Prognostic factors for relapse in patients with clinical stage I testicular non-seminoma: A nationwide, population-based cohort study.

BACKGROUND: Approximately 30% of patients with clinical stage I non-seminoma (CSI-NS) relapse. Current risk stratification is based on lymphovascular invasion (LVI) alone. The extent to which additional tumor characteristics can improve risk prediction remains unclear. OBJECTIVE: To determine the most important prognostic factors for relapse in CSI-NS patients. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study including all patients with CSI-NS diagnosed in Denmark between 2013 and 2018 with follow-up until 2022. Patients were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, histological slides from the orchiectomy specimens were retrieved. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Histological slides were reviewed blinded to the clinical outcome. Clinical data were obtained from medical records. The association between prespecified potential prognostic factors and relapse was assessed using Cox regression analysis. Model performance was evaluated by discrimination (Harrell's C-index) and calibration. RESULTS: Of 453 patients included, 139 patients (30.6%) relapsed during a median follow-up of 6.3 years. Tumor invasion into the hilar soft tissue of the testicular hilum, tumor size, LVI and embryonal carcinoma were independent predictors of relapse. The estimated 5-year risk of relapse ranged from < 5% to > 85%, depending on the number of risk factors. After internal model validation, the model had an overall concordance statistic of 0.75. Model calibration was excellent. CONCLUSION AND RELEVANCE: The identified prognostic factors provide a much more accurate risk stratification than current clinical practice, potentially aiding clinical decision-making.

Postchemotherapy Retroperitoneal Lumpectomy in Patients with Nonseminoma Testicular Cancer: A Nationwide Study.

BACKGROUND AND OBJECTIVE: Optimal treatment outcomes in patients with metastatic nonseminoma testicular cancer are achieved with chemotherapy and subsequent surgery in cases with residual tumor. In Denmark, postchemotherapy retroperitoneal lumpectomy (RPLP) is performed in patients with residual tumors >1 cm. There is a need to clarify whether this surgical method provides acceptable treatment results. Our objective was to describe morbidity and oncological outcomes of postchemotherapy RPLP. METHODS: This was a retrospective population-based multicenter study including patients with nonseminoma testicular cancer and postchemotherapy RPLP performed in Denmark between 1990 and 2015. A total of 219 patients were eligible, with median follow-up of 19 yr. Postoperative complications were evaluated according to the Clavien-Dindo classification. The cumulative incidence of recurrence inside or outside the borders of a bilateral surgical template, progression-free survival (PFS), and overall survival estimates were calculated using the Kaplan-Meier method. KEY FINDINGS AND LIMITATIONS: After median follow-up of 19 yr, 31/219 patients (14%) experienced a surgical complication, of which 5% were Clavien-Dindo grade ≥III. In total, 37 patients experienced a recurrence. The 5-yr, 10-yr, and 20-yr cumulative risk of recurrence inside a bilateral template was 4.3%, 5.9%, and 5.9%, respectively. The 10-yr PFS rate was 83% and the 10-yr overall survival rate was 96%. The main limitation of the study is the retrospective design. CONCLUSIONS AND CLINICAL IMPLICATIONS: With few patients experiencing a major postoperative complication and a 10-yr cumulative rate of 5.9% for recurrence inside a bilateral surgical template, postchemotherapy RPLP appears to be a safe alternative to template surgery for disseminated nonseminoma. PATIENT SUMMARY: We looked at minimal surgery to remove tumor tissue remaining after chemotherapy in patients with testicular cancer. We found a low frequency of complications, tumor recurrence, and death.

Prognostic Factors for Relapse in Patients With Clinical Stage I Testicular Seminoma: A Nationwide, Population-Based Cohort Study.

