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Purpose: Cisplatin is a first-line chemotherapeutic for many cancers, but causes neurotoxicity including hearing loss, tinnitus, and peripheral sensory neuropathy. However, no study has comprehensively characterized risk factors for developing multiple (>1) severe neurotoxicities. Experimental Design: The relationship between multiple severe neurotoxicities and age, cumulative cisplatin dose, medical history, and lifestyle/behavioral factors was evaluated in 300 cisplatin-treated testicular cancer survivors using logistic regression. Case–control genome-wide association study (GWAS; cases, n = 104 and controls, n = 196) was also performed. Results: Age at clinical examination (P = 6.4 × 10−16) and cumulative cisplatin dose (P = 5.4 × 10−4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P = 0.02), tobacco use (ever smoker, P = 0.001 and current smoker, P = 0.002), and hypertension (P = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P = 0.01), Raynaud phenomenon (P = 3.7 × 10−9), and symptoms consistent with peripheral motor neuropathy (P = 4.3 × 10−14) after age and dose adjustment. These patients also reported poorer overall health (P = 2.7 × 10−5) and a greater use of psychotropic medications (P = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 (P = 3.9 × 10−5) and FAM20C (P = 5.5 × 10−5) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines. Conclusions: Certain survivors are more susceptible to cisplatin-induced neurotoxicity, markedly increasing likelihood of developing numerous neuro-otological symptoms that affect quality of life. Genome-wide analysis identified genetic variation in FAM20C as a potentially important risk factor.

Significantly increased risks of cardiovascular disease occur in testicular cancer survivors given cisplatin-based chemotherapy. The postulated mechanism of platinum-based chemotherapy’s vascular toxicity has been thought secondary to its different early- and late- effects on vascular injury, endothelial dysfunction, and induction of a hypercoagulable state. We highlight for the first time the similarities between platinum-associated vascular adverse events and the vascular toxicity associated with other xenobiotic-metal contaminants. The vascular toxicity seen in large epidemiologic studies of testicular cancer survivors may in part be similar and mechanistically linked to the risk seen in environmental heavy metal contaminants linked to cardiovascular disease. Future research should be directed to better understand the magnitude of the adverse cardiovascular effects of platinum and to elucidate the underlying mechanisms of action.

Purpose: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1–35 years after CBC and evaluate genetic contributions to these levels. Experimental Design: Eligible TCS given 300 or 400 (±15) mg/m2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a biexponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model. Results: Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P = 2.13 × 10−3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P = 6.58 × 10−3). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted ORhigh/low = 1.46; P = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low = 1.68, P = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (P = 4.6 × 10−8, a SNP intronic to MYH14). Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.

Background: This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. Patients and Methods: Eligible TCS were Results: Of 491 TCS (median age at assessment, 38.2 years; range, 18.7–68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P= .006) and body mass index of 25 to 2 (OR, 2.08; P= .011) or ≥30 kg/m2 (OR, 2.36; P= .005) compared with 2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P= .09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P= .07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P= .003), to take medications for hypercholesterolemia (20.1% vs 6.0%; PP= .013), and to report erectile dysfunction (19.6% vs 11.9%; P= .018) or peripheral neuropathy (30.7% vs 22.5%; P= .041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P= .07) or anxiety/depression (14.8% vs 9.3%; P= .06) was observed. Conclusions: At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.

Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin-induced ototoxicity, neurotoxicity, and nephrotoxicity. Traditional genome-wide association studies have identified single-nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy, with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression, and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities and currently available means to prevent or treat their occurrence.

10550 Background: Cranial radiation therapy (CRT) for pediatric cancer often results in ototoxicity in the form of hearing loss and tinnitus. We sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with cranial radiation. Methods: Relationships between age at last observation, sex, cumulative CRT dose and self-reported ototoxicity were evaluated for hearing loss and tinnitus among 1,991 (tinnitus) and 2,198 (hearing loss) survivors in the Childhood Cancer Survivor Study who received CRT. Logistic regression evaluated associations with non-genetic risk factors and comorbidities as well as SNP dosages in GWAS of CRT-related tinnitus (cases: 146; controls: 1,845) and hearing loss (cases: 270; controls: 1,928). Results: Males were more likely to report CRT-related tinnitus (9.4% vs. 5.4%; p = 5.81x10−4) and hearing loss (14.0% vs. 10.7%; p = 0.02) than females after adjusting for dose and age at last observation. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: p < 2.00x10−16; hearing loss: p = 6.35x10−9), take antidepressants (tinnitus: p = 0.02; hearing loss: p = 0.01) and report poorer overall health (tinnitus: p = 9.40x10−7; hearing loss: p = 1.30x10−6) compared to survivors without tinnitus or hearing loss after age-adjustment. GWAS of CRT-related tinnitus revealed a prominent signal in chromosome 1 led by rs203248 (p = 1.50x10−9), while GWAS of CRT-related hearing loss identified rs332013 (p = 5.79x10−7) in chromosome 8 and rs67522722 (p = 7.78x10−7) in chromosome 6 as approaching genome-wide significance. Replication analysis in an independent cohort of pediatric cancer survivors (SJLIFE) indicated that rs67522722, intronic to ATXN1, a gene associated with the neurodegenerative disorder spinocerebellar ataxia type 1, was significantly associated with CRT-related hearing loss (p = 0.03). Enrichment analysis and LD score regression with previous GWAS results of cisplatin-related hearing loss and tinnitus in testicular cancer survivors showed no detectable enrichment in genetic architecture with CRT-related hearing loss and tinnitus, respectively. Conclusions: Radiation-associated ototoxicity was associated with sex, several neuro-otological symptoms, increased antidepressant use and poorer self-reported health. GWAS of CRT-related hearing loss identified rs67522722 that was replicated in an independent cohort of pediatric cancer survivors.

