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Objective To validate Vergouwe's prediction model using the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) RETROP database and to define its clinical utility. Materials and methods Vergouwe's prediction model for benign histopathology in post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) uses the following variables: presence of teratoma in orchiectomy specimen; pre-chemotherapy level of alpha-fetoprotein; β-Human chorionic gonadotropin and lactate dehydrogenase; and lymph node size pre- and post-chemotherapy. Our validation cohort consisted of patients included in RETROP, a prospective population-based database of patients in Sweden and Norway with metastatic nonseminoma, who underwent PC-RPLND in the period 2007–2014. Discrimination and calibration analyses were used to validate Vergouwe's prediction model results. Calibration plots were created and a Hosmer–Lemeshow test was calculated. Clinical utility, expressed as opt-out net benefit (NBopt-out), was analysed using decision curve analysis. Results Overall, 284 patients were included in the analysis, of whom 130 (46%) had benign histology after PC-RPLND. Discrimination analysis showed good reproducibility, with an area under the receiver-operating characteristic curve (AUC) of 0.82 (95% confidence interval 0.77–0.87) compared to Vergouwe's prediction model (AUC between 0.77 and 0.84). Calibration was acceptable with no recalibration. Using a prediction threshold of 70% for benign histopathology, NBopt-out was 0.098. Using the model and this threshold, 61 patients would have been spared surgery. However, only 51 of 61 were correctly classified as benign. Conclusions The model was externally validated with good reproducibility. In a clinical setting, the model may identify patients with a high chance of benign histopathology, thereby sparing patients of surgery. However, meticulous follow-up is required.

Background Both testicular germ cell tumours (TGCT) and neurodevelopmental disorders are associated with urogenital malformations. Few studies have investigated the association between psychiatric disorders and TGCT. We investigated whether history of any psychiatric or neurodevelopmental disorder is associated with increased risk or mortality of TGCT. Method This is a nested case–control study including 6166 TGCT patients diagnosed during 1992–2014, individually matched for age and calendar period to 61,660 controls. We calculated odds ratios (ORs) for the association between type of psychiatric diagnoses and TGCT risk. Among the cases, we used a cohort design and calculated hazard ratios (HRs) of the association between psychiatric diagnose and all-cause and TGCT-specific death. Results History of a neurodevelopmental disorder (attention deficit hyperactivity disorder, autism spectrum disorder and intellectual disabilities) was associated with an increased risk of seminoma (OR: 1.54; 1.09–2.19). Seminoma patients with neurodevelopmental disorders were younger (34 versus 38 years, p = 0.004) and had more stage IV disease (5.4% versus 1.2%) than those without. Psychiatric history overall was not associated with TGCT. Patient history of any psychiatric disorder was associated with an increased all-cause and TGCT-specific death. Conclusions We report an association between neurodevelopmental disorders and testicular seminoma, and an increased TGCT-specific mortality for TGCT patients with psychiatric disorders.

Purpose Hirschsprung disease (HSCR) has previously been associated with increased risk of medullary thyroid cancer. The aim of this study was to assess the overall risk of malignancies in patients with Hirschsprung disease in a population-based cohort. Methods This was a nationwide, population-based cohort study. The study exposure was HSCR and the study outcome was malignancy. The cohort included all individuals with HSCR registered in the Swedish National Patient Register between 1964 and 2013 and ten age- and sex-matched controls per patient, randomly selected from the Population Register. Data were linked with the Swedish National Cancer Register to identify individuals with malignancy diagnosis. Results The cohort comprised 739 individuals with HSCR (565 male) and 7390 controls (5650 male). Median age of the cohort was 19 years (range 2–49). In total nine (1.2%) individuals in the exposed cohort were diagnosed with malignancies compared to 57 (0.8%) in the non-exposed cohort (p = 0.195). Median age at malignancy diagnosis was 3 years (range 0–46) in the exposed group, compared to 23 (range 0–42), p = 0.132. No cases with medullary carcinoma of the thyroid were found in this cohort. Conclusions There was no significant difference in risk of malignancies in the exposed group compared to the unexposed group.

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 = 70), one cycle of adjuvant BEP (bleomycin, etoposide, cisplatin, 5 day regimen) (BEP, N = 62), one cycle of adjuvant carboplatin AUC 7 (Carbo, N = 22), and patients managed by surveillance (SURV, N = 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 = 11) were observed in most treatment groups except for in the BEP group. During follow-up, 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. (Less)

Background The distribution of retroperitoneal lymph node metastases for patients with nonseminoma and a residual tumour of 10–49 mm in a population-based setting is unknown. This information is needed to justify selection of patients for a unilateral template resection. Objective To describe the location of retroperitoneal metastases and recurrences in patients with nonseminoma germ cell tumour (NSGCT) with a residual tumour of 10–49 mm. Design, setting, and participants RETROP is a population-based prospective observational mapping study of 213 patients in Sweden and Norway with a retroperitoneal residual tumour of 10–49 mm who underwent postchemotherapy retroperitoneal lymph node dissection for metastatic NSGCT during 2007–2014 with median follow-up of 100 mo. Patients were classified according to the testis primary tumour and the distribution of unilateral or bilateral lymph node metastases (with reference to the aorta) present on pre- and/or postchemotherapy computed tomography (CT) scans. Outcome measurements and statistical analysis The distribution and rate of teratoma or cancer in unilateral or bilateral retroperitoneal fields and the location and rate of retroperitoneal recurrence were measured. Results and limitations In total, 65% of the patients had unilateral retroperitoneal lymph node metastases (RLNMs) on CT scans. Patients with unilateral RLNMs had a low risk of contralateral teratoma or cancer (1.6% for right- and 2.6% for left-sided NSGCT) or retroperitoneal recurrence (0% for right- and 4% for left-sided NSGCT). A weakness of the study is that the pathology specimen could not be fully designated to one specific area for some of the patients. Conclusions Men with postchemotherapy residual disease of 10–49 mm and unilateral metastases on pre- and postchemotherapy CT scans have a low risk of contralateral disease and should be considered for a unilateral template resection. Patient summary The surgeon can use computed tomography (CT) scans in deciding on the extent of lymph node dissection in patients with testicular cancer.