PURPOSE: Approximately 20% of patients with clinical stage I seminoma relapse. Tumor size and rete testis invasion have been identified as risk factors for relapse. However, the level of evidence supporting the use of these risk factors in clinical decision making is low. Previous studies have been hampered by selection bias and variable pathology reporting that limit interpretation and generalization of results. We assessed prognostic factors for relapse in an unselected nationwide population-based setting with centralized pathology review. METHODS: Patients with clinical stage I seminoma diagnosed from January 2013 to December 2018 were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, histologic slides from the orchiectomy specimens were retrieved and reviewed blinded to the clinical outcome. Clinical data were obtained from medical records with follow-up until July 2022. The association between prespecified potential clinical and histopathologic prognostic factors and relapse was assessed by the use of Cox regression analysis. RESULTS: Of 924 patients included, 148 (16%) patients relapsed during a median follow-up of 6.3 years. Invasion of the testicular hilum (rete testis and hilar soft tissue), lymphovascular invasion, and elevated preorchiectomy levels of ß-human chorionic gonadotropin and lactate dehydrogenase were independent predictors of relapse. The estimated 5-year risk of relapse ranged from 6% in patients with no risk factors to 62% in patients with all four risk factors with tumor extension into the hilar soft tissue of the testicular hilum. After internal model validation, the prognostic model had an overall concordance statistic of 0.70. CONCLUSION: The provided prognostic factors could replace current risk factors in guidelines and be used in future studies investigating risk-adapted follow-up and treatment strategies.

Insulin-like Factor 3, Basal and Human Chorionic Gonadotropin-Stimulated Testosterone as Biomarkers to Predict the Effect of Testosterone Replacement in Testicular Cancer Survivors With Mild Leydig Cell Insufficiency.

INTRODUCTION: Mild Leydig cell insufficiency affects a substantial proportion of testicular cancer survivors. Previous studies have not shown a beneficial effect of testosterone replacement therapy, however, with a pronounced interindividual effect. Thus, biomarkers identifying the subgroups that might benefit are wanted. We aimed to determine if insulin-like factor 3 (INSL3), basal and human chorionic gonadotropin (hCG)-stimulated testosterone can predict the effect of testosterone replacement therapy in testicular cancer survivors with mild Leydig cell insufficiency. PATIENTS AND METHODS: We randomized adult testicular cancer survivors with mild Leydig cell insufficiency 1:1 to 12 months of transdermal testosterone replacement therapy (Tostran gel 2%) or placebo. INSL3, basal, and hCG-stimulated testosterone were measured at baseline. Outcomes (glucose, insulin, HbA1C, lipids, blood pressure, and body composition) were measured at baseline, 6 and 12 months. We applied a linear mixed-effect model comparing patients receiving testosterone with placebo in subgroups by biomarker. RESULTS: We included and randomized 69 patients between October 2016 and February 2018. Patients with INSL3 and hCG-stimulated testosterone concentrations below the median had a -1.7 kg (95% CI: -3.1, -0.4) and -2.0 kg (95% CI: -3.5, -0.6) change in fat mass after 12 months of testosterone replacement therapy compared with placebo. This was not the case in patients with INSL3 and hCG-stimulated testosterone above the median. We did not find any effect of these biomarkers on glucose, insulin, HbA1c, or lipids. CONCLUSION: Patients with INSL3 and hCG-stimulated testosterone concentrations below the median had decreased fat mass after 12 months of testosterone replacement therapy compared with placebo. It should be evaluated in larger trials if these biomarkers can be used as predictive markers identifying testicular cancer patients with mild Leydig cell insufficiency who might benefit from testosterone substitution.

Outcomes of relapsed clinical stage I versus de novo metastatic testicular cancer patients: an analysis of the IGCCCG Update database.