Background: This study examined sociodemographic factors, cisplatin-related adverse health outcomes (AHO), and cumulative burden of morbidity (CBMPt) scores associated with medication use for anxiety and/or depression in testicular cancer survivors (TCS). Methods: A total of 1,802 TCS who completed cisplatin-based chemotherapy ≥12 months previously completed questionnaires regarding sociodemographic features and cisplatin-related AHOs [hearing impairment, tinnitus, peripheral sensory neuropathy (PSN), and kidney disease]. A CBMPt score encompassed the number and severity of cisplatin-related AHOs. Multivariable logistic regression models assessed the relationship of individual AHOs and CBMPt with medication use for anxiety and/or depression. Results: A total of 151 TCS (8.4%) used medications for anxiety and/or depression. No cisplatin-related AHOs were reported by 511 (28.4%) participants, whereas 622 (34.5%), 334 (18.5%), 287 (15.9%), and 48 (2.7%), respectively, had very low, low, medium, and high CBMPt scores. In the multivariable model, higher CBMPt scores were significantly associated with medication use for anxiety and/or depression (P < 0.0001). In addition, tinnitus (P = 0.0009), PSN (P = 0.02), and having health insurance (P = 0.05) were significantly associated with greater use of these medications, whereas being employed (P = 0.0005) and vigorous physical activity (P = 0.01) were significantly associated with diminished use. Conclusions: TCS with higher CBMPt scores had a higher probability of using medications for anxiety and/or depression, and conversely, those who were employed and physically active tended to have reduced use of these medications. Impact: Healthcare providers should encourage TCS to increase physical activity to improve both physical and mental health. Rehabilitation programs should assess work-related skills and provide career development counseling/training.

Survivors of adolescent and young adult cancers (AYAs) often live 50 to 60 years beyond their diagnosis. This rapidly growing cohort is at increased risk for cancer- and treatment-related ‘late effects’ that persist for decades into survivorship. Recognition of similar issues in pediatric cancer survivors has prompted the development of evidence-based guidelines for late effects screening and care. However, corresponding evidence-based guidelines for AYAs have not been developed. We hosted an AYA survivorship symposium for a large group of multidisciplinary AYA stakeholders (approximately 200 were in attendance) at Princess Margaret Cancer Centre (Toronto, Ontario, Canada) to begin addressing this disparity. The following overview briefly summarizes and discusses the symposium’s stakeholder-identified high-priority targets for late effects screening and care and highlights knowledge gaps to direct future research in the field of AYA survivorship. This overview, although not exhaustive, is intended to stimulate clinicians to consider these high-priority screening and care targets when seeing survivors in clinical settings and, ultimately, to support the development of evidence-based late effects screening and care guidelines for AYAs.

BackgroundFew data exist on the relationship of cisplatin-related adverse health outcomes (AHOs) with disability, unemployment, and self-reported health (SRH) among testicular cancer survivors (TCS).MethodsA total of 1815 TCS at least 1 year postchemotherapy underwent clinical examination and completed questionnaires. Treatment data were abstracted from medical records. A cumulative burden of morbidity score (CBMPt) encompassed the number and severity of platinum-related AHOs (peripheral sensory neuropathy [PSN], hearing loss, tinnitus, renal disease). Multivariable regression assessed the association of AHOs and CBMPt with employment status and SRH, adjusting for sociodemographic and clinical characteristics. Unemployment was compared with a male normative population of similar age, race, and ethnicity.ResultsAlmost 1 in 10 TCS was out of work (2.4%, disability leave; 6.8%, unemployed) at a median age of 37 years (median follow-up = 4 years). PSN (odds ratio [OR] = 2.89, 95% confidence interval [CI] = 1.01 to 8.26, grade 3 vs 0, P = .048), renal dysfunction defined by estimated glomerular filtration rate (OR = 12.1, 95% CI = 2.06 to 70.8, grade 2 vs 0, P = .01), pain (OR = 10.6, 95% CI = 4.40 to 25.40, grade 2 or 3 vs 0, P ConclusionsOur findings have important implications regarding treatment-associated productivity losses and socioeconomic costs in this young population. Survivorship care strategies should include inquiries about disability and unemployment status, with efforts made to assist affected TCS in returning to the workforce.

