Neil E. Martin

Testicular cancer survivors (TCS) experience excess cardiovascular disease (CVD) incidence and mortality. To address the urgent need for new risk prediction tools, we evaluated the AHA’s 2024 PREVENT-equation among 1759 TC survivors (TCS; median baseline age = 37 years). Baseline median 10- and 30-year CVD risks were 1.3% and 9.1%. Among evaluated survivors with follow-up (n = 737; median age = 45), each 5% increase in 10-year PREVENT risk conferred 2.94-fold odds (95% CI = 1.99 to 4.35, P < .001) of incident CVD. Those with 10-year PREVENT absolute risk defined as intermediate-high (≥7.5% per AHA) had 12.11-fold higher odds (P < .001). Associations were strongest after 4 cycles of etoposide/cisplatin (EPX4) (OR = 4.93, P < .001), possibly driven by lower eGFR and slightly older age (P < .001 each), and among TCS without vigorous baseline physical activity (OR = 4.25, P < .001). EPX4 patients were among those less engaged in activity (P = .005). PREVENT equations, utilizing routine measures, can identify high-risk TCS, highlighting physical activity as a key modifiable factor for early intervention.

Background: Master clinical trial protocol structures offer administrative, procedural, and statistical advantages but have not been applied in assessing new radiotherapy devices. Herein, we report on a pooled analysis from a first-of-kind master trial evaluating stereotactic MRI-guided adaptive radiotherapy (SMART). Methods: Subjects were enrolled in a prospective master protocol evaluating SMART for multiple oncologic indications. CTCAE v5 toxicities, patient-reported outcome measures (PROMs), and treatment efficiency metrics were assessed across the entire cohort and in anatomic subsets. Results: One hundred and ninety three subjects were enrolled into 20 sub-protocols for different SMART indications. Data were analyzed from the first 161 subjects. The median time from subprotocol amendment submission to activation was 70.5 days (range: 63-93). All completed phase I sub-protocols (n = 9) met the primary endpoints of safety and feasibility. The risk of grade 3+ toxicity was 1.9% (95% CI 0.4% to 5.3%), 7.1% (95% CI 0.9% to 23.5%), 1.8% (95% CI 0.05% to 9.6%) and 0% (95% CI 0.0% to 4.7%) in the overall cohort and thoracic, abdominal and pelvic subsets, respectively. PROMs (PROMIS-10) during and after SMART were unchanged from baseline in all subsets. SMART delivery efficiency improved over the study period (first vs. final 3 months: 78.5 vs. 48.2 minutes, P < .001). Adaptive planning performed for 771 fractions resulted in clinically significant plan improvements in 93.0% of fractions (52.7% for organ-at-risk sparing, 20.5% for target coverage, and 19.8% for both). Conclusions: SMART is feasible and safe for multiple thoracic, abdominal and pelvic radiotherapy indications. The master protocol platform offers an adaptable approach for assessment of new oncologic treatment technologies applicable to multiple indications. Clinical Trial: NCT04115254.

Background: To comprehensively evaluate the longitudinal progression of cumulative burden of morbidity (CBM) in testicular cancer survivors (TCS) following standard-dose cisplatin-based chemotherapy and the impact of modifiable risk factors on morbidity and early mortality. Methods: Participants completed first-line chemotherapy at or longer than 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) were 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 postchemotherapy (median = 11 years, interquartile range = 7-15). Declines were driven by worsening treatment-related AHOs: tinnitus (29.7%), hearing loss (24.4%), Raynaud’s disease (22.6%), neuropathy (18.5%), and neuropathic pain (10.7%). Baseline factors associated with worsening neuropathy included lack of aerobic physical activity (odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.06 to 3.72), and obesity (OR = 1.85, 95% CI = 1.17 to 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 1830 5-year TCS (4.2% cumulative hazard) (median age = 48 years, range = 22-74). Participants reporting neuropathic pain (hazard ratio [HR] = 3.64, 95% CI = 1.45 to 9.10), no aerobic (HR = 6.56, 95% CI = 2.73 to 15.8), or no low-impact physical activity (HR = 3.96, 95% CI = 1.40 to 11.2) had significantly higher mortality, as did TCS indicating fair (HR = 9.23, 95% CI = 3.08 to 27.8) or poor (HR = 18.5, 95% CI = 3.30 to 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.

No study has comprehensively examined associated factors (adverse health outcomes, health behaviors, and demographics) impacting cognitive function in long-term testicular cancer survivors (TC-survivors). TC-survivors given cisplatin-based chemotherapy completed comprehensive, validated surveys, including those which assessed cognition. Medical record abstraction provided cancer and treatment history. Multivariable logistic regression examined relationships between potential associated factors and cognitive impairment. Among 678 TC-survivors [median age: 46 (IQR: 38, 54); median time-since-chemotherapy: 10.9 years (IQR = 7.9, 15.9)], 13.7% reported cognitive dysfunction. Hearing loss (OR = 2.02; P = .040), neuropathic-pain (OR = 2.06; P = .028), fatigue (OR = 6.11; P<.001), and anxiety/depression (OR = 1.96; P = .029) were associated with cognitive impairment in multivariable analyses. Being on disability (OR = 9.57; P = .002) or retired (OR = 3.64; P = .029) were also associated with cognitive declines. Factors associated with impaired cognition identify TC-survivors requiring closer monitoring, counseling, and focused interventions. Hearing loss, neuropathic-pain, fatigue, and anxiety/depression constitute potential targets for prevention or reduction of cognitive impairment in long-term TC-survivors.