BACKGROUND: Active surveillance after orchiectomy is the preferred management in clinical stage I (CSI) germ-cell tumours (GCT) associated with a 15 to 30% relapse rate. PATIENTS AND METHODS: In the IGCCCG Update database, we compared the outcomes of gonadal disseminated GCT relapsing from initial CSI to outcomes of patients with de novo metastatic GCT. RESULTS: A total of 1014 seminoma (Sem) [298 (29.4%) relapsed from CSI, 716 (70.6%) de novo] and 3103 non-seminoma (NSem) [626 (20.2%) relapsed from CSI, 2477 (79.8%) de novo] were identified. Among Sem, no statistically significant differences in PFS and OS were found between patients relapsing from CSI and de novo metastatic disease [5-year progression-free survival (5y-PFS) 87.6% versus 88.5%; 5-year overall survival (5y-OS) 93.2% versus 96.1%). Among NSem, PFS and OS were higher overall in relapsing CSI patients (5y-PFS 84.6% versus 80.0%; 5y-OS 93.3% versus 88.7%), but there were no differences within the same IGCCCG prognostic groups (HR = 0.89; 95% CI: 0.70-1.12). Relapses in the intermediate or poor prognostic groups occurred in 11/298 (4%) Sem and 112/626 (18%) NSem. CONCLUSION: Relapsing CSI GCT patients expect similar survival compared to de novo metastatic patients of the same ICCCCG prognostic group. Intermediate and poor prognosis relapses from initial CSI expose patients to unnecessary toxicity from more intensive treatments.

Predicting Hearing Loss in Testicular Cancer Patients after Cisplatin-Based Chemotherapy.

Testicular cancer is predominantly curable, but the long-term side effects of chemotherapy have a severe impact on life quality. In this research study, we focus on hearing loss as a part of overall chemotherapy-induced ototoxicity. This is a unique approach where we combine clinical data from the acclaimed nationwide Danish Testicular Cancer (DaTeCa)-Late database. Clinical and genetic data on 433 patients were collected from hospital files in October 2014. Hearing loss was classified according to the FACT/GOG-Ntx-11 version 4 self-reported Ntx6. Machine learning models combining a genome-wide association study within a nested cross-validated logistic regression were applied to identify patients at high risk of hearing loss. The model comprising clinical and genetic data identified 67% of the patients with hearing loss; however, this was with a false discovery rate of 49%. For the non-affected patients, the model identified 66% of the patients with a false omission rate of 19%. An area under the receiver operating characteristic (ROC-AUC) curve of 0.73 (95% CI, 0.71-0.74) was obtained, and the model suggests genes SOD2 and MGST3 as important in improving prediction over the clinical-only model with a ROC-AUC of 0.66 (95% CI, 0.65-0.66). Such prediction models may be used to allow earlier detection and prevention of hearing loss. We suggest a possible biological mechanism for cisplatin-induced hearing loss development. On confirmation in larger studies, such models can help balance treatment in clinical practice.

A Validated Algorithm for Register-Based Identification of Patients with Relapse of Clinical Stage I Testicular Cancer.

Purpose: The Danish Testicular Cancer (DaTeCa) database aims to monitor and improve quality of care for testicular cancer patients. Relapse data registered in the DaTeCa database rely on manual registration. Currently, some safeguarding against missing registrations is attempted by a non-validated register-based algorithm. However, this algorithm is inaccurate and entails time-consuming medical record reviews. We aimed (1) to validate relapse data as registered in the DaTeCa database, and (2) to develop and validate an improved register-based algorithm identifying patients diagnosed with relapse of clinical stage I testicular cancer. Patients and Methods: Patients registered in the DaTeCa database with clinical stage I testicular cancer from 2013 to 2018 were included. Medical record information on relapse data served as a gold standard. A pre-specified algorithm to identify relapse was tested and optimized on a random sample of 250 patients. Indicators of relapse were obtained from pathology codes in the Danish National Pathology Register and from diagnosis and procedure codes in the Danish National Patient Register. We applied the final algorithm to the remaining study population to validate its performance. Results: Of the 1377 included patients, 284 patients relapsed according to the gold standard during a median follow-up time of 5.9 years. The completeness of relapse data registered in the DaTeCa database was 97.2% (95% confidence interval (CI): 95.2-99.1). The algorithm achieved a sensitivity of 99.6% (95% CI: 98.7-100), a specificity of 98.9% (95% CI: 98.2-99.6), and a positive predictive value of 95.9% (95% CI: 93.4-98.4) in the validation cohort (n = 1127, 233 relapses). Conclusion: The registration of relapse data in the DaTeCa database is accurate, confirming the database as a reliable source for ongoing clinical quality assessments. Applying the provided algorithm to the DaTeCa database will optimize the accuracy of relapse data further, decrease time-consuming medical record review and contribute to important future clinical research.