Background No large US population-based study focusing on recent decades, to our knowledge, has comprehensively examined risks of second malignant solid and hematological neoplasms (solid-SMN and heme-SMN) after testicular cancer (TC), taking into account initial therapy and histological type. Methods Standardized incidence ratios (SIR) vs the general population and 95% confidence intervals (CI) for solid-SMN and heme-SMN were calculated for 24 900 TC survivors (TCS) reported to the National Cancer Institute’s Surveillance, Epidemiology, and End Results registries (1973–2014). All statistical tests were two-sided. Results The median age at TC diagnosis was 33 years. Initial management comprised chemotherapy (n = 6340), radiotherapy (n = 9058), or surgery alone (n = 8995). During 372 709 person-years of follow-up (mean = 15 years), 1625 TCS developed solid-SMN and 228 (107 lymphomas, 92 leukemias, 29 plasma cell dyscrasias) developed heme-SMN. Solid-SMN risk was increased 1.06-fold (95% CI = 1.01 to 1.12), with elevated risks following radiotherapy (SIR = 1.13, 95% CI = 1.06 to 1.21) and chemotherapy (SIR = 1.36, 95% CI = 1.12 to 1.41) but not surgery alone (SIR = 0.83, 95% CI = 0.75 to 0.92). Corresponding risks for seminoma were 1.13 (95% CI = 1.06 to 1.21), 1.28 (95% CI = 1.02 to 1.58), and 0.87 (95% CI = 0.74 to 1.01) and for nonseminoma were 1.05 (95% CI = 0.67 to 1.56), 1.25 (95% CI = 1.08 to 1.43), and 0.80 (95% CI = 0.70 to 0.92), respectively. Thirty-year cumulative incidences of solid-SMN after radiotherapy, chemotherapy, and surgery alone were 16.9% (95% CI = 15.7% to 18.1%), 10.1% (95% CI = 8.8% to 11.5%), and 8.8% (95% CI = 7.8% to 9.9%), respectively (P Conclusions We report statistically significant excesses of solid-SMN affecting 1 in 6 TCS 30 years after radiotherapy, and 2.7-fold risks of leukemias after chemotherapy, mostly acute myeloid leukemia. Efforts to minimize chemotherapy and radiotherapy exposures for TC should continue. TCS should be counseled about cancer prevention and screening.

Purpose: Invasive cervical cancer (ICC) is one of the HIV-associated cancers with a high burden in Nigeria. ICC occurs at relatively younger age in HIV infected women, with HIV known to promote aging and related diseases, including cancer. DNA methylation changes with increasing age, various health-related exposures, and age-related health outcomes, suggesting a role of DNA methylation in biological aging and disease. We sought to understand the effect of HIV infection on epigenetic age acceleration (EpiAgeAccel) in Nigerian women with ICC. Methods: Epigenetic age (EpiAge) was estimated by Horvath's calculator using genome-wide methylation data in 116 cervical tissue samples from three groups of women: a) HIV positive with ICC (n=39); b) HIV positive and cancer-free (n=53); and c) HIV negative with ICC (n=24). EpiAgeAccel was computed as the regression residuals of EpiAge against chronological age (ChronAge), representing the independent deviation of EpiAge from ChronAge. We compared EpiAgeAccel across the 3 HIV/ICC groups using multiple linear regressions adjusting for ChronAge, education, parity, employment, cancer stage, body mass index, and study site. Among the ICC women, we compared EpiAgeAccel between 26 tumor tissues and their surrounding normal tissues using paired t-tests, stratified by HIV status. Results: EpiAgeAccel among HIV positive women with ICC was 4.5 years higher than HIV positive and cancer-free women (p=0.019). We did not find substantial differences in EpiAgeAccel between HIV-positive women with ICC and HIV-negative women with ICC. EpiAgeAccel was 7.9 and 2.9 years higher in tumor tissues compared to the surrounding normal tissues among HIV positive women (p=0.021) and negative women (p=0.295), respectively. Conclusion: EpiAge is accelerated in cervical tissue of HIV-infected women with ICC. EpiAgeAccel may be a potential biomarker for ICC screening and early detection for women living with HIV in low- and middle-income countries. Citation Format: Jonah Musa, Kyeezu Kim, Yinan Zheng, Yishu Qu, Brian Joyce, Jun Wang, Lois Travis, Demirkan Gursel, Olugbenga Silas, Fatimah Abdulkareem, Godwin Imade, Alani Akanmu, Jian-Jun Wei, Masha Kocherginsky, Kwnag-Youn Kim, Firas Wehbe, Chad Achenbach, Rose Anorlu, Melissa Simon, Atiene Sagay, Folasade Ogunsola, Robert Murphy, Lifang Hou. Accelerated Epigenetic Age among HIV-infected Nigerian Women with Invasive Cervical Cancer [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 71.