Background Reports on perioperative complications after postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for nonseminoma germ cell tumour (NSGCT) are from experienced single centres, with a lack of population-based studies. Objective To assess the complications of bilateral and unilateral PC-RPLND. Design, setting, and participants A prospective, population-based, observational multicentre study included all patients with NSGCT who underwent PC-RPLND in Norway and Sweden during 2007–2014. Of a total of 318 patients, 87 underwent bilateral PC-RPLND and 231 underwent unilateral PC-RPLND. The median follow-up was 6 yr. Outcome measurements and statistical analysis Bilateral and unilateral PC-RPLND were compared for the outcomes of intra- and postoperative complications (graded by Clavien-Dindo) and retrograde ejaculation (with or without nerve-sparing surgery). Complications were reported as absolute counts and percentages. The χ2 test was used for comparisons. Results and limitations The incidence of intraoperative complications was higher for bilateral PC-RPLND than for unilateral PC-RPLND (14% vs 4.3%, p = 0.003), with ureteral injury as the most frequent reported complication (2% of the patients). Postoperative complications were more common after bilateral than after unilateral PC-RPLND (45% vs 25%, p = 0.001) with Clavien ≥3b reported in 8.3% and 2.2%, respectively (p = 0.009). Lymphatic leakage was the most common complication occurring in 11% of the patients. Retrograde ejaculation occurred more frequently after bilateral than after unilateral surgery (59% vs 32%, p

PURPOSE Clinical stage I (CSI) nonseminoma (NS) is a disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant chemotherapy. Little is known about the outcome of patients who experience relapse after such treatment. PATIENTS AND METHODS Data from 51 patients with CSI NS who experienced a relapse after adjuvant bleomycin, etoposide, and cisplatin (BEP) from 18 centers/11 countries were collected and retrospectively analyzed. Primary outcomes were overall and progression-free survivals calculated from day 1 of treatment at first relapse. Secondary outcomes were time to, stage at, and treatment of relapse and rate of subsequent relapses. RESULTS Median time to relapse was 13 months, with the earliest relapse 2 months after start of adjuvant treatment and the latest after 25 years. With a median follow-up of 96 months, the 5-year PFS was 67% (95% CI, 54% to 82%) and the 5-year OS was 81% (95% CI, 70% to 94%). Overall, 19 (37%) of 51 relapses occurred later than 2 years. Late relapses were associated with a significantly higher risk of death from NS (hazard ratio, 1.10 per year; P = .01). Treatment upon relapse was diverse: the majority of patients received a combination of chemotherapy and surgery. Twenty-nine percent of patients experienced a subsequent relapse. At last follow-up, 41 patients (80%) were alive and disease-free, eight (16%) had died of progressive disease, and one patient (2%) each had died from therapy-related or other causes. CONCLUSION Outcomes of patients with relapse after adjuvant BEP seem better compared with patients who experience relapse after treatment of metastatic disease but worse compared with those who have de-novo metastatic disease. We found a substantial rate of late and subsequent relapses. There seem to be three patterns of relapse with different outcomes: pure teratoma, early viable NS relapse (< 2 years), and late viable NS relapse (> 2 years).

Spermatogenesis is an androgen-regulated process that depends on the action of androgen receptor (AR). Sperm production may be affected in men treated for testicular cancer (TC), and it is important to identify the factors influencing the timing of spermatogenesis recovery following cancer treatment. It is known that the CAG and GGN repeat numbers affect the activity of the AR; therefore, the aim of this study is to investigate if the CAG and GGN polymorphisms in the AR gene predict recovery of sperm production after TC treatment. TC patients (n = 130) delivered ejaculates at the following time points: postorchiectomy and at 6, 12, 24, 36, and 60 months posttherapy (T0, T6, T12, T24, T36, and T60). The CAG lengths were categorized into three groups, 23 CAG, and the GGN tracts were also categorized into three groups, 23 GGN. At T12, men with 22-23 CAG presented with a statistically significantly (P = 0.045) lower sperm concentration than those with other CAG numbers (8.4 × 106 ml−1 vs 16 × 106 ml−1 ; 95% CI: 1.01-2.65). This association was robust to omitting adjustment for treatment type and sperm concentration at T0 (P = 0.021; 3.7 × 106 ml−1 vs 10 × 106 ml−1 ; 95% CI: 1.13-4.90). The same trends were observed for total sperm number. The least active AR variant seems to be associated with a more rapid recovery of spermatogenesis. This finding adds to our understanding of the biology of postcancer therapy recovery of fertility in males and has clinical implications.

Background Because of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk. Methods and findings In this nationwide register study, all singletons born in Sweden 1994–2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19–1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment–to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54–1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25–4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995–2000—both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited. Conclusions No additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients., Yahia Al-Jebari and colleagues reveal no increased risk of congenital malformations in children of men treated for testicular germ cell cancer., Author summary Why was this study done? Chemotherapy and radiotherapy have both been shown to cause mutations and genetic damage in animal studies, leading to fears that men being treated with these therapies might be more prone to have children with genetic diseases and birth defects. This study investigates whether receiving treatment for testicular cancer, being the most common cancer among young men (in child-having ages), leads to a higher risk of fathering a child with a birth defect. What did the researchers do and find? By accessing data from Swedish national registries, we gathered data on more than 2 million newborns and their fathers. Among them, 2,380 fathers had testicular cancer and they had, in total, 4,207 children. When comparing the children conceived after the father received cancer treatment to the children born before treatment, we could not find any evidence showing that chemotherapy or radiotherapy leads to an increased risk of birth defects. We did see that there was, irrespectively of cancer treatment, a small risk increase associated with the fathers’ testicular cancer itself, meaning that men with testicular cancer have an approximately 30% higher relative risk of having a child with a birth defect (an increase from 3.5% to 4.4%). What do these findings mean? There was no risk increase due to cancer therapies. The risk increase detected was associated with testicular cancer. However, this risk increase is very small and relates to rare conditions. Because the risk increase is small, we therefore do not consider this cause for concern and wish this reassuring information to be passed on to patients.

Background: Germ cell tumor patients with intermediate prognosis (IPGCT) according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification represent a heterogeneous group with different clinical features. This analysis was performed to investigate the prognostic impact of different tumor marker levels prior to first line chemotherapy within IPGCT. Methods: For this study an international registry for IPGCT was established. Eligibility criteria were intermediate prognosis according to IGCCCG criteria, nonseminomatous histology, male sex, and age ≥ 16 years. Uni- and multivariate analysis were conducted to identify characteristics associated with survival outcomes. Receiver-Operating-Characteristic curve analysis was applied to find cut-off parameters. Five-year overall survival (OS) rate was the primary and 5-year progression-free survival rate the secondary endpoint. Results: This database included 634 IPGCT with a median follow-up of 9.0 years (interquartile range: 14.35). Patients received first line treatment with platinum based chemotherapy, associated with a 5-year OS rate of 87%. The stratification of patients according to AFP levels revealed a correlation between AFP levels and outcome, associated with 5-year OS rates of 88% for AFP levels 2,000 to 6,000 IU/ml (n = 121), and 82% for >6,000 IU/ml (n = 57) prior first course of chemotherapy, respectively (P= 0.013). LDH levels prior fist course of chemotherapy also correlated with outcome associated with 5-year OS rates of 92% for 3 to 4 UNL (n = 34), and 77% for >4 UNL (n = 79), respectively (P= 0.03). Different HCG levels prior chemotherapy were not associated with outcome. In multivariable analysis AFP levels >6,000 IU/ml (P= 0.023; hazard ratio HR 2.263) or >1,982 IU/ml (P= 0.031; HR 1.722), and LDH levels >3 UNL (P< 0.001; HR 2.616) were independent prognosticators for OS. Conclusions: Prognostication according to LDH and AFP levels prior chemotherapy could offer a new approach to stratify patients within the intermediate prognosis cohort. According to our findings, patients with AFP values above 6,000 IU/ml or/and LDH > 3 UNL represent an independent high risk cohort. Our results need to be confirmed in the upcoming IGCCCG reclassification.

