Factors associated with longitudinal progression of the cumulative burden of morbidity and overall mortality after cisplatin-based chemotherapy for testicular cancer.

Background: To comprehensively evaluate the longitudinal progression of cumulative burden of morbidity (CBM) in testicular cancer survivors (TCS) following standard-dose cisplatin-chemotherapy and the impact of modifiable risk factors on morbidity and early-mortality.

Methods: Participants completed first-line chemotherapy ≥6 months before baseline assessments with comprehensive questionnaires and physical-examinations. Based on follow-up assessments (median: 7 years later), longitudinal progression of adverse health outcomes (AHOs) and CBM score (encompassing AHO number and severity) was examined. Baseline health behaviors and AHOs were evaluated for associations with mortality using mixed-effects parametric proportional-hazards regression to identify modifiable risk factors.

Results: Among 616 TCS longitudinally assessed, 23% experienced worsening CBM post-chemotherapy (median: 11 years [IQR = 7-15]). Declines were driven by worsening treatment-related AHOs: tinnitus (29.7%), hearing loss (24.4%), Raynaud's (22.6%), neuropathy (18.5%), and neuropathic-pain (10.7%). Baseline factors associated with worsening neuropathy included lack of aerobic physical-activity (OR = 1.98, 95%CI = 1.06-3.72) and obesity (OR = 1.85, 95%CI = 1.17-2.92). These were also related to worsening neuropathic-pain (OR = 2.82, p = .009; and OR = 2.29; p = .023). Twenty-nine deaths occurred among 1,830 five-year TCS (4.2% cumulative hazard) (median age: 48-years [range = 22-74]). Participants reporting neuropathic-pain (HR = 3.64, 95%CI = 1.45-9.10), no aerobic (HR = 6.56, 95%CI = 2.73-15.8), or no low-impact physical-activity (HR = 3.96, 95%CI = 1.40-11.2) had significantly higher mortality, as did TCS indicating fair (HR = 9.23, 95%CI = 3.08-27.8) or poor (HR = 18.5, 95%CI = 3.30-103) health. Relationships between pain and mortality were mediated through lowered physical-activity (p = .036).

Conclusions: Clinically-actionable factors associated with early mortality identify high-risk TCS in need of closer monitoring and targeted interventions. The significant relationship between neuropathic-pain and mortality, mediated by low physical-activity, is the first to our knowledge in TCS.