We evaluated for the first time, to our knowledge, adverse health outcomes (AHOs) among US testicular cancer survivors (TCS) given chemotherapy (n = 381) vs surgery-only patients (n = 98) managed at a single institution, accounting for non-treatment-related risk factors to delineate chemotherapy’s impact. Chemotherapy consisted largely of bleomycin-etoposide-cisplatin (BEP) administered in three or four cycles (BEPx3, n = 235; BEPx4, n = 82). Incidence of at least 3 AHOs was lowest in surgery-only TCS and increased with BEPx3, BEPx4, and other cisplatin-based regimens (12.2%, 40.8%, 52.5%, 54.8%; P

Testicular cancer (TC) is the most common cancer among men aged 18 to 39 years. It is highly curable, with a 10-year relative survival approaching 95% due to effective cisplatin-based chemotherapy. Given the increasing incidence of TC and improved survival, TC survivors (TCS) now account for approximately 4% of all US male cancer survivors. They have also become a valuable cohort for adult-onset cancer survivorship research, given their prolonged survival. Commensurately, long-term treatment-related complications have emerged as important survivorship issues. These late effects include life-threatening conditions, such as second malignant neoplasms and cardiovascular disease. Moreover, TCS can also experience hearing loss, tinnitus, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, infertility, anxiety, depression, cognitive impairment, and chronic cancer-related fatigue. Characterization of the number and severity of long-term adverse health outcomes among TCS remains critical to develop risk-stratified, evidence-based follow-up guidelines and to inform the development of preventive measures and interventions. In addition, an improved understanding of the long-term effects of TC treatment on mortality due to noncancer causes and second malignant neoplasms remains paramount. Future research should focus on the continued development of large, well-characterized clinical cohorts of TCS for lifelong follow-up. These systematic, comprehensive approaches can provide the needed infrastructure for further investigation of long-term latency patterns of various medical and psychosocial morbidities and for more in-depth studies investigating associated etiopathogenetic pathways. Studies examining premature physiologic aging may also serve as new frontiers in TC survivorship research.

12004 Background: Cisplatin is an essential component of first-line chemotherapy for many cancers, but causes neurotoxicity, including hearing loss (CisHL), tinnitus (CisTinn), and peripheral sensory neuropathy (CisPNeuro). However, few opportunities exist to identify risk factors and comorbidities for cisplatin-induced neurotoxicities among large numbers of homogenously treated patients without the confounding effect of cranial radiotherapy. Methods: Within a well-characterized clinical cohort of 1,680 cisplatin-treated testicular cancer survivors, linear and logistic regression analysis were utilized to analyze associations of CisHL (n = 1,258), CisTinn (n = 1,217), and CisPNeuro (n = 1,653) with non-genetic risk factors. Genome-wide association studies and gene-based analysis were performed on each phenotype. Results: Cisplatin-induced neurotoxicities (CisHL CisTinn, CisPNeuro), adjusting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension (CisTinn: OR = 2.62, p < 0.0001; CisHL: β = 0.25, p = 8.5 x10-4; CisPNeuro: OR = 1.86, p < 0.0001) and were more likely to report their health as poor (CisTinn: OR = 0.54, p < 0.0001; CisHL: β = -0.11, p < 0.0001; CisPNeuro: OR = 0.61, p < 0.0001). Persistent vertigo was significantly associated with both CisTinn (OR = 7.18, p < 0.0001) and CisPNeuro (OR = 4.29, p < 0.0001). In addition, CisTinn was significantly associated with hypercholesterolemia (OR = 1.78, p = 0.01). Importantly, gene-based association analyses identified significant associations between CisTinn and WNT8A (n = 1,037, p = 2.52x10-6) , encoding a signaling protein important in germ cell tumors; and marginal significance between CisHL and TXNRD1 (n = 1,071, p = 4.21x10-6) , thioredoxin reductase-1, which plays a key role in redox regulation. In silico analysis showed high expression levels of TXNRD1 were significantly correlated with cellular resistance to cisplatin in central nervous system tumor cells (Spearman Rho = 0.35, p = 0.04; R2= 0.14, p = 0.03), indicating TXNRD1 is protective for cisplatin-induced cytotoxicity. Previously, rs62283056 in WFS1 found to be significantly associated with CisHL (n = 511; subset of current population), was marginally significant in an independent replication cohort (p = 0.06; n = 606; subset of current population). Conclusions: Cisplatin-induced neurotoxicities are significantly associated with multiple clinical characteristics, including hypertension and self-reported poor health. WNT8A and TXNRD1 are notable risk factors for CisTinn and CisHL, respectively . Future studies should further investigate these genes and their potential impact on chemotherapy strategies. This study, based on the largest number of testicular cancer survivors investigated to date, highlights the clinical importance of these iatrogenic toxicities and their associated risk factors.