No study has quantified the impact of pain and other adverse health outcomes (AHOs) on global physical/mental health in long-term U.S. testicular cancer survivors (TCS) or evaluated patient-reported functional impairment due to pain. TCS given cisplatin-based chemotherapy completed validated surveys, including PROMIS-v1.2 Global-Physical-and-Mental-Health, PROMIS pain questionnaires, and others. Multivariable linear regression examined relationships between 25 AHOs with Global-Physical (GPH) and Mental-Health (GMH) scores, and Pain-Interference Scores. AHOs with β > 2 are clinically important and reported below. Among 358 TCS [median age: 46 (IQR: 38-53); median time-since-chemotherapy: 10.7 years; IQR = 7.2-16.0)], median AHO number was 5 (IQR = 3-7). 12% TCS had ≥10 AHOs, and 19% reported chemotherapy-induced neuropathic pain. Increasing AHO numbers were associated with decreases in physical and mental health (P < 0.0001 each). In multivariable analyses, chemotherapy-induced neuropathic pain (β = -3.72; P = 0.001), diabetes (β = -4.41; P = 0.037), obesity (β = -2.01; P = 0.036) and fatigue (β = -8.58; P < 0.0001) were associated with worse GMH, while being married/living-as-married benefitted GMH (β = 3.63; P = 0.0006). Risk factors for pain-related functional-impairment included lower extremity location (β = 2.15; P = 0.04) and concomitant peripheral artery disease (β = 4.68; P < 0.001). GPH-score reductions were associated with diabetes (β = -3.81; P = 0.012), balance/equilibrium problems (β = -3.82; P = 0.003), cognitive-dysfunction (β = -4.43; P < 0.0001), obesity (β = -3.09; P < 0.0001), peripheral-neuropathy-score (β = -2.12; P < 0.0001), and depression (β = -3.17; P < 0.0001). TCS suffer AHOs that negatively impact long-term GMH, GPH, and pain-related functional-status. Clinically important factors associated with worse physical/mental health identify TCS requiring closer monitoring, counseling, and interventions. Chemotherapy-induced neuropathic pain must be addressed, given its detrimental impact on patient-reported functional-status and mental health 10+ years after treatment.

PURPOSE: Cisplatin is widely used and highly ototoxic, but patient-reported functional impairment because of cisplatin-related hearing loss (HL) and tinnitus has not been comprehensively evaluated. PATIENTS AND METHODS: Testicular cancer survivors (TCS) given first-line cisplatin-based chemotherapy completed validated questionnaires, including the Hearing Handicap Inventory for Adults (HHIA) and Tinnitus Primary Function Questionnaire (TPFQ), each of which quantifies toxicity-specific functional impairment. Spearman correlations evaluated associations between HL and tinnitus severity and level of functional handicap quantified with the HHIA and TPFQ, respectively. Associations between HL or tinnitus and five prespecified adverse health outcomes (cognitive dysfunction, fatigue, depression, anxiety, and overall health) were evaluated. RESULTS: HL and tinnitus affected 137 (56.4%) and 147 (60.5%) of 243 TCS, respectively. Hearing aids were used by 10% TCS (14/137). Of TCS with HL, 35.8% reported clinically significant functional impairment. Severe HHIA-assessed functional impairment was associated with cognitive dysfunction (odds ratio [OR], 10.62; P < .001), fatigue (OR, 5.48; P = .003), and worse overall health (OR, 0.19; P = .012). Significant relationships existed between HL severity and HHIA score, and tinnitus severity and TPFQ score ( P < .0001 each). TCS with either greater hearing difficulty or more severe tinnitus were more likely to report cognitive dysfunction (OR, 5.52; P = .002; and OR, 2.56; P = .05), fatigue (OR, 6.18; P < .001; and OR, 4.04; P < .001), depression (OR, 3.93; P < .01; and OR, 3.83; P < .01), and lower overall health (OR, 0.39; P = .03; and OR, 0.46; P = .02, respectively). CONCLUSION: One in three TCS with HL report clinically significant functional impairment. Follow-up of cisplatin-treated survivors should include routine assessment for HL and tinnitus. Use of the HHIA and TPFQ permit risk stratification and referral to audiologists as needed, since HL adversely affects functional status and is the single largest modifiable risk factor for cognitive decline and dementia in the general population.

97 Background: Clinical pathways increase compliance with treatment guidelines, improve outcomes, and reduce costs. Guidelines recommend single fraction radiation therapy (SFRT) for palliation of uncomplicated bone metastases, but implementation is variable. We examined the effects of a clinical pathway tool on appropriate SFRT rates in an academic radiation oncology practice. Methods: Clinical pathways increase compliance with treatment guidelines, improve outcomes, and reduce costs. Guidelines recommend single fraction radiation therapy (SFRT) for palliation of uncomplicated bone metastases, but implementation is variable. We examined the effects of a clinical pathway tool on appropriate SFRT rates in an academic radiation oncology practice. Results: The final pathway was used in 38% of 723 bone metastases radiation prescription made since March 2016, with appropriate SFRT rates rising from 18% prior to implementation to 48% post-launch in cases where the pathway was used (p < 0.01). There was no increase in the appropriate SFRT rate for cases treated after March 2016 but not entered into the pathway tool as compared to cases prior to pathway tool implementation. Major reasons for rejecting recommendations included disagreement with life expectancy prognostication and patient convenience. The pathway increased physicians’ confidence regarding compliance with treatment guidelines and made it easier to find well-supported treatment recommendations. Workflow disruptions and the inability to handle nuanced situations emerged as limitations. Conclusions: Our experience demonstrates the utility of clinical pathway decision support for bone metastases in complex academic settings. Pathway use significantly increased appropriate care, more than doubling appropriate treatment rates relative to a synchronous group. Next steps include increasing the pathway’s ease of use, refining its prognostic abilities, and measuring related value effects.