Testicular cancer.

Testicular cancer is the most frequent solid tumour in young men and accounts for 1% of newly diagnosed malignant tumours. Tumours are divided into seminomas and non-seminomas. Approximately 50% of patients are cured by orchiectomy alone, while the other half in addition will need chemotherapy or radiotherapy for metastatic disease. Survival in patients treated for metastatic disease depends on prognostic criteria. Patients treated with systemic therapy have an increased risk of subsequent cancer and cardiovascular disease, as argued in this review.

Smoking as a prognostic factor for survival in patients with disseminated germ cell cancer.

We investigated the impact of smoking on overall survival (OS) in testicular germ cell cancer (TC) patients receiving first-line combination chemotherapy (bleomycin-etoposide-cisplatin [BEP]). Patients who received BEP for metastatic TC were identified in the Danish Testicular Cancer database. Information on smoking status at the time of diagnosis was obtained by medical record review. OS and cause of death were compared between current smokers and never-smokers. Of 1883 eligible patients, information on smoking status was available in 1156 patients, of whom 602 were current smokers. The 10-year OS was 92% in never-smokers compared with 83% in current smokers (P < .001) (hazard ratio for death = 1.85, 95% confidence interval = 1.29 to 2.66, P = .001). A higher proportion of current smokers died of TC compared with nonsmokers (P < .01). Smoking negatively affects survival after BEP in patients with disseminated TC. Vigorous smoking cessation programs are advocated in TC patients.

A randomized double-blind single center study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention).

INTRODUCTION: Elevated luteinizing hormone (LH) in combination with low-normal testosterone (mild Leydig cell insufficiency) is common in testicular cancer (TC) survivors and is associated with impaired insulin sensitivity and metabolic syndrome. The aim was to evaluate if testosterone replacement therapy (TRT) improves metabolic health in this subgroup of TC survivors. PATIENTS AND METHODS: This was a single-center, double-blind, randomized, controlled trial. The main eligibility criterion was LH above the age-adjusted upper limit of normal in combination with free testosterone in the lower half of the age-adjusted normal range (mild Leydig cell insufficiency) >1 year after TC treatment. Eligible patients were randomly assigned (1:1) to 12 months transdermal TRT (Tostran, gel, 2%) or placebo with a maximum daily dose of 40 mg. The primary outcome was difference in Δ2 hour glucose measured with oral glucose tolerance test between groups assessed at 12 months. Outcomes were assessed after 6-, 12- and 3 months post-treatment. The study was registered at www. CLINICALTRIAL: gov (NCT02991209) and ended June 2019. RESULTS: Between October 2016 and February 2018, 140 patients were screened for eligibility and 69 were randomized to testosterone (n = 35, 51%) or placebo (n = 34, 49%). TRT was not associated with a statistically significant difference in Δ2 hour glucose compared to placebo after 12 months of treatment (0.04 mmol/L (95% CI: -0.53, 0.60)). There was no statistically significant difference in Δ2 hour insulin between the groups after 12 months of treatment (28.23 pmol/L (95% CI: -34.40, 90.86)). Similarly, TRT was not associated with significant improvement in components of metabolic syndrome. TRT was associated with a decrease in fat mass after 12 months compared to placebo (-1.35 kg, (95% CI: -2.53, -0.18)). CONCLUSION: In TC survivors with mild Leydig cell insufficiency, TRT was not associated with improvement of metabolic health. These findings do no not support routine use of TRT in these patients.

Effect of Testosterone Replacement Therapy on Quality of Life and Sexual Function in Testicular Cancer Survivors With Mild Leydig Cell Insufficiency: Results From a Randomized Double-blind Trial.