12063 Background: Platinum levels are measurable in the serum for decades after cisplatin therapy and higher levels may be related to chemotherapy-induced toxicities. Since cisplatin is cleared exclusively by the kidney, we hypothesized that a genetic predictor of kidney function, an estimated glomerular filtration rate polygenic risk score (eGFR PRS), would significantly associate with serum platinum levels and could improve prediction models. Methods: Within a large well-characterized, multicenter clinical cohort of cisplatin-treated testicular cancer survivors (TCS), we conducted analyses on all patients with genetic data and serum platinum levels. Genotyping was performed on the HumanOmniExpressExome chip and standard QC measures were included. Serum platinum concentrations were quantified by inductively coupled plasma mass spectrometry. For all TCS, time since therapy (TIME) and cumulative cisplatin dose were collected. The eGFR PRS was developed from the Chronic Kidney Disease Genetics (CKDGen) consortium meta-analysis summary statistics using PRS-CS. Using principal component analysis, we restricted the analysis to TCS of genetically determined European ancestry, then calculated the genome-wide PRS for all participants. We performed Cox regression analyses to evaluate prediction models of serum platinum that included cumulative dose and TIME, as well as a model including eGFR PRS. Data are presented as median(interquartile range). Results: 901 patients were included in our analysis with a median diagnosis age of 31 (26 - 38) years, cumulative cisplatin dose of 400 (300-400) mg/m2, and time since first cisplatin dose of 4.6 (2.3-9.5) years. The median serum platinum level for all TCS was 305 (121-981) ng/L. When stratified into quartiles by eGFR PRS, TCS in the lowest quartile had a median serum platinum level of 316 (139-1014) ng/L while TCS in the highest had a median of 268 (106-731) ng/L. Comparison of two Cox regression models for serum platinum prediction, one including only cumulative dose and TIME as predictors and a second including dose, TIME, eGFR PRS, and an eGFR PRS*TIME interaction term, we determined the model including eGFR PRS had a lower AIC (14350 vs 16180) suggesting a more parsimonious model. Further, eGFR PRS was a significant independent predictor of serum platinum levels (p = 0.02) and the impact of eGFR PRS varies over time (eGFR PRS*TIME, p = 0.05). Conclusions: The genetic predictor of kidney function circumvents the use of renal function measures that may have been impaired by initial cisplatin administration. It is a significant independent predictor of serum platinum levels and consistent with expectation: TCS with higher genetically predicted kidney function had lower serum platinum levels. Our results suggest kidney function inferred by genetics may improve the prediction of serum platinum levels.

5025 Background: Cancer survivors are at increased risk of anxiety and depression that can affect health-related quality of life. There is no study to date that has examined the characteristics of testicular cancer survivors (TCS) taking medications for anxiety or depression since pharmacological interventions are typically reserved for more severe cases of these disorders. In this study, we aimed to examine sociodemographic factors, cisplatin-related adverse health outcomes (AHOs), and cumulative burden of morbidity (CBMPt) scores associated with medication use for anxiety and/or depression in TCS. Methods: A total of 1,802 TCS who completed CBCT ≥12 months previously completed validated questionnaires regarding sociodemographic features and cisplatin-related AHOs (hearing impairment, tinnitus, peripheral sensory neuropathy (PSN), kidney disease). Patients were recognized as users of medications for anxiety and/or depression if they used pharmacological classes of these medications and also indicated that the reason for use was for anxiety or depression. Individual AHOs were graded 0-to-4 based on severity according to NCI Common Terminology Criteria for Adverse Events version 4.03. A CBMPt score encompassed the number and severity of cisplatin-related AHOs. Multivariable logistic regression models assessed the relationship of individual AHOs and CBMPt with medication use for anxiety and/or depression. Results: A total of 151 TCS (8.4%) used medications for anxiety and/or depression. Any grade of HL, tinnitus, PSN, and kidney disease were reported by 37.9%, 39.5%, 55.2%, and 2.4% of 1,802 participants, respectively. No cisplatin-related AHO were reported by 511 (28.4%) participants, whereas 622 (34.5%), 334 (18.5%), 287 (15.9%), and 48 (2.7%), respectively, had very low, low, medium, and high CBMPt scores. Higher CBMPt scores were significantly associated with greater medication use for anxiety and/or depression (CBMPt scores of low (OR = 2.96, 95%CI, 1.67-5.24), medium (OR = 3.47, 95%CI, 1.95-6.18), and high (OR = 3.18, 95%CI, 1.22-8.3). A multivariable model including individual AHOs indicated that tinnitus ( P= 0.0009), PSN ( P= 0.02), and having health insurance (OR = 2.15, 95%CI, 1.01-4.56) were associated with significantly greater use of these medications; whereas being employed (OR = 0.39, 95%CI, 0.23-0.66) and vigorous physical activity (OR = 0.63, 95%CI,0.44-0.89) were associated with significantly diminished use. Conclusions: We found that TCS with higher CBMPt scores had a higher probability of using medications for anxiety and/or depression and conversely, those who were employed and physically active tended to have reduced use. These findings deserve further investigation in longitudinal studies. In the interim, healthcare providers should be aware of these associations in formulating survivorship care plans.

