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.

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.

Psychological stress in long-term testicular cancer survivors: a Danish nationwide cohort study.

PURPOSE: Long-term cancer survivors may develop psychological late effects. The aim of the present study was to determine prevalence of high level of stress in testicular cancer survivors (TCS) compared with the general population and prevalence of high level of stress among TCS stratified by type of treatment (surveillance, bleomycin, etoposide and cisplatin (BEP), or abdominal radiotherapy (RT)). METHODS: In this large, nationwide and population-based, cross-sectional study, a total of 2252 TCS filled in a questionnaire between 2014-2016 covering psychological stress (Perceived Stress Scale (PSS)), sociodemographic factors, and physical health variables. Results were compared with a reference population. The reference population consisted of 61,927 men without prior or present cancer and sampled at random from the central population. High level of stress was defined as a PSS score ≥ 16, equivalent to the highest scoring quintile in the reference population. Logistic regression models adjusted for relevant covariates were used to estimate prevalence ratios of high level of stress. RESULTS: Distribution of TCS was: surveillance, n = 1134; BEP, n = 807; and RT, n = 311 (median time since diagnosis was 19 years). TCS were more likely to have high level of stress compared to the reference population with a prevalence ratio of 1.56 (95% CI, 1.40-1.73). Individually, surveillance, BEP and RT groups had higher level of stress compared to the reference population. CONCLUSIONS: TCS are more likely to have high level of stress. Screening programs for psychological stress should be considered as part of the follow-up program. IMPLICATIONS FOR CANCER SURVIVORS: A higher level of stress is observed in TCS irrespective of treatment.

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.

Quality of Life in Long-Term Testicular Cancer Survivors With Compensated Leydig Cell Dysfunction.

BACKGROUND: Compensated Leydig cell (LC) dysfunction, defined by elevated serum levels of luteinizing hormone (LH) in combination with normal total testosterone levels, is common in testicular cancer (TC) survivors. The association between this condition and quality of life is unknown. We aimed to clarify if TC survivors with compensated LC dysfunction have impaired quality of life. PATIENTS AND METHODS: In total, 147 long-term TC survivors were included. On the basis of a single measurement of testosterone and LH, compensated LC dysfunction was defined by age-adjusted levels of LH above normal range combined with testosterone levels within the normal range. Quality-of-life outcomes including sexual function, anxiety and depression, fatigue, and overall self-evaluated quality of life were compared between patients with and without compensated LC dysfunction with adjustment for age. RESULTS: In total, 60 TC survivors had compensated LC dysfunction and 87 TC survivors had normal LC function. TC survivors with compensated LC dysfunction had lower serum levels of total testosterone (11 vs. 13 nmol/L, P = .016). There were no significant differences in the investigated quality-of-life outcomes (anxiety, depression, sexual function, fatigue) between the 2 groups. CONCLUSION: Compensated LC dysfunction in TC survivors was not associated with symptoms of depression, anxiety, sexual dysfunction, fatigue, or impaired overall self-evaluated quality of life. Limitations include the few cases of symptoms of depression (n = 7). Our findings do not suggest that testosterone substitution is indicated in TC survivors with compensated LC dysfunction.

Sexual Function in a Nationwide Cohort of 2,260 Survivors of Testicular Cancer after 17 Years of Followup.

PURPOSE: Evidence on the long-term impact of testicular cancer treatment on sexual function is not clear. Our aim was to estimate the effect of testicular cancer treatment on the risk of sexual dysfunction in long-term survivors of testicular cancer. MATERIALS AND METHODS: We performed a cross-sectional study of 2,260 long-term survivors of testicular cancer with a median followup of 17 years (IQR 12-24), including 1,098 who underwent orchiectomy alone (surveillance), 788 treated with bleomycin, etoposide and cisplatin alone or post-chemotherapy retroperitoneal surgery, 300 treated with abdominal radiotherapy and 74 who received more than 1 line of treatment. Sexual function was evaluated by the IIEF-15 (International Index of Erectile Function-15) questionnaire. Results were compared between treatment groups using logistic regression analysis with the results on each of the 5 IIEF-15 dimensions as the outcome and treatment as exposure using surveillance as the referent. RESULTS: The risk of erectile dysfunction was increased in all treatment groups compared to surveillance, including bleomycin, etoposide and cisplatin alone (OR 1.5, 95% CI 1.0-2.1, p <0.05), bleomycin, etoposide and cisplatin with post-chemotherapy surgery (OR 2.1, 95% CI 1.4-3.4, p <0.005), radiotherapy (OR 1.7, 95% CI 1.1-2.5, p <0.05) and more than 1 line of treatment (OR 3.2, 95% CI 1.6-6.3, p <0.005). Orgasmic dysfunction was associated with radiotherapy, bleomycin, etoposide and cisplatin with post-chemotherapy surgery and more than 1 line of treatment. CONCLUSIONS: Treatment with bleomycin, etoposide and cisplatin, radiotherapy and more than 1 treatment line increased the risk of erectile dysfunction in long-term survivors of testicular cancer compared to surveillance. Patients should be informed about this as part of the information on treatment related late effects.

Cohort Profile: The Danish Testicular Cancer Late Treatment Effects Cohort (DaTeCa-LATE).

The cohort was set up in order to analyze late effects in long-term testicular cancer survivors (TCS) and to contribute to the design of future follow-up programs addressing and potentially preventing late effects. Data for this cross-sectional study were collected between January 1, 2014, and December 31, 2016, among living Danish TCS and 60% agreed to participate in the cohort (N = 2,572). Mean time since testicular cancer (TC) diagnosis was 18 years (range 7-33) and mean age of participants was 53 years (range 25-95). Data consist of results of a questionnaire with patient reported outcomes which covers a broad range of items on late-effects. The study also included data obtained through linkages to Danish registries, a biobank, and clinical data from hospital files and pathology reports originating from the Danish Testicular Cancer Database (DaTeCa). The treatment during the observation period has been nearly the same for all stages of TC and is in agreement with today's standard treatment, this allows for interesting analysis with a wide timespan. We have extensive data on non-responders and are able to validate our study findings. Data from a Danish reference population (N = 162,283) allow us to compare our findings with a Danish background population. The cohort can easily be extended to access more outcomes, or include new TCS. A limitation of the present study is the cross-sectional design and despite the large sample size, The Danish Testicular Cancer Late Treatment Effects Cohort (DaTeCa-LATE) lacks statistical power to study very rare late effects. Since it was voluntary to participate in the study we have some selection bias, for instance, we lack responders who were not in a paired relationship, but we would still argue that this cohort of TCSs is representative for TCSs in Denmark. COLLABORATION AND DATA ACCESS: Researches interested in collaboration with the DaTeCa-LATE study group please contact Professor Gedske Daugaard kirsten.gedske.daugaard@regionh.dk.