Purpose To define characteristics, treatment response, and outcomes of men with brain metastases (BM) from germ cell tumors (GCT). Patients and Methods Data from 523 men with BM from GCT were collected retrospectively from 46 centers in 13 countries by using standardized questionnaires. Clinical features were correlated with overall survival (OS) as the primary end point. Results BM were present at initial diagnosis in 228 men (group A) and at relapse in 295 men (group B). OS at 3 years (3-year OS) was superior in group A versus group B (48% v 27%; P < .001). Multiple BM and the presence of liver or bone metastasis were independent adverse prognostic factors in both groups; primary mediastinal nonseminoma (group A) and elevations of α-fetoprotein of 100 ng/mL or greater or of human chorionic gonadotropin of 5,000 U/L or greater (group B) were additional independent adverse prognostic factors. Depending on these factors, the 3-year OS ranged from 0% to 70% in group A and from 6% to 52% in group B. In group A, 99% of patients received chemotherapy; multimodality treatment or high-dose chemotherapy was not associated with statistically improved survival in multivariable analysis. In group B, only 54% of patients received chemotherapy; multimodality treatment was associated with improved survival compared with single-modality therapy (hazard ratio, 0.51; 95% CI, 0.36 to 0.73; P < .001), as was high-dose compared with conventional-dose chemotherapy (hazard ratio, 0.41; 95% CI, 0.24 to 0.70; P = .001). Conclusion Men with BM from GCT have poor OS, particularly if additional risk factors are present. High-dose chemotherapy and multimodality treatment seemed to improve survival probabilities in men with BM at relapse.

An increasing number of anticancer drugs have been reported to cause pneumonitis. Chemotherapy-induced pneumonitis may cause severe morbidity and event death. As there has been a lack of effective treatment, new treatment strategies are needed. A previous case report has indicated that imatinib may be useful.The SWENOTECA experience of four cases with severe life-threatening chemotherapy-induced pneumonitis treated with imatinib is presented.All four patients responded to treatment with imatinib.Imatinib appears to be an effective treatment of severe chemotherapy-induced pneumonitis in germ cell cancer patients.

Background For metastatic germ cell tumour patients with intermediate prognosis (IPGCT) according to the IGCCCG classification 5-year overall survival (OS) rates of 79% were described, but recent data suggest significant changes. Patients and methods To compare the outcome of current IPGCT with former patients and to find new prognosticators a retrospective observational study was performed. Eligibility criteria were: age ≥16 years, diagnosed between 1979 and 2014. Primary end-point was the 5-year OS rate. Results This database includes 707 IPGCT: group 1 was diagnosed 1979–1996 (n = 237), and group 2 1997–2014 (n = 470). Median follow-up was 8.6 years (IQR: 14.4). Group 1 and 2 received first-line treatment with BEP (median 4 cycles; range 1–6) in 99% (group 1) and 95% (group 2), respectively. The proportion of first-line chemotherapy responders (CR and marker negative PR) was similar: 94% (group 1) and 96% (group 2), respectively (P = 0.290), but OS was superior in group 2 with a 5-year OS rate of 89% compared with 83% in group 1 (P = 0.035). In refractory disease, high-dose chemotherapy and treatment beyond second line was performed more often in group 2. A lactate dehydrogenase (LDH) cut-off value of 2 ULN (P = 0.002; HR 2.121) and alpha-fetoprotein (AFP) levels of 6200 IU/ml (P = 0.032; HR 2.155) pre-chemotherapy were independent prognosticators for OS in a multivariate analysis. Conclusion Outcome of IPGCT has improved and is now closer to the good prognosis category. LDH and AFP levels represent potential markers to stratify IPGCT before treatment initiation.

The aim of this article is to present the Swedish and Norwegian Testicular Cancer Group (SWENOTECA), with an emphasis on the history of SWENOTECA, organization, results and current status.SWENOTECA was founded in 1981 as a binational organization open to hospitals in Sweden and Norway treating testicular cancer. It has since published treatment protocols for testicular cancer and prospectively registered patients with testicular cancer. Today, all hospitals in Norway and Sweden involved in the care of testicular cancer participate in SWENOTECA, and all patients with testicular cancer are prospectively registered in a population-based database.Nine protocols with standardized guidelines on the diagnosis, treatment and follow-up of testicular cancer have been published. In addition to the guidelines, several studies have been performed or initiated within the scope of SWENOTECA. The details are presented in this article.SWENOTECA has been a very fruitful binational collaboration and has thoughtfully evolved over time. The group's continuous work and dedication have provided an example for other national and international cancer networks. The binational implementation of standardized guidelines has resulted in excellent patient outcomes, regardless of place of residence. Although testicular cancer is a relatively rare disease, the population-based binational organization of SWENOTECA has made it possible to publish some of the largest studies in the field of testicular cancer.

Testicular cancer (TC) is the most common neoplasm in males aged 15-40 years. The majority of patients have no evidence of metastases at diagnosis and thus have clinical stage I (CSI) disease [Oldenburg J, Fossa SD, Nuver J et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi125-vi132; de Wit R, Fizazi K. Controversies in the management of clinical stage I testis cancer. J Clin Oncol 2006; 24: 5482-5492.]. Management of CSI TC is controversial and options include surveillance and active treatment. Different forms of adjuvant therapy exist, including either one or two cycles of carboplatin chemotherapy or radiotherapy for seminoma and either one or two cycles of cisplatin-based chemotherapy or retroperitoneal lymph node dissection for non-seminoma. Long-term disease-specific survival is similar to 99% with any of these approaches, including surveillance. While surveillance allows most patients to avoid additional treatment, adjuvant therapy markedly lowers the relapse rate. Weighing the net benefits of surveillance against those of adjuvant treatment depends on prioritizing competing aims such as avoiding unnecessary treatment, avoiding more burdensome treatment with salvage chemotherapy and minimizing the anxiety, stress and life disruption associated with relapse. Unbiased information about the advantages and disadvantages of surveillance and adjuvant treatment is a prerequisite for informed consent by the patient. In a clinical scenario like CSI TC, where different disease-management options produce indistinguishable long-term survival rates, patient values, priorities and preferences should be taken into account. In this review, we provide an overview about risk factors for relapse, potential benefits and harms of adjuvant chemotherapy and active surveillance and a rationale for involving patients in individualized decision making about their treatment rather than adopting a uniform recommendation for all.

Purpose. To investigate if testicular cancer survivors (TCSs) have a higher incidence of work loss compared with the population, accounting for stage, treatment and relapse.Material and methods. A cohort of 2146 Swedish TCSs diagnosed 1995–2007 (seminoma n = 926, non-seminoma n = 1220) was identified in the SWENOTECA (Swedish-Norwegian Testicular Cancer Group) register, and matched 1:4 to population comparators. Prospectively recorded work loss data (both before and after diagnosis) were obtained from national registers through September 2013. Adjusted relative risks (RR) and 95% confidence intervals (CI) of sick leave and/or disability pension were calculated annually and overall with Poisson- and Cox regression, censoring at relapse. The mean number of annual work days lost was also estimated.Results. TCSs were at a modestly increased annual risk of work loss up to the third year of follow-up (RR3rd year 1.25, 95% CI 1.08, 1.43), attributed to a more pronounced risk among extensively treated patients (4 chemotherapy courses: RR3rd year 1.60, 95% CI 1.19, 2.15; > 4 courses: RR3rd year 3.70, 95% CI 2.25, 6.11). Patients on surveillance or limited treatment (radiotherapy, 1–3 chemotherapy courses) did not have an increased risk of work loss beyond the first year. TCSs receiving > 4 chemotherapy courses had higher mean number of annual days of work loss up to the 10th year post-diagnosis, and a five-fold risk of disability pension (RR 5.16, 95% CI 2.00, 10.3).Conclusion. Extensively treated TCSs, but not those on surveillance or limited treatment, are at increased risk of work loss long-term, not explained by relapse. These patients may benefit from early rehabilitation initiatives.