5019 Background: Preferential fat accumulation in the visceral compartment (i.e. central adiposity) increases cardiovascular risk in the general population independent of body mass index (BMI). We investigated how body fat distribution modulates the cardiometabolic risk of male germ cell tumor (GCT) survivors after cisplatin-based chemotherapy. Methods: For 456 patients in The Platinum Study enrolled at Memorial Sloan Kettering Cancer Center, visceral (VAT) and subcutaneous (SAT) adipose tissue compartments were quantified on pre-chemotherapy computed tomography (CT) scans (median time between CT and chemotherapy: 13 days, range: 0-56). The VAT/SAT ratio was calculated as a quantitative indicator of central adiposity. Endpoints were (I) post-chemotherapy cardiovascular risk as per the office-based Framingham risk calculator, and (II) incidence of post-chemotherapy cardiometabolic disease defined as need for new anti-hypertensive drugs, or lipid-lowering drugs, or medication used to treat diabetes. Changes in fat distribution after chemotherapy were analyzed in a subgroup with post-chemotherapy CTs (n = 108; median interval from chemotherapy start: 18 months, range: 7-185). Linear regression with interaction terms (endpoint 1, subgroup analysis) and Cox proportional hazard regression (endpoint 2) were applied. Results: For all 456 patients, median age at chemotherapy initiation was 31 years and median follow-up was 27 months (range: 7, 207). At baseline (pre-chemotherapy), the median BMI was 26.2 kg/m2, and 102 patients (22.4%) had a BMI of ≥30 kg/m2. The median VAT/SAT ratio at baseline CT was 0.49, and positively associated with higher post-chemotherapy Framingham risk scores after adjustment for age, BMI, and blood pressure measurements at chemotherapy start, as well as post-therapy follow-up time (adjusted β-estimate: 1.36, 95% CI: 1.15, 1.59, p < 0.001). A higher VAT/SAT ratio also inferred a higher likelihood of new onset cardiometabolic disease in patients with BMI ≥30 kg/m2 (age-adjusted HR: 3.11, 95%CI: 1.01, 9.62, p = 0.048), but not in those with BMI < 30 kg/m2. In the subgroup analysis, we observed a significant increase of BMI after chemotherapy (mean: +1.1 kg/m2, 95% CI: +0.58, +1.54; p < 0.001). Changes in BMI were positively associated with changes of the VAT/SAT ratio (β-estimate: 3.0, 95% CI: 2.23, 4.04; p < 0.001), meaning that weight gain occurred preferentially in the VAT compartment, while weight loss tended to be paralleled by an improved body fat distribution. Conclusions: In male GCT patients, central adiposity at baseline increases cardiometabolic risk after cisplatin-based chemotherapy, particularly for obese individuals. Quantification of an individual’s body fat distribution on pre-chemotherapy CT could potentially help to identify high risk individuals who may benefit from intensified risk-modulating interventions.