BACKGROUND: Testicular cancer (TC) treatment leaves many patients with low levels of testosterone. While most TC patients with low testosterone (< - 2 SD) and hypogonadal symptoms will initiate testosterone replacement therapy (TRT), the role of TRT in patients with mild Leydig cell insufficiency, defined as elevated luteinizing hormone in combination with borderline low testosterone, is unknown. To clarify if TRT improves symptoms of depression and anxiety, sexual function, fatigue, and quality of life in TC survivors with mild Leydig cell insufficiency. MATERIALS AND METHODS: In total, 69 men aged between 18 and 65 years with mild Leydig cell insufficiency after TC treatment were randomized 1:1 to 12 months daily transdermal testosterone (maximum dose 40 mg/daily) vs. placebo. Patient reported anxiety, depression, sexual function, fatigue, and overall quality of life were assessed at baseline, after 6- and 12 months treatment, and 3 months post-treatment using validated questionnaires. RESULTS: After 12 months of treatment, median luteinizing hormone and median free testosterone were normalized in the testosterone group. Compared to placebo, TRT was not associated with statistically significant improvement of symptoms of anxiety and depression, sexual function, fatigue, and overall quality of life. Testosterone replacement therapy did not improve anxiety, depression, sexual function, fatigue, or overall quality of life in patients with mild Leydig cell insufficiency compared to placebo. CONCLUSION: Routine TRT in TC survivors with mild Leydig cell insufficiency to improve sexual function and quality of life cannot be generally recommended. The findings should preferably be validated in a larger cohort.

Paternity After Treatment for Testicular Germ Cell Cancer: A Danish Nationwide Population-Based Cohort Study.

BACKGROUND: Testicular germ cell cancer (TC) incidence peaks during reproductive age, but knowledge on fertility after treatment is insufficient. The aim was to evaluate paternity after today's TC treatment. METHODS: Clinical data were extracted from the Danish Testicular Cancer database, and patients were divided into 4 groups: 1) surveillance; 2) bleomycin, etoposide, and cisplatin (BEP); 3) BEP + postchemotherapy retroperitoneal surgery (BEP + surgery); and 4) abdominal radiotherapy. For each patient, 10 men matched on date of birth were randomly sampled from the normal population. Paternity was defined as date of birth of first child after TC treatment with or without the use of assisted reproductive technology and was assessed by linkage to the Danish Medical Birth Register and the Danish in vitro fertilization register. RESULTS: We included 4846 unilateral TC patients and 48 456 men from the normal population. The 20-year predicted chance of obtaining fatherhood for a 30-year-old man was 39.7% in TC patients compared with 42.5% in the normal population. The chance of obtaining fatherhood was statistically significantly decreased after BEP (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.78 to 0.97) and BEP + surgery (HR = 0.74, 95% CI = 0.63 to 0.87), but not after radiotherapy (HR = 0.89, 95% CI = 0.75 to 1.06) or surveillance (HR = 0.95, 95% CI = 0.89 to 1.02). The risk of needing assisted reproductive technology to obtain fatherhood was increased after all treatment modalities. CONCLUSIONS: The chance of obtaining fatherhood after TC treatment was substantially higher than previously reported. Patients followed on a surveillance program had a similar chance of obtaining fatherhood as noncancerous men.

Oncological outcome and complications of post-chemotherapy retroperitoneal surgery in non-seminomatous germ cell tumours - a systematic review.