A contralateral tumor occurs in 3.5-5% of men diagnosed with testicular germ cell cancer (TGCC). Biopsy of the contralateral testis may detect intratubular germ cell neoplasia ITGCNU, a precursor of TGCC. Biopsy of the contralateral testis to detect ITGCNU is controversial. If adjuvant chemotherapy (ACT) protects against bilateral cancer is debated.A total of 1003 patients with clinical stage I (CS I) non-seminomatous testicular germ cell cancer (NSGCT) were included in two prospective, population-based protocols. Fifteen patients were excluded. Treatment was either adjuvant chemotherapy (n = 494), or surveillance (n = 494). Contralateral testicular biopsy was recommended for all patients, but was performed only in 282 patients. In case of ITGCNU radiotherapy (RT) to 16 Gy was recommended.During a follow-up of 8.3 years, 31 (3.6%) patients developed contralateral TGCC. ITGCNU was detected in 3.2% (9/282) of biopsied patients. The incidence of bilateral TGCC was similar following ACT, 2.5% (11/494), and surveillance, 3.4% (13/494), p = 0.41. Young age was a risk factor for metachronous TGCC (HR 0.93; 95% CI 0.88-0.99, p = 0.02). In total 2.2% (6/273) of patients without ITGCNU in the biopsy developed contralateral TGCC. One irradiated patient developed contralateral cancer, and one developed contralateral tumor before RT was given.ACT did not reduce the incidence of contralateral TGCC. Young patients had the highest risk of developing contralateral TGCC. The proportion of false negatives biopsies was higher than reported in earlier trials, but this may in part be related to patient selection, single biopsies and lack of mandatory immunohistochemistry.

Context: This is an update of the previous European Association of Urology testis cancer guidelines published in 2011, which included major changes in the diagnosis and treatment of germ cell tumours. Objective: To summarise latest developments in the treatment of this rare disease. Recommendations have been agreed within a multidisciplinary working group consisting of urologists, medical oncologists, and radiation oncologists. Evidence acquisition: A semi-structured literature search up to February 2015 was performed to update the recommendations. In addition, this document was subjected to double-blind peer review before publication. Evidence synthesis: This publication focuses on the most important changes in treatment recommendations for clinical stage I disease and the updated recommendations for follow-up. Conclusions: Most changes in the recommendations will lead to an overall reduction in treatment burden for patients with germ cell tumours. In advanced stages, treatment intensification is clearly defined to further improve overall survival rates. Patient summary: This is an update of a previously published version of the European Association of Urology guidelines for testis cancer, and includes new recommendations for clinical stage I disease and revision of the follow-up recommendations. Patients should be fully informed of all the treatment options available to them. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Purpose Adjuvant carboplatin is one of three management strategies that may follow inguinal orchiectomy in clinical stage I seminoma. However, little is known about the outcome of patients who experience a relapse after such treatment. Patients and Methods Data from 185 patients who relapsed after adjuvant carboplatin between January 1987 and August 2013 at 31 centers/groups from 20 countries were collected and retrospectively analyzed. Primary outcomes were disease-free survival and overall survival. Secondary outcomes were time to, stage at, and treatment of relapse as well as rate of subsequent relapses. Results With a median follow-up of 53 months (95% CI, 48 to 60 months) the 5-year disease-free survival was 82% (95% CI, 77% to 89%), and the 5-year overall survival was 98% (95% CI, 95% to 100%). The median time from orchiectomy to relapse was 19 months (95% CI, 17 to 23 months); 15% (95% CI, 10% to 21%) of relapses occurred > 3 years after treatment. The majority of relapses were detected by computed tomography scan during routine follow-up, 98% in the International Germ Cell Cancer Collaborative Group good prognosis group. Chemotherapy was administered to 92% of patients, mostly as standard first-line treatment corresponding to stage; 8% of patients had additional local treatments. Only 28 patients experienced a second relapse. At last follow-up, 174 (94%) of 185 patients were alive without disease, and four patients with disease. Seven patients died, three of whom due to progressive disease. Conclusion Within the limitations of a retrospective analysis, the results suggest that the majority of patients who experience a relapse after adjuvant carboplatin for clinical stage I seminoma can be successfully treated with a cisplatin-based chemotherapy regimen adequate for stage. Because 15% of the relapses occurred > 3 years after adjuvant treatment, a minimum of 5 years follow-up is recommended.

Although clinical stage I (CS I) testicular cancer is highly curable, the optimal management is controversial. The aims of the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) studies for CS I non-seminoma (NS) and seminoma (S) have been to reduce treatment intensity while maintaining high survival rates, reduce the number of patients needing salvage treatment and implement patient autonomy with regard to adjuvant treatment. During 1998-2010 NS CSI patients with lymphovascular invasion (LVI) of the primary tumor (high risk) were recommended bleomycin, etoposide, cisplatin (BEP) × 1. During 2000-2006 S CS I patients had the option to choose surveillance or adjuvant radiotherapy (AR). In 2004, carboplatin × 1 (AUC7) was added as a third treatment option. In 2007 a new risk-adapted treatment protocol for S CS I was initiated. Patients with two risk factors (tumor size 4 cm, tumor growth in the rete testis) were recommended carboplatin × 1 and patients with 0-1 risk factor were recommended surveillance. All patients were provided with oral and written information of possible management options and could choose the other alternative. The relapse rate for NS CS I with BEP × 1 was 3.2% for high risk, and 1.6% for low-risk patients. Five-year cause-specific survival was 100%. For S CS I-patients treated before 2007, 14.3% on surveillance relapsed, 3.9% after carboplatin, and 0.8% after AR. Five-year cause-specific survival was 99.9%. For S CS I-patients treated from 2007, a relapse rate3% was confirmed for patients without risk factors. SWENOTECA considers BEP × 1 standard adjuvant treatment in NS CS I high-risk patients. Low-risk patients should have the opportunity to receive BEP × 1 following thorough information regarding pros and cons. For S CS I patients without risk factors, adjuvant treatment is not necessary. For patients with risk factors, patient autonomy should be respected.