5016 Background: Although pure-tone audiometry is the gold standard to evaluate hearing loss (HL), patient-reported outcomes are practically more time and cost effective. However, no data exist on factors associated with discrepancies between patient-reported and audiometrically-defined HL in adult-onset cancer survivors after cisplatin-based chemotherapy (CBCT); and few comprehensive assessments of factors associated with audiometrically-defined HL have been conducted. Methods: A total of 1,410 testicular cancer survivors (TCS) ≥6 months post-CBCT completed comprehensive audiometric assessments (0.25-12 kHz) and detailed questionnaires of sociodemographic, clinical, and health behaviors. Audiometrically-defined HL severity was defined using American Speech-Language-Hearing Association (ASHA) criteria. Multivariable multinomial logistic regression identified factors associated with discrepancies (overestimation and underestimation vs. concordance), between patient-reported and audiometrically-defined HL and multivariable ordinal logistic regression evaluated factors associated with the HL severity. Results: Overall, 34.8% of TCS self-reported HL, while 77.8% had audiometrically-defined HL. Among TCS without tinnitus, those with audiometrically-defined HL at only extended high frequencies (EHFs) (10-12 kHz) (17.8%) or at both EHFs and standard frequencies (0.25-8 kHz) (23.4%) were significantly more likely to self-report HL than those with no audiometrically-defined HL (8.1%) (OR = 2.48; 95%CI, 1.31-4.68 and OR = 3.49; 95%CL,1.89-6.44, respectively). Older age (OR = 1.09; P< 0.0001), absence of prior noise exposure (OR = 1.40; P= 0.02), and mixed/conductive HL (OR = 2.01; P= 0.0007) were associated with greater underestimation of audiometrically-defined HL severity. Hearing aid use (OR = 0.18; P= 0.003) and higher education ( P= 0.004) were associated with less underestimation of audiometrically-defined HL severity, while tinnitus was associated with greater overestimation ( P< 0.0001). Older age (OR = 1.13; P< 0.0001), cumulative cisplatin dose ( > 300 mg/m2, OR = 1.47; P= 0.0001), and hypertension (OR = 1.80; P= 0.0007) were associated with greater ASHA-defined HL severity, whereas post-graduate education (OR = 0.58; P= 0.005) was associated with less severe HL. Conclusions: Discrepancies between patient-reported and audiometrically-defined HL after CBCT are associated with several factors including age, education, tinnitus, prior noise exposure, use of hearing aids, and conductive HL. Understanding these factors will help clinicians to better interpret self-reported HL as a surrogate for audiometric assessments. For survivors who self-report HL, but have normal audiometric findings at standard frequencies, referral to an audiologist for additional testing and inclusion of EHFs in audiometric assessments, should be considered.

e17504 Background: Invasive cervical cancer (ICC) is one of the HIV-associated cancers with a high burden in Nigeria. ICC occurs at relatively younger age in HIV infected women, with HIV known to promote aging and related diseases, including cancer. DNA methylation changes with increasing age, various health-related exposures, and age-related health outcomes, suggesting a role of DNA methylation in biological aging and disease. We sought to understand the effect of HIV infection on epigenetic age acceleration (EpiAgeAccel) in Nigerian women with ICC. Methods: Epigenetic age (EpiAge) was estimated by Horvath’s calculator using genome-wide methylation data in 116 cervical tissue samples from three groups of women: a) HIV positive with ICC (n=39); b) HIV positive and cancer-free (n=53); and c) HIV negative with ICC (n=24). EpiAgeAccel was computed as the regression residuals of EpiAge against chronological age (ChronAge), representing the independent deviation of EpiAge from ChronAge. We compared EpiAgeAccel across the 3 HIV/ICC groups using multiple linear regressions adjusting for ChronAge, education, parity, employment, cancer stage, body mass index, and study site. Among the ICC women, we compared EpiAgeAccel between 26 tumor tissues and their surrounding normal tissues using paired t-tests, stratified by HIV status. Results: EpiAgeAccel among HIV positive women with ICC was 4.5 years higher than HIV positive and cancer-free women (p=0.019). We did not find substantial differences in EpiAgeAccel between HIV-positive women with ICC and HIV-negative women with ICC. EpiAgeAccel was 7.9 and 2.9 years higher in tumor tissues compared to the surrounding normal tissues among HIV positive women (p=0.021) and negative women (p=0.295), respectively. Conclusions: EpiAge is accelerated in cervical tissue of HIV-infected women with ICC. EpiAgeAccel may be a potential biomarker for ICC screening and early detection for women living with HIV in low- and middle-income countries.

Background: Pancreatic cancer risk is elevated among testicular cancer (TC) survivors. However, the roles of specific treatments are unclear. Methods: Among 23 982 5-year TC survivors diagnosed during 1947–1991, doses from radiotherapy to the pancreas were estimated for 80 pancreatic cancer patients and 145 matched controls. Chemotherapy details were recorded. Logistic regression was used to estimate odds ratios (ORs). Results: Cumulative incidence of second primary pancreatic cancer was 1.1% at 30 years after TC diagnosis. Radiotherapy (72 (90%) cases and 115 (80%) controls) was associated with a 2.9-fold (95% confidence interval (CI) 1.0–7.8) increased risk. The OR increased linearly by 0.12 per Gy to the pancreas (P-trend