INTRODUCTION: Post-chemotherapy surgery constitutes an integral part of the management of patients with non-seminomatous germ-cell tumours with a residual mass in the retroperitoneum. Published data on recurrence rates and complications to bilateral retroperitoneal lymph node dissection (RPLND), unilateral template RPLND, and resection of residual mass only according to different surgical techniques (open, laparoscopic, and robotic surgery) were reviewed. MATERIAL AND METHODS: PubMed/Medline, Embase, and the Cochrane databases were searched systematically. The risk of bias was assessed with the Newcastle Ottawa Scale. RESULTS: In total, 28 studies were included. Eight studies reported on open surgery with the bilateral template, seven on the unilateral template, and three on resection of mass only. Median follow-up was 39, 39, and 70 months, respectively. Recurrences were found in 11, 12, and 14%, respectively. Major complications (Clavien-Dindo III or more) were observed in 18, 8, and 17%, respectively. Two studies reported on laparoscopic bilateral surgery, eight on unilateral, and two on residual mass only. A total of Median follow-up was 52, 29, and 55 months, respectively. Recurrences were found in 0, 1, and 9%, respectively. Major complications were not documented for bilateral but were observed in 4% for unilateral and 0% for resection of tumour only. Four studies on robotic bilateral surgery, three on unilateral and two on resection of tumour only were included. Follow-up was 18, 35, and 30 months, respectively. Recurrences were found in 0, 0, and 2%, respectively. Major complications were observed in 0, 10. and 2%, respectively. CONCLUSIONS: When patient selection is made, recurrence rates for the open unilateral template are comparable to the bilateral template. The risk of complications is highest after an open bilateral template. Laparoscopic and robotic surgery should not be used as a standard procedure. More studies are required with larger patient populations and longer follow-up.

Late adverse effects and quality of life in survivors of testicular germ cell tumour.

Currently, ~95% of patients with testicular germ cell tumour (TGCT) are cured, resulting in an increasing number of TGCT survivors. Although cured, these men face potential late adverse effects and reduced quality of life. Survivors face a twofold increased risk of second malignant neoplasms after chemotherapy and radiotherapy, with evidence of dose-dependent associations. For survivors managed with surveillance or treated with radiotherapy, the risk of cardiovascular disease (CVD) is comparable to the risk in the general population, whereas treatment with chemotherapy increases the risk of life-threatening CVD, especially during treatment and after 10 years of follow-up. Other adverse effects are organ-related toxicities such as neuropathy and ototoxicity. Pulmonary and renal impairment in patients with TGCT treated with chemotherapy is limited. Survivors of TGCT might experience psychosocial distress including anxiety disorders, fear of cancer recurrence and TGCT-specific issues, such as sexual dysfunction. Late adverse effects can be avoided in most patients with stage I disease if followed on a surveillance programme. However, patients with disseminated disease can experience toxicities associated with radiotherapy and chemotherapy, and/or adverse effects related to surgery for residual disease. The severity of adverse effects increases with dose of both chemotherapy and radiotherapy. This Review discusses the most recent data concerning the late adverse effects of today's standard treatments for TGCT.

Long-term neurotoxicity and quality of life in testicular cancer survivors-a nationwide cohort study.

PURPOSE: To evaluate neurotoxicity in testicular cancer survivors (TCSs) years after treatment and secondly the influence of neurotoxicity on quality-of-life (QoL). METHODS: We identified 2234 TCSs who completed the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity questionnaire. QoL was evaluated with the European Organization for Research and Treatment of Cancer QLQ-C30. Patients were grouped according to treatment strategy: surveillance (N = 1113), infradiaphragmatic radiotherapy (N = 301), cisplatin-etoposide-bleomycin (BEP) (N = 759), and more than one line of treatment (MTOL) (N = 61). Association of treatment modality with long-term neurotoxicity was analyzed with ordinal logistic regression. Secondly, associations between neurotoxicity and QoL were analyzed in BEP-treated patients. Analyses were age-adjusted and repeated with additional adjustment for comorbidity, smoking, and alcohol consumption. RESULTS: After a median follow-up of 18.4 years, treatment with BEP and MTOL was associated with overall increased risk of neurotoxicity (odds ratio 2.4-4.7 depending on treatment intensity, P < 0.001) as well as subscales (peripheral neuropathy, ototoxicity, and dysfunction associated with neuropathy, all P < 0.001). Radiotherapy and surveillance were not associated with neurotoxicity. In patients treated with BEP, neurotoxicity was highly associated with all indicators of worse QoL outcomes (P-trend: 1.5 × 10-17 to 1.1 × 10-28) after almost 20 years of follow-up. CONCLUSIONS: Treatment with BEP was associated with long-term neurotoxicity, which was highly associated with decreased QoL. Strategies to ameliorate or prevent neurotoxicity should be investigated. IMPLICATIONS FOR CANCER SURVIVORS: Treatment with chemotherapy for testicular cancer induces long-term neuro- and ototoxicity which may have severe influence on quality-of-life years after treatment cessation.

