the cisplatin chemotherapy groups than in the radiotherapy group (13% and 17.8%, respectively, versus 30.8%). Yet, pair-wise comparison of these proportions revealed non-significant differences (P = 0.083 and P = 0.096, respectively). If both chemotherapy groups are combined, the hypogonadism rate
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Surveillance Radiotherapy Two cycles PEB Three or more cycles PEB Carboplatin Total
Eligible (N)
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Annals of Oncology Table 3. Hazard ratios of developing malignant event (ME) according to treatment arms using radiotherapy as standard based on Cox proportional hazards model Treatment
Hazard ratio
95% CI
Radiotherapy Chemotherapy two or more cycles PEB Chemotherapy three or more cycles PEB Carboplatin Surveillance
1.0 29.1 11.5 63.6 12.3
8.41–100.85 3.15–42.30 17.21–235.11 2.88–52.35
Table 4. Synopsis of patients with hypogonadism in relation to treatment Hypogonadism (N) (%) 95% CI
10 117 23 45 10
4 36 3 8 4
40 30.8 13.0 17.8 40
12.16–73.76 22.41–39.13 2.78–33.59 8.0–32.05 12.16–73.76
in chemotherapy patients (16.2%) is significantly lower than in irradiated cases (P = 0.028). Endocrine deficit is associated with increasing age (P = 0.0186) in an overall analysis of all treatment modalities. The association is strongest (P = 0.0044) in irradiated patients (Supplementary Table S5, available at Annals of Oncology online).
discussion There are two central results of this study. First, radiotherapy is highly efficacious in curing TIN but isolated failures occur. Second, cisplatinum-based chemotherapy is far less effective than radiotherapy and there is a clear dose–response relationship in regard to clearance of TIN. Low-dose localized radiotherapy was shown to cure TIN in 1986 [23], and its efficacy was repeatedly confirmed thereafter [24–26]. Accordingly, in a historical series of 1000 GCT patients receiving abdominal radiotherapy with inclusion of the remaining gonad in the radiation field, no case of contralateral GCT developed [27]. Testicular biopsies taken after radiotherapy usually reveal seminiferous tubules devoid of both TIN cells and germ cells but with preservation of Sertoli cells within the tubules and seemingly unaffected Leydig cells in the interstitial spaces (Figure 1). The present study fully confirmed the efficacy of radiotherapy, though three failures were noted (2.5%). Revision of the treatment protocols of the failing patients did not reveal any violations of radiotherapeutic treatment standards. Only three such cases had been documented previously [28,29]. Primary resistance of TIN to irradiation is the most probable reason for failure. The long intervals between radiotherapy and occurrence of second tumours would support this hypothesis. Accordingly, two of our failures occurred after long intervals (Supplementary Table S3, available at Annals of Oncology
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Surveillance Radiotherapy Two or fewer cycles PEB Three or more cycles PEB Carboplatin
Patients eligible (N)
online), but one presented after only 18 months. Technical problems may have accounted for this failure because the very small atrophic testicle of this patient probably caused targeting problems. The high cure rate of 97.5% reported here accords with the experience in more than 300 irradiated patients documented to date [13,16,25,26,28,30,31]. Chemotherapy is significantly less effective than local radiotherapy in eradicating TIN. In the 1980s, there was some suggestion of control of the lesion by chemotherapy [24]. However, that view contrasted with the experience of sequential bilateral GCTs occurring despite chemotherapy [32,33,34]. Also, two histopathological studies revealed the persistence of TIN after chemotherapy in >30% of cases [16,17], and in an observation study on 33 patients with TIN, a 10-year progression rate of 42% was reported [18]. Our results are in line with that experience demonstrating a high failure rate but obviously, there is evidence of at least some efficacy of chemotherapy. This contention is corroborated by a population-based study from Norway where contralateral tumours occurred less frequently in patients receiving systemic therapy [35]. The present study confirmed the importance of chemotherapy dosage in tackling TIN [20]. MEs occurred much more frequently in patients with low-dose chemotherapy (two cycles PEB or carboplatin) than in those with standard dose (50% and 66.6%, respectively, versus 23.5%). Accordingly, the median EFS was significantly higher in the standard-dose group (9.83 years) than in the groups with low-dose PEB (3.0 years) and carboplatin (0.92 years), respectively. The differences in EFS between the treatment modalities are very clear-cut; however, some caution is required with these results because the timing of control biopsies might influence the calculation of median EFS time. Although only 15 cases with carboplatin treatment were investigated, the unequivocally poor outcome with respect to control of TIN does not support the hypothesis of carboplatin being protective against second GCTs [36]. Importantly, a number of MEs occurred >5 years after chemotherapy (Figure 2). Probably, more events could have been registered if follow-up had been longer. This assumption is supported by the Norwegian study where bilateral tumours continued to occur in the chemotherapy group even after >20 years [35]. These observations endorse the view that TIN is temporarily suppressed or reduced in number rather than being completely eradicated by chemotherapy. Whether or not the blood–testis barrier [37] contributes to this effect or whether there is a primarily chemotherapy-resistant subfraction of TIN cells remains unsettled. Testicular biopsies may be inaccurate in pre-treated patients. In chemotherapy-naïve patients, false-negative biopsies are encountered in only 1% because usually most of the seminiferous tubules are populated by TIN cells [38]. Sensitivity of the biopsy is apparently inferior in pre-treated patients because TIN has been cleared from many tubules and is no more widely dispersed. Re-seeding of tubules with TIN takes time and if biopsy is done early after chemotherapy sampling errors may occur. Accordingly, a rate of false-negative biopsies of 12.5% was encountered in this study. Seven of the nine false-negative biopsies had been carried out within 1 year
original articles
| Dieckmann et al.