Azoospermia is a serious potential side effect following treatment for testicular cancer (TC). Our purpose was to examine possible predictors of long-term azoospermia in TC survivors. Ejaculates and blood samples were obtained from 217 patients at post-orchidectomy but before further treatment (T0 ) and/or at one or more of the time points 6, 12, 24, 36-60 months after treatment (T6 , T12 , T24 , T36-60 ). All patients delivered ejaculates at T36-60 , of which 117 also had confirmed presence of spermatozoa in the ejaculate at T0 , enabling longitudinal analyses. Types of therapy, cryptorchidism and Inhibin B before and after treatment were evaluated in relation to risk of azoospermia at T36 . Inhibin B levels at T6 , T12 and T24 were predictors of azoospermia at T36 with cut-off levels at 49.7, 55.9 and 97.8 ng/L respectively (sensitivity 100%, specificity 57-78%). The frequency of azoospermia in all patients at T36-60 was 7.8% (95% CI 4.9-12%). As compared to surveillance patients, only those receiving >4 cycles of chemotherapy or ≥4 cycles of chemotherapy + radiotherapy (RT) had increased risk of long-term azoospermia (63% vs. 4.4% in the surveillance group; p = 0.0018). In conclusion, all patients with sperm production at post-orchidectomy but before further treatment and Inhibin B >56 ng/L 12 months after treatment had sperm production 3 years post-treatment. Eight per cent of TC survivors had azoospermia 3-5 years post-treatment, with highest risk in those receiving >4 cycles of chemotherapy or ≥4 cycles of chemotherapy in combination with RT.

510 Background: Clin. stage I (CSI) non-seminoma (NS) is disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant (adjuv) chemotherapy with BEP after which relapses are rare. Little is known about the outcome of patients (pts) relapsing after such treatment. Methods: Data from 51 pts with CSI NS and relapse after adjuv BEP from 18 centers/11 countries was collected and retrospectively analyzed. Primary endpoints were OS and PFS calculated from start of treatment of relapse. Secondary outcomes were time to, stage at, and treatment of relapse as well as rate of subsequent relapses. Results: 23 pts received one cycle adjuv BEP and 28 pts two. Median time to relapse was 13 months, with the earliest relapse two months after start of adjuv BEP and the latest relapse recorded after 26 years. According to IGCCCG, 84% of pts classified as good prognosis at relapse. With a median follow up of 50 months 5y PFS was 64% (95% CI 52-80%) and 5y OS 79% (95% CI 68-92%). Treatment upon relapse was diverse, the majority of pts received combination- chemotherapy and surgery. 10 pts (20%) had pure mature teratoma at relapse treated with surgery alone. None of these pts experienced a second relapse. If teratoma relapses were excluded, 5y PFS dropped to 58% (44-77%) and 5y OS to 76% (63-92%). Relapses later than three years after adjuv therapy occured in 15/51 pts. (29%) and were associated with a statistically significant higher risk of death from germ-cell cancer (p=0.02). 15/51 pts (29%) experienced a subsequent relapse. Excluding pts with teratoma only, subsequent relapses occured in 15 of the remaining 41 pts (37%). At last follow-up, 41/51 (80%) pts were alive and disease-free, 8/51 (16%) had died from progressive disease and one pt each had died from therapy-related or other causes. Conclusions: Outcome of pts with relapse after adjuv BEP seems to be better compared to pts with relapse after metastatic disease, but worse compared to de novo metastatic pts. There is a substantial rate of late and subsequent relapses. Pts and care-takers need to be informed about this and therapy intensification at first relapse might be considered. However, considering the low rate of relapses, OS in general for CSI NS pts receiving adjuv BEP is excellent.

In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377-1399; 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; 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 II. Eur Urol 2008; 53: 497-513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, similar to 50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.

Resumen Contexto La Asociacion Europea de Urologia (EAU) establecio la guia clinica para el diagnostico, la terapia y el seguimiento del cancer de testiculo. Objetivo Este articulo es una version abreviada de la guia clinica del cancer de testiculo de la EAU y resume las conclusiones principales de la guia sobre el tratamiento del cancer testicular. Obtencion de evidencia Un equipo multidisciplinar de guias clinicas compilo esta guia. Se llevo a cabo una revision sistematica mediante Medline y Embase, tomando tambien datos Cochrane e informacion del European Germ Cell Cancer Consensus Group . Un grupo de expertos valoro las referencias y se asigno un nivel de evidencia y grado de recomendacion. Resultados La bibliografia, especialmente con respecto al seguimiento a mas largo plazo, es escasa y los resultados de varios ensayos en curso estan a la espera. La eleccion del centro de tratamiento es de suma importancia y el tratamiento en centros de referencia en ensayos clinicos, especialmente en tumores de celulas germinativas no seminomatosos, proporciona mejores resultados. En los pacientes con seminoma en estadio clinico I, en base a informacion publicada recientemente sobre toxicidad a largo plazo, ya no se recomienda la radioterapia adyuvante como tratamiento adyuvante de primera linea. Se recomienda la clasificacion TNM del 2009. Conclusiones Esta guia contiene informacion para el tratamiento normalizado de los pacientes con cancer de testiculo en base a las apreciaciones cientificas mas recientes. Las tasas de curacion son generalmente excelentes, pero como el cancer de testiculo afecta principalmente a hombres en su tercera o cuarta decada de vida, los efectos del tratamiento en la fertilidad requieren ayuda psicologica para los pacientes. Ademas, el tratamiento debe ser individualizado teniendo en cuenta las circunstancias individuales y las preferencias del paciente. Mensaje a principal Aunque el cancer de testiculo presenta unas tasas de curacion excelentes, la eleccion del centro de tratamiento es de capital importancia. Los centros expertos logran mejores resultados tanto para el cancer testicular en estadio inicial (tasas de recidiva mas bajas) como para la supervivencia global (estadios mas altos en los ensayos clinicos). En los pacientes con seminoma en estadio clinico I, ya no se recomienda la radioterapia adyuvante como tratamiento adyuvante de primera linea.

Background 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) has been recommended in international guidelines in the evaluation of postchemotherapy seminoma residuals. Our trial was designed to validate these recommendations in a larger group of patients. Patients and methods FDG-PET studies in patients with metastatic seminoma and residual masses after platinum-containing chemotherapy were correlated with either the histology of the resected lesion(s) or the clinical outcome. Results One hundred and seventy seven FDG-PET results were contributed. Of 127 eligible PET studies, 69% were true negative, 11% true positive, 6% false negative, and 15% false positive. We compared PET scans carried out before and after a cut-off level of 6 weeks after the end of the last chemotherapy cycle. PET sensitivity, specificity, negative predictive value (NPV), and positive predictive value were 50%, 77%, 91%, and 25%, respectively, before the cut-off and 82%, 90%, 95%, and 69% after the cut-off. PET accuracy significantly improved from 73% before to 88% after the cut-off (P = 0.032). Conclusions Our study confirms the high specificity, sensitivity, and NPV of FDG-PET for evaluating postchemotherapy seminoma residuals. When carried out at an adequate time point, FDG-PET remains a valuable tool for clinical decision-making in this clinical setting and spares patients unnecessary therapy.