Adverse health behaviours in long-term testicular cancer survivors: a Danish nationwide study.

BACKGROUND: Treatment for disseminated testicular cancer increases the risk of secondary malignancy and cardiovascular disease. The risk of developing these serious adverse effects may be positively affected by healthy living. The purpose of this study was to identify health behaviours with possible influence on late effects that could be targets for intervention. MATERIAL AND METHODS: In this cross-sectional study, testicular cancer survivors diagnosed in the period 1984-2007 from the Danish Testicular Cancer database completed a questionnaire on health behaviours (2014-2016). We estimated prevalence of smoking, alcohol consumption, sedentary lifestyle and overweight. Prevalence ratios described with 95% confidence intervals of adverse health behaviours were stratified by treatment modalities and compared to a reference population by means of logistic regression with adjustment for sociodemographic confounders. RESULTS: In total, 2395 testicular cancer survivors (surveillance, 1175; chemotherapy, 897; radiotherapy, 323), median time since diagnosis 19 years, and 65,289 noncancer males were included, questionnaire response rates were 60% and 54%, respectively. There were more current smokers (prevalence ratio; 1.14, 95% confidence interval (CI): 1.03-1.26) and patients with body mass index above 25 kg/m2 (prevalence ratio; 1.10, 95% CI: 1.01-1.20) among testicular cancer survivors than in the reference population. Testicular cancer survivors reported less sedentary lifestyle (prevalence ratio; 95% CI: 0.74, 0.64-0.85) and everyday drinkers were fewer (prevalence ratio; 0.79, 95% CI: 0.68-0.92) than in the reference population. CONCLUSION: We identified smoking cessation as primary target for intervention studies in testicular cancer survivors. The effect of smoking cessation interventions as part of treatment should be investigated. Whether drug-based intervention is effective in minimising the risk of exposure to conventional risk factors for cardiovascular disease is also of interest.

Prediction of Nephrotoxicity Associated With Cisplatin-Based Chemotherapy in Testicular Cancer Patients.

BACKGROUND: Cisplatin-based chemotherapy may induce nephrotoxicity. This study presents a random forest predictive model that identifies testicular cancer patients at risk of nephrotoxicity before treatment. METHODS: Clinical data and DNA from saliva samples were collected for 433 patients. These were genotyped on Illumina HumanOmniExpressExome-8 v1.2 (964 193 markers). Clinical and genomics-based random forest models generated a risk score for each individual to develop nephrotoxicity defined as a 20% drop in isotopic glomerular filtration rate during chemotherapy. The area under the receiver operating characteristic curve was the primary measure to evaluate models. Sensitivity, specificity, and positive and negative predictive values were used to discuss model clinical utility. RESULTS: Of 433 patients assessed in this study, 26.8% developed nephrotoxicity after bleomycin-etoposide-cisplatin treatment. Genomic markers found to be associated with nephrotoxicity were located at NAT1, NAT2, and the intergenic region of CNTN6 and CNTN4. These, in addition to previously associated markers located at ERCC1, ERCC2, and SLC22A2, were found to improve predictions in a clinical feature-trained random forest model. Using only clinical data for training the model, an area under the receiver operating characteristic curve of 0.635 (95% confidence interval [CI] = 0.629 to 0.640) was obtained. Retraining the classifier by adding genomics markers increased performance to 0.731 (95% CI = 0.726 to 0.736) and 0.692 (95% CI = 0.688 to 0.696) on the holdout set. CONCLUSIONS: A clinical and genomics-based machine learning algorithm improved the ability to identify patients at risk of nephrotoxicity compared with using clinical variables alone. Novel genetics associations with cisplatin-induced nephrotoxicity were found for NAT1, NAT2, CNTN6, and CNTN4 that require replication in larger studies before application to clinical practice.