additional chemotherapy in about one-quarter of irradiated cases. Only 8 of 36 hypogonadal men after radiotherapy had received that dual therapy. Apparently, combining chemotherapy with radiotherapy does not result in a significantly further impairment of endocrinological function though minor deterioration cannot be ruled out. Although disputed by others [15], we found an association of hypogonadism with age in irradiated patients. As, radiotherapy patients had a somewhat higher median age than chemotherapy patients, it appears questionable whether the statistically significant advantage of chemotherapy over radiotherapy regarding endocrinological dysfunction is of clinical significance, likewise. Nonetheless, endeavours to reduce radiation dosage are undoubtedly mandatory. Two major studies yielded conflicting results [14,31]. Possibly, hyperfragmentation of irradiated dosage may afford both an efficacious and less toxic treatment of TIN [49]. Based on the present results, the 20 Gy regimen appears to be an appropriate standard until further data become available [12]. There are clearly limitations to this study. First, selection bias must be considered because cases have been enrolled retrospectively from 64 institutions. Second, there was no treatment protocol for radiotherapy nor were there any predefined quality standards regarding chemotherapy. Third, the median follow-up of 4 years is rather short particularly in light of late MEs occurring after chemotherapy. Fourth, follow-up was incomplete in many cases because aftercare was mostly done by office urologists not aware of the peculiarity of TIN. However, despite these drawbacks we believe that the results of this report deserve credit, because our study is by far the largest of its kind and the results are certainly sound. It is to be considered that contralateral TIN is an exceptionally rare entity and the final outcome of any treatment can only be assessed after very long observation periods. Thus, prospective controlled clinical trials based on the rules of evidence-based medicine will hardly ever be feasible. So, evidence for the efficacy of treatment modalities can only be obtained pragmatically by means of the classical skills of scholarly physicians, i.e. methodologically collecting cases, meticulous observation of patients, abstracting valuable information, analyzing data carefully and finally interpreting the results. In conclusion, local radiotherapy with 18–20 Gy eradicates TIN in ∼98%. Isolated failures may occur. Chemotherapy is less effective than radiotherapy, but there is evidence of some basic activity with regard to TIN. The effect of chemotherapy seems to be dose-dependent. Radiotherapy is inexorably associated with sterility. As the interval between diagnosis of TIN and clinical tumour manifestation is usually more than 1 year, further treatment may be deferred in patients with residual spermatogenesis for the purpose of achieving paternity. Hypogonadism must be expected in about one-third of patients irradiated with current standard doses. Refinement of the radiotherapeutic standard is mandatory.
disclosure The authors have declared no conflicts of interest.
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after completion of therapy. So, the efficacy of chemotherapy to treat TIN may be overestimated if the analysis mainly relies on control biopsies, methodologically. To obtain a safe control of TIN, it thus appears useful to apply additional radiotherapy in those patients who only require low-dose chemotherapy according to the clinical stage of the primary. In those receiving more than two cycles, definitive treatment of TIN should be postponed until rebiopsy has evidenced persistence of the lesion. Measurement of serum levels of follicle-stimulating hormone might aid in the detection of persisting TIN [39]; however, the sensitivity and specificity of this test are probably low. Ten patients underwent surveillance for TIN. Expectedly, half of them progressed to invasive cancer within a median time of 7 years. Though based on a very small number, this figure is entirely corresponding to previous data [9,40]. Treatment of TIN is not without adverse effects. The exocrine function of the testis was not addressed in this study. Radiotherapy of the testis inevitably results in sterility because germ cells are extremely vulnerable to ionizing impact [41]. Accordingly, the disappearance of germ cells secondary to radiotherapy was confirmed histologically (Figure 1). However, the clinical significance of sterility resulting from radiotherapy must be valued with caution. TIN is part of the testicular dysgenesis syndrome [42] and thus, various forms of spermatogenic arrest are typical, histologically [43]. Hence, infertility is a common clinical feature in TIN patients [7,44,45]. In all, the additional burden of sterility resulting from irradiation is probably modest. Further, the high cure rate needs to be balanced against a 30% rate of hypogonadism [13,16,41]. Evidently, this functional loss secondary to radiotherapy is dose dependent [41,15], and it develops despite grossly unchanged morphology of Leydig cells [24,16]. Moreover, a primary testicular dysfunction with subnormal endocrinological function must be considered in patients with TIN [45] as also observed in the present surveillance group. Moreover, testosterone deficiency may even develop in GCT patients with healthy contralateral gonad in up to one-quarter of cases in the long run as a consequence of a presumed primary Leydig cell dysfunction in GCT patients [46,47]. Thus, the hypogonadism rate observed subsequent to local radiotherapy must be weighted against the bottom-line of a pre-existing endocrine dysfunction in GCT patients. Cisplatin-based chemotherapy produced hypogonadism rates around 16% in TIN patients. Chemotherapy-related reduction of Leydig cell function is well documented [46,48], and evidently, there is a graded response to chemotherapy dosage. Accordingly, hypogonadism rates are slightly but not significantly different between the two PEB regimens (13% versus 18%). Moreover, these frequencies accord with hypogonadism rates generally found in GCT patients during the late course [47]. Radiotherapy appears to cause a higher rate of hypogonadism than the PEB regimens (30.8% versus 16.2%, P = 0.0028). However, this result requires caution because statistical significance was only obtained when the chemotherapy patients were taken together. Methodologically, comparison of the treatment modalities is confounded by
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Annals of Oncology
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Volume 24 | No. 5 | May 2013
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