Background. The SWENOTECA IV protocol from 1995 is a prospective population-based study in metastatic non-seminomatous germ cell testicular cancer (NSGCT), designed for early identification of patients with poor response to standard cisplatin-based chemotherapy. A slow tumor marker decline (HCG T(1/2) > 3 days, AFP T(1/2) > 7 days) after BEP or BEP plus ifosfamide was regarded as poor response. The aim of this study was to present survival and toxicity data for patients treated with high-dose chemotherapy (HDCT) within the SWENOTECA IV cancer care program. Material and methods. In total 882 adult men diagnosed with metastatic NSGCT between July 1995 and June 2007 in Sweden and Norway (except one center) were included in SWENOTECA IV and treated accordingly. Among these, 55 men (6.2%) were treated with HDCT according to three different indications in the protocol: A) poor response to standard-dose intensified chemotherapy (BEP plus ifosfamide); B) vital cancer at surgery after intensified chemotherapy; and C) selected relapses after previous chemotherapy. In situation A and C two HDCT cycles and in situation B one HDCT cycle was recommended. Situation A was the reason for HDCT in 36 patients, B in seven and C in 12 patients. The first HDCT cycle consisted of carboplatin 28 x (GFR + 25) mg, cyclofosfamide 6000 mg/m(2) and etoposide 1750 mg/m(2), administered over four days. In cycle two, etoposide was replaced by tiotepa 480 mg/m(2). Results. After a median follow-up of 7.5 years, overall survival was 72%, 100% and 58%, while failure-free survival was 64%, 71% and 42% in situation A, B and C, respectively. Three patients (5.5%) died during HDCT (renal failure or intracerebral hemorrhage). Nephrotoxicity was the most common non-hematological grade 4 toxicity (n = 5, 9%). Conclusion. The population-based SWENOTECA strategy, selecting patients who do not respond adequately to primary standard-dose chemotherapy for immediate treatment intensification with HDCT, is feasible and might be advantageous.

Testicular cancer represents 1%-1.5% of male neoplasms and 5% of urologic tumors in general, with 3-6 new cases occurring per 100 000 males/y in Western society.1,2 An increase in the incidence of testicular cancer was detected during the 1970s and 1980s, in particular in Northern European countries. Also, a clear trend has been seen toward an increased testicular cancer incidence in the past 30 years in most of the industrialized countries in North America, Europe, and Oceania, although surprising differences in incidence rates have been seen between neighboring countries.

Context: On behalf of the European Association of Urology (EAU), guidelines for the diagnosis, therapy, and follow-up of testicular cancer were established. Objective: This article is a short version of the EAU testicular cancer guidelines and summarises the main conclusions from the guidelines on the management of testicular cancer. Evidence acquisition: Guidelines were compiled by a multidisciplinary guidelines working group. A systematic review was carried out using Medline and Embase, also taking Cochrane evidence and data from the European Germ Cell Cancer Consensus Group into consideration. A panel of experts weighted the references, and a level of evidence and grade of recommendation were assigned. Results: There is a paucity of literature especially regarding longer term follow-up, and results from a number of ongoing trials are awaited. The choice of treatment centre is of the utmost importance, and treatment in reference centres within clinical trials, especially for poor-prognosis nonseminomatous germ cell tumours, provides better outcomes. For patients with clinical stage I seminoma, based on recently published data on long-term toxicity, adjuvant radiotherapy is no longer recommended as first-line adjuvant treatment. The TNM classification 2009 is recommended. Conclusions: These guidelines contain information for the standardised management of patients with testicular cancer based on the latest scientific insights. Cure rates are generally excellent, but because testicular cancer mainly affects men in their third or fourth decade of life, treatment effects on fertility require careful counselling of patients, and treatment must be tailored taking individual circumstances and patient preferences into account. Take Home Message: Although testicular cancer has excellent cure rates, the choice of treatment centre is of the utmost importance. Expert centres achieve better results for both early stage testicular cancer (lower relapse rates) and overall survival (higher stages within clinical trials). For patients with clinical stage I seminoma, adjuvant radiotherapy is no longer recommended as first-line adjuvant treatment. (C) 2011 AEU. Published by Elsevier Espana, S.L. All rights reserved

Purpose From 1995 to 2003, 603 adult patients from Sweden and Norway with metastatic testicular nonseminomatous germ cell tumor (NSGCT) were included prospectively in a population-based protocol with strict guidelines for staging, treatment, and follow-up. Patients with extragonadal primary tumor or previous treatment for contralateral testicular tumor were excluded. The basic strategy was to individualize treatment according to initial tumor marker response. Methods Initial treatment for all patients was two courses of standard bleomycin, etoposide, and cisplatin (BEP), with tumor markers analyzed weekly. Good response was defined as a half-life (t1/2) for α-fetoprotein (AFP) of ≤ 7 days and/or for β–human chorionic gonadotropin (β-HCG) of ≤ 3 days. Patients with prolonged marker t1/2 (ie, poor response) received intensification with addition of ifosfamide (BEP-if/PEI) in step 1. If poor response continued, the treatment was intensified with high-dose chemotherapy with stem-cell rescue as step 2. Results Overall, 99% of all patients with metastatic testicular NSGCT in the population were included in the protocol. Median follow-up was 8.2 years. Seventy-seven percent of the patients were treated with BEP alone; 18% received intensification step 1%, and 5% received intensification step 2. Grouped according to International Germ Cell Consensus Classification, 10-year overall survival was 94.7% in good-prognosis patients, 90.0% in intermediate-prognosis patients, and 67.4% in poor-prognosis patients. Conclusion With detailed treatment protocols and a dedicated collaborative group of specialists, treatment results comparable to those reported from large single institutions can be achieved at national level. With the treatment principles used in Swedish-Norwegian Testicular Cancer Group study SWENOTECA IV, the survival of intermediate-prognosis patients is remarkable and close to that of good-prognosis patients.

Increasing incidence of testicular germ cell cancer (TGCC) is most probably related to environment and lifestyle. However, an underlying genetic predisposition may play a role and since sex steroids are assumed to be important for the rise and progression of TGCC, a study of androgen receptor (AR) gene polymorphisms in relation to the risk, histological type and progression of TGCC was undertaken. In 367 TGCC cases and 214 controls, AR CAG and GGN repeat lengths were determined and 11 haplotype-tagging single nucleotide polymorphisms (SNPs) were genotyped. By binary logistic regression, odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated for the risk of TGCC, non-seminoma versus seminoma and metastatic versus localised (stage I) disease. For the non-coding SNP, rs12014709, the minor genotype (G) was found in 10% of the cases and in 5.1% of the controls, conferring an OR of 2.07 (95% CI: 1.03-4.15) for having TGCC. Furthermore, short GGN (

