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| (1) Overarching recommendation: lifelong follow-up of all testicular cancer survivors (TCS) |
| (i) Integrate observational and analytic epidemiologic studies with molecular and genetic approaches to ascertain the risk of emerging toxicities and to understand the evolution of known late effects, especially with the aging of TCS. |
| (ii) Evaluate the influence of race and socioeconomic status (SES) on the late effects of TC and its treatment. |
| (iii) Characterize long-term tissue deposition of platinum (sites and reactivity), serum levels, and correlation with late effects. |
| (iv) Evaluate the life-long burden of medical and psychosocial morbidity by treatment. |
| (v) Utilize research findings to establish evidence-based, risk-adapted, long-term follow-up care. |
| (2) Specific recommendations |
| (i) Second malignant neoplasms (SMN) and late relapses |
| (a) Determine the effect of reductions in field size and dose of radiotherapy, along with the use of carboplatin as adjuvant therapy in seminoma patients, on the risk of SMN. |
| (b) Examine relation between platinum-based chemotherapy and site-specific risk of solid tumors, the associated temporal patterns, and the influence of age at exposure and attained age. |
| (c) Compare risk of SMN in TCS managed with surgery alone to cancer incidence in the general male population. |
| (d) Examine delaying influence of platinum-based chemotherapy (and duration and magnitude of effect) on development of contralateral testicular cancer. |
| (e) Characterize the evolution of cured testicular cancer, in particular, the molecular underpinnings of late recurrences. |
| (ii) Cardiovascular disease (CVD) |
| (a) Evaluate the contributions and interactions of subclinical hypogonadism, platinum-based chemotherapy, radiotherapy, lifestyle factors (diet, tobacco use, and physical activity), body mass index, family history of CVD, race, socioeconomic status, abnormal laboratory values, and genetic modifiers. |
| (b) Develop comprehensive risk prediction models, considering the above variables, to stratify TCS into risk groups in order to customize follow-up strategies and develop evidence-based interventions. |
| (iii) Neurotoxicity |
| (a) Evaluate evolution of neurotoxicity across TCS lifespan, role of genetic modifiers, and extent to which symptoms impact on work ability and quality of life. |
| (iv) Nephrotoxicity |
| (a) Determine whether the natural decline in renal function associated with aging is accelerated in TCS, any influence of low-level platinum exposure, and the impact of decreased GFR on CVD and all-cause mortality. |
| (b) Determine the incidence of hypomagnesemia, together with the role of modifying factors and resultant medical consequences, in long-term TCS. |
| (v) Hypogonadism and decreased fertility |
| (a) Address the incidence, course, and clinical effects of subclinical hypogonadism. |
| (b) Evaluate effect of all levels of gonadal dysfunction in TCS on CVD, premature aging, fatigue, osteoporosis, mental health, quality of life, and sexuality. |
| (vi) Pulmonary function |
| (a) Examine role of platinum compounds on long-term pulmonary damage in TCS, and interactions with other influences, including bleomycin, tobacco use, and occupational risk factors. |
| (vii) Psychosocial effects |
| (a) Identify prevalence and predictors of depression, cancer-related anxiety, fatigue, infertility-related distress, problems with sexuality and paired relationships, and posttraumatic growth. |
| (b) Examine the impact of different cultural backgrounds on posttreatment quality of life. |
| (c) Evaluate TCS work ability throughout life. |
| (d) Determine whether normal age-related declines in cognitive function are accelerated in TCS. |
| (3) Interventions |
| (i) Conduct targeted intervention trials aimed at promoting smoking cessation, healthy dietary habits, and an increase in physical activity. |
| (ii) Evaluate the role of information and communication technologies in promoting a healthy lifestyle among TCS. |
| (iii) Consider randomized, pharmacologic intervention trials among TCS with biochemical parameters approaching threshold values to avoid accelerated development into treatment-requiring CVD. |
| (iv) Determine optimal schedule of testosterone replacement therapy among TCS with clinical hypogonadism. |
| (v) Consider screening strategies for selected SMN. |
| (4) Genetic and molecular considerations |
| (i) Evaluate genetic risk factors (identified in the general male population) as modifiers for all late effects in TCS, in particular, CVD, SMN, neurotoxicity, nephrotoxicity, hypogonadism, and psychosocial effects. |
| (ii) Investigate the role of genome-wide association studies, epigenetics, mitochrondrial DNA, microRNA, proteomics and related approaches in identifying genetic variants that contribute to the late effects of treatment. |
| (iii) Develop standardized procedures for biospecimen collection to support genetic and molecular studies, as reviewed previously. |
| (5) Risk prediction models |
| (i) Develop comprehensive risk prediction models that incorporate genetic modifiers of late sequelae. |
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