Sexual Function and Quality of Life in a National Cohort of Survivors of Bilateral Testicular Cancer.

BACKGROUND: Sexual function and quality of life remain unexplored among long-term survivors of bilateral testicular cancer (TC). OBJECTIVE: To investigate sexual function, fatigue, anxiety, and depression among long-term survivors of bilateral TC (unilateral TC with contralateral germ cell neoplasia in situ [TC+GCNIS] or bilateral TC [BTC]). DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study of 2479 long-term TC survivors, of whom 126 were treated with contralateral radiotherapy for GCNIS, 93 were treated with bilateral orchiectomy for BTC, and 2260 had unilateral TC (reference group). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were assessed using validated questionnaires at a median time since diagnosis of 17 yr (interquartile range 12-23). Results for survivors of TC+GCNIS and of BTC were compared with those for the reference group. Adjustment was made for age and treatment for disseminated disease. RESULTS AND LIMITATIONS: The age-adjusted risk of anxiety was significantly higher among BTC survivors (odds ratio 1.7, 95% confidence interval [CI] 1.1-2.8; p=0.002) than in the reference group. Apart from a higher risk of reduced motivation among survivors of TC+GCNIS (ß=0.067, 95% CI 0.0013-0.13; p=0.046) there were no significant differences between the groups. Limitations include the low number of cases with symptoms of depression. CONCLUSIONS: Survivors of BTC had a higher risk of anxiety but did not experience impairment of other aspects of quality of life when compared to survivors of unilateral TC. These results are of importance for evidence-based information on late effects for bilateral TC patients. PATIENT SUMMARY: We evaluated quality of life and sexual function among long-term survivors of bilateral testicular cancer. Reassuringly, we did not find impaired quality of life apart from a higher risk of anxiety when comparing survivors of bilateral testicular cancer with survivors of unilateral testicular cancer.

Cardiovascular Risk Factors and Disease After Male Germ Cell Cancer.

PURPOSE: To analyze the risk of cardiovascular disease (CVD) after treatment of male germ cell cancer (GCC). METHODS: Clinical data were extracted from the Danish Testicular Cancer database. For each patient, 10 men matched on date of birth were identified in the Danish normal population by risk-set sampling. Cardiovascular risk factors, CVD, and associated deaths were identified in Danish registries. The association between treatment and outcomes was analyzed by separate Cox models for each outcome. Cancer treatment was included as a time-varying covariate. RESULTS: We included 5,185 patients with GCC and 51,850 men in the normal population. Median follow-up was 15.8 years. Treatment with bleomycin-etoposide-cisplatin (BEP; n = 1,819) was associated with increased risks of hypertension and hypercholesterolemia. Hazard ratios (HRs) of CVD < 1 year after initiation of BEP treatment were as follows: myocardial infarction (HR, 6.3; 95% CI, 2.9 to 13.9), cerebrovascular accident (HR, 6.0; 95% CI, 2.6 to 14.1), and venous thromboembolism (HR, 24.7; 95% CI, 14.0 to 43.6). One year after BEP treatment, the risk of CVD decreased to normal levels, but after 10 years, increasing risks were found for myocardial infarction (HR, 1.4; 95% CI, 1.0 to 2.0) and cardiovascular death (HR, 1.6; 95% CI, 1.0 to 2.5). Radiotherapy (n = 780) increased the risk of diabetes at long-term follow-up (HR, 1.4; 95% CI, 1.0 to 2.0) but not that of other outcomes. With surveillance (n = 3,332), cardiovascular risk factors, CVD, and cardiovascular death data were comparable to that of the normal population. CONCLUSION: Treatment with BEP was associated with highly increased risks of CVD < 1 year after treatment start and mildly increased risks after 10 years of follow-up. Radiotherapy increased the risk of diabetes but not incident CVD. The risk of CVD in patients followed in a surveillance program was comparable to that of the normal population.