Introduction. Testicular germ cell cancer (TGCC) patients may be at risk of developing sexual dysfunction after treatment. Aim. The aim of this study was to assess the prevalence of sexual dysfunctions in TGCC patients 3 to 5 years after treatment, and relate findings to biochemical hypogonadism, treatment intensity, and the expected prevalence in the Swedish male population. Methods. A questionnaire study on 129 consecutive TGCC patients 3 to 5 years post-treatment was performed. Comparators were an age-matched nationally representative group of men (N = 916) included in a study on sexual life in Sweden. Main Outcome Measures. Sexual functions (including erectile dysfunctional distress), time since last intercourse, sexual satisfaction, and experience of sexological treatment seeking were assessed using the same questions used in the epidemiological study on sexual life in Sweden. The findings in TGCC patients were correlated to biochemical signs of hypogonadism and type of oncological treatment: Surveillance, adjuvant chemotherapy, adjuvant radiotherapy, or standard doses of chemotherapy. Results. A higher proportion of TGCC patients than comparators were likely to report low sexual desire (odds ratio [OR] 6.7 [95% confidence interval {CI} 2.1-21]) as well as erectile dysfunction (OR 3.8 [95% CI 1.4-10]). No significant differences were observed regarding erectile dysfunctional distress, change of desire over time, interest in sex, premature or delayed ejaculation, time since last intercourse, need for or receiving sexual advice, or sexual satisfaction. Hypogonadism did not predict erectile dysfunction (OR 1.1 [95% CI 0.26-4.5]) or low sexual desire (OR 1.2 [95% CI 0.11-14]). Treatment modality had no obvious impact on sexual function. Conclusion. Men treated for testicular cancer had higher risk of having low sexual desire and erectile dysfunction 3 to 5 years after completion of therapy than comparators. These sexual dysfunctions were not significantly associated with treatment intensity or hypogonadism. Eberhard J, Stahl O, Cohn-Cedermark G, Cavallin-Stahl E, Giwercman Y, Rylander L, Eberhard-Gran M, Kvist U, Fugl-Meyer KS, and Giwercman A. Sexual function in men treated for testicular cancer. J Sex Med **;**:**-**. (Less)

Purpose To offer minimized risk-adapted adjuvant treatment on a nationwide basis for patients with clinical stage 1 (CS1) nonseminomatous germ-cell testicular cancer (NSGCT). The aim was to reduce the risk of relapse and thereby reducing the need of later salvage chemotherapy while maintaining a high cure rate. Patients and Methods From 1998 to 2005, 745 Norwegian and Swedish patients were included into a prospective, community-based multicenter Swedish and Norwegian Testicular Cancer Project (SWENOTECA) management program. Treatment strategy depended on the presence or absence of vascular tumor invasion (VASC). VASC-positive patients were recommended brief adjuvant chemotherapy (ACT) with bleomycin, etoposide, and cisplatin (BEP), whereas VASC-negative patients could choose between ACT and surveillance. Results At a median follow-up of 4.7 years, there have been 51 relapses. On surveillance, 41.7% of VASC+ patients relapsed, compared with 13.2% of VASC− patients. After one course of BEP, 3.2% of VASC+ and 1.3% of VASC− patients relapsed. The toxicity of adjuvant BEP was low. Eight patients have died, none died from progressive disease. Conclusion One course of adjuvant BEP reduces the risk of relapse by approximately 90% in both VASC+ and VASC− CS1 NSGCT, and may be a new option as initial treatment for all CS1 NSGCT. One course of adjuvant BEP for VASC+ CS1 reduces the total burden of chemotherapy compared with surveillance or two courses of BEP. SWENOTECA currently recommends one course of BEP as standard treatment of VASC+ CS1 NSGCT, whereas both surveillance and one course of BEP are options for VASC− CS1 NSGCT.

Objectives: The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. Methods: Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. Results: The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. Conclusions: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged. (C) 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Objective To up-date the 2001 version of the EAU testicular cancer guidelines. Methods A non-structured literature review until January 2005 using the MEDLINE database has been performed. Literature has been classified according to evidence-based medicine levels. Results Testicular cancer is a highly curable disease. Excellent cure rates have been achieved by standardization of treatment, interdisciplinary management, and tremendous success in performing clinical trials. Currently, the aims of testicular cancer treatment are as follows: for patients with low-stage disease, a reduction in treatment is proposed to improve long-term toxicity in these patients with unaltered life expectancy; for about 10% of patients with advanced disease and poor prognosis, intensification of treatment (including high-dose chemotherapy and new drugs as well as aggressive surgical approaches) is being investigated to improve long-term cure rates. Conclusion Guidelines will improve clinical practice only if they are regularly updated. This update presents the state-of-the-art management of testicular cancer patients in 2005.

TPS4593 Background: Clinical stage I seminomatous testicular cancer is by far the most frequent presentation of testicular cancer. Treatment options include surveillance or adjuvant treatment, internationally one course of adjuvant carboplatin (AUC7) is the preferred adjuvant treatment. Tumor size and stromal invasion in the rete testis can be used to identify patients with a higher risk of relapse. Recent data have showed only a modest effect of adjuvant carboplatin in preventing relapse, and more potent adjuvant therapies should be explored to this group of patients. Methods: The ABC-study is a investigator initiated randomized, open, phase III study comparing standard adjuvant chemotherapy in the form of one course carboplatin AUC7 to one course of BEP (Bleomycin, etoposide and cisplatin), in patients with one or two risk factors. Based on SWENOTECA data from one course of adjuvant carboplatin AUC7 we estimate the relapse rate in patients with one or two risk factors to be 9 %. We consider a reduction in relapse free survival of 7 % to be the minimum difference that will lead to routine use of one course of adjuvant BEP. To demonstrate an improvement in relapse rate from 9 to 2 % with an α = 0.05 and β = 0.80, 332 evaluable patients are required. We expect a dropout rate of maximum 5 %, and therefore intend to randomize a total of 348 patients. Enrollment in the study started in 2015, and as of February 1. 2017 a total of 66 patients have been enrolled. Accrual have been slower than expected, but the current accrual rate is about 6-7 patients a month. We invite institutions and collaboratory groups to participate in this study. NCT02341989. EUDRACT 2014-004075-23. Clinical trial information: NCT02341989.

4560 Background: The IGCCCG classification published in 1997 is based on data from the 1970-80s. Approximately 25% of metastatic GCT patients belong to the intermediate prognosis category, that was associated with a 5-year overall survival (OS) rate of 79%. However, more recent data suggest significant changes. We have thus performed an international registry of IPGCT patients to analyze current treatment, outcome, and potential prognostic factors. Methods: Data of IPGCT patients, diagnosed between 1979-2012, were retrospectively collected from 14 centers. Treatment and outcome before and after implementation of IGCCCG were analyzed. For patients diagnosed since 1997 prognostic factors were investigated by uni- and multivariate analysis to test whether current patients or subgroups may require less intensive treatment. Results: This registry includes 637 patients: group 1 diagnosed prior 1997 (n = 237), and group 2 since 1997 (n = 400). Mean follow-up duration was 128.4 months (IQR: 168.9). Patients in group 1 and 2 received first-line treatment with BEP (median 4 cycles; range 1 - 6) in 98% and 97%, respectively. Response to chemotherapy (CR and marker negative PR) was similar: 91% group 1; 94% group 2; (p = 0.233), but survival curves were significantly superior in group 2 associated with a 5-year OS rate of 87% (group 2) and 81% (group 1), respectively (p = 0.011; 95%CI 294-317). Recurrence rates were higher in group 1 (36% versus 24%; p = 0.001). Patients treated with 3 cycles BEP (n = 58) in both groups had a similar outcome concerning OS compared to patients treated with 4 cycles (n = 489) (p = 0.415). Uni- and multivariate analysis revealed LDH levels < 2.0 UNL prior chemotherapy (p = 0.018; HR 0.35) and an adequate tumor marker decline at days 18-21 (half-life) of first cycle (p = 0.025; HR 2.58) as independent prognosticators, both associated with 5-year OS rates of 94%, respectively. Conclusions: Outcome of intermediate patients seems improved after implementation of the IGCCCG classification and less intensive regimes may also be sufficient. Here, patients treated with 3xBEP had a non-inferior outcome. A baseline LDH < 2.0 UNL and an adequate tumor marker decline after first treatment cycle can be used for further stratification.

4521 Background: Residual disease is a frequent finding after chemo for metastatic seminoma. Watchful waiting is recommended for residual lesions < 3 cm or lesions ≥3 cm with negative PET. Data on the optimal management of PET positive residual lesions is lacking. Methods: A retrospective analysis within the G3 Group identified 91 patients (pts) from 9 countries with metastatic seminoma and residual PET positive lesions after chemo. Pts with elevated AFP ( > 2xULN) or non-seminomatous components at diagnosis were excluded. We analyzed the post PET management chosen and its impact on relapse and survival. Results: Median follow-up was 29 (IQR 10 – 64) months. Median age at diagnosis was 41 (range 19 – 69) years. The primary tumor was gonadal in 68 pts (76%), retroperitoneal in 12 pts (13%) and mediastinal in 10 pts (11%). Prior to chemo the median size of the largest metastasis was 10 (range 1.4 – 23) cm, 67 pts (74%) had elevated LDH and 51 pts (57%) elevated HCG. Median diameter of the largest residual mass was 4.8 (range 1.1 – 14) cm mainly located in the retroperitoneum (77%), pelvis (15%), mediastinum (16%) or lung (4%). Median time from last day of chemo to PET was 7 (IQR 4 – 10) weeks. Post PET management was repeated imaging in 46 pts (51%), resection in 32 pts (35%), biopsy in 9 pts (10%) and radiotherapy in 4 pts (4%). Histology of the resected specimen was necrosis only in 25 (78%) and vital seminoma in 7 cases (22%). No biopsy revealed vital seminoma. Relapses occurred after a median of 3.7 (IQR 2.5 – 4.9) months in 16 pts (18%): 2/9 (22%) after biopsy, 12/46 (26%) on repeated imaging and 2/32 (6%) after resection (one necrosis, one < 10% vital seminoma). Site of relapse was the area of residual disease in 14 pts (88%) and additional distant relapse (one bone, one lung) in 2 pts (12%). All relapsed pts received successful salvage chemo apart from one who died from treatment and two pts who are alive with ongoing treatment. Conclusions: PET positive post chemo residual lesions in seminoma pts are false positive in about 75%. Relapses in PET positive pts occur early and can be salvaged with chemo. Further analysis is needed to identify risk factors for relapse.

Purpose To evaluate the performance of active surveillance as a management strategy in broad populations and to inform the development of surveillance schedules by individual patient data regarding timing and type of relapse. Methods Retrospective study including data from 2,483 clinical stage I (CSI) patients, 1,139 CSI nonseminoma and 1,344 CSI seminoma managed with active surveillance, with the majority treated between 1998 and 2010. Clinical outcomes including relapse and death, time distribution, extent of relapse and method of relapse detection observed on active surveillance were recorded. Results Relapse occurred in 221 (19%) CSI-nonseminoma and 173 (13%) CSI-seminoma patients. Median time to relapse was 4 months (range, 2-61 months), 8 months (range, 2-77 months) and 14 months (range, 2-84 months) for lymphovascular invasion–positive CSI nonseminoma, lymphovascular invasion–negative CSI nonseminoma and CSI seminoma. Most relapses were observed within the first 2 years/3 years after orchiectomy for CSI nonseminoma (90%)/CSI seminoma (92%). Relapses were detected by computed tomography scan/tumor-markers in 87%/3% of seminoma recurrences, in 48%/38% of lymphovascular invasion–negative and 41%/61% of lymphovascular invasion–positive patients, respectively. 90% of CSI-nonseminoma and 99% of CSI-seminoma relapses exhibited International Germ Cell Collaborative Group good-risk features. Three patients with CSI nonseminoma died of disease (0.3%). One patient with CSI seminoma and two patients with CSI nonseminoma died because of treatment-related events. Overall, advanced disease was seen in both early- and late-relapse patients. All late recurrences were cured with standard therapy. Five-year disease-specific survival was 99.7% (95% CI, 99.24% to 99.93%). Conclusion Active surveillance for CSI testis cancer leads to excellent outcomes. The vast majority of relapses occur within 2 years of orchiectomy for CSI nonseminoma and within 3 years for CSI seminoma. Late and advanced stage relapse are rarely seen. These data may inform further refinement of rationally designed surveillance schedules.

SWENOTECA has since 1998 offered patients with clinical stage I (CS I) nonseminoma, adjuvant chemotherapy with one course of bleomycin, etoposide and cisplatin (BEP). The aim has been to reduce the risk of relapse, sparing patients the need of toxic salvage treatment. Initial results on 312 patients treated with one course of adjuvant BEP, with a median follow-up of 4.5 years, have been previously published. We now report mature and expanded results.In a prospective, binational, population-based risk-adapted treatment protocol, 517 Norwegian and Swedish patients with CS I nonseminoma received one course of adjuvant BEP. Patients with lymphovascular invasion (LVI) in the primary testicular tumor were recommended one course of adjuvant BEP. Patients without LVI could choose between surveillance and one course of adjuvant BEP. Data for patients receiving one course of BEP are presented in this study.At a median follow-up of 7.9 years, 12 relapses have occurred, all with IGCCC good prognosis. The latest relapse occurred 3.3 years after adjuvant treatment. The relapse rate at 5 years was 3.2% for patients with LVI and 1.6% for patients without LVI. Five-year cause-specific survival was 100%.The updated and expanded results confirm a low relapse rate following one course of adjuvant BEP in CS I nonseminoma. One course of adjuvant BEP should be considered a standard treatment in CS I nonseminoma with LVI. For patients with CS I nonseminoma without LVI, one course of adjuvant BEP is also a treatment option.

Large, prospective, randomized trials with long term follow-up are required to obtain an unbiased evaluation of the significance of resection margins in patients with cutaneous melanoma.The Swedish Melanoma Study Group performed a prospective, randomized, multicenter study of patients with primary melanoma located on trunk or extremities and with a tumor thickness0.8 mm and/= 2 mm. Patients were allocated randomly to a 2-cm excision margin or a 5-cm excision margin. In total, 989 patients were recruited during the period 1982-1991. The median follow-up was 11 years (range, 7-17 years) for estimation of survival and 8 years (range, 0-17 years) for evaluation of recurrent disease.The crude rate of local recurrence, defined as a recurrence in the scar or transplant, was1% (8 of 989 patients). Twenty percent of the patients (194 of 989 patients) experienced any disease recurrence, and 15% (146 of 989 patients) died of melanoma. There were no statistically significant differences between the two treatment arms. In a multivariate Cox analysis with patients allocated to wide excision as the reference group, the estimated relative hazards for overall survival and recurrence free survival among those allocated to a 2-cm resection margin were 0.96 (95% confidence interval, 0.75-1.24), and 1.02 (95% confidence interval, 0.80-1.30), respectively.In this long term follow-up study, local recurrences were found to be rare among patients with tumors0.8 mm thick and/= 2.0 mm thick. No difference in recurrence rate or survival between the two treatment groups was found. Patients in this category can be treated with a resection margin of 2 cm as safely as with a resection margin of 5 cm.