Purpose: Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. Experimental Design: TCS (n = 762) were dichotomized to cases (moderate/severe tinnitus; n = 154) and controls (none; n = 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. Results: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P = 0.007) and cumulative cisplatin dose (P = 0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared with 300 (P = 0.41), but doses >400 mg/m2 (median 580, range 402–828) increased risk by 2.61-fold (P < 0.0001). CisIT cases had worse hearing at each frequency (0.25–12 kHz, P < 0.0001), and reported more vertigo (OR = 6.47; P < 0.0001) and problems hearing in a crowd (OR = 8.22; P < 0.0001) than controls. Cases reported poorer health (P < 0.0001) and greater psychotropic medication use (OR = 2.4; P = 0.003). GWAS suggested a variant near OTOS (rs7606353, P = 2 × 10−6) and OTOS eQTLs were significantly enriched independently of that SNP (P = 0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q = 0.007). Conclusions: CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.

Purpose In this multicenter study, we evaluated the cumulative burden of morbidity (CBM) among > 1,200 testicular cancer survivors and applied factor analysis to determine the co-occurrence of adverse health outcomes (AHOs). Patients and Methods Participants were ≤ 55 years of age at diagnosis, finished first-line chemotherapy ≥ 1 year previously, completed a comprehensive questionnaire, and underwent physical examination. Treatment data were abstracted from medical records. A CBM score encompassed the number and severity of AHOs, with ordinal logistic regression used to assess associations with exposures. Nonlinear factor analysis and the nonparametric dimensionality evaluation to enumerate contributing traits procedure determined which AHOs co-occurred. Results Among 1,214 participants, approximately 20% had a high (15%) or very high/severe (4.1%) CBM score, whereas approximately 80% scored medium (30%) or low/very low (47%). Increased risks of higher scores were associated with four cycles of either ifosfamide, etoposide, and cisplatin (odds ratio [OR], 1.96; 95% CI, 1.04 to 3.71) or bleomycin, etoposide, and cisplatin (OR, 1.44; 95% CI, 1.04 to 1.98), older attained age (OR, 1.18; 95% CI, 1.10 to 1.26), current disability leave (OR, 3.53; 95% CI, 1.57 to 7.95), less than a college education (OR, 1.44; 95% CI, 1.11 to 1.87), and current or former smoking (OR, 1.28; 95% CI, 1.02 to 1.63). CBM score did not differ after either chemotherapy regimen ( P = .36). Asian race (OR, 0.41; 95% CI, 0.23 to 0.72) and vigorous exercise (OR, 0.68; 95% CI, 0.52 to 0.89) were protective. Variable clustering analyses identified six significant AHO clusters (χ2 P < .001): hearing loss/damage, tinnitus (OR, 16.3); hyperlipidemia, hypertension, diabetes (OR, 9.8); neuropathy, pain, Raynaud phenomenon (OR, 5.5); cardiovascular and related conditions (OR, 5.0); thyroid disease, erectile dysfunction (OR, 4.2); and depression/anxiety, hypogonadism (OR, 2.8). Conclusion Factors associated with higher CBM may identify testicular cancer survivors in need of closer monitoring. If confirmed, identified AHO clusters could guide the development of survivorship care strategies.

Testicular cancer has become the paradigm of adult-onset cancer survivorship, due to the young age at diagnosis and 10-year relative survival of 95%. This clinical review presents the current status of various treatment-related complications experienced by long-term testicular cancer survivors (TCS) free of disease for 5 or more years after primary treatment. Cardiovascular disease and second malignant neoplasms represent the most common potentially life-threatening late effects. Other long-term adverse outcomes include neuro- and ototoxicity, pulmonary complications, nephrotoxicity, hypogonadism, infertility, and avascular necrosis. Future research efforts should focus on delineation of the genetic underpinning of these long-term toxicities to understand their biologic basis and etiopathogenetic pathways, with the goal of developing targeted prevention and intervention strategies to optimize risk-based care and minimize chronic morbidities. In the interim, health care providers should advise TCS to adhere to national guidelines for the management of cardiovascular disease risk factors, as well as to adopt behaviors consistent with a healthy lifestyle, including smoking cessation, a balanced diet, and a moderate to vigorous intensity exercise program. TCS should also follow national guidelines for cancer screening as currently applied to the general population.

Second malignant neoplasms, cardiovascular disease, neurotoxicity and ototoxicity, pulmonary complications, hypogonadism, and nephrotoxicity are potentially life-threatening long-term complications of testicular cancer and its therapy. This article describes the pathogenesis, risks, and management of these late effects experienced by long-term testicular cancer survivors, who are defined as individuals who are disease free 5 years or more after primary treatment. Testicular cancer survivors should follow applicable national guidelines for cancer screening and management of cardiovascular disease risk factors. In addition, health care providers should capitalize on the time of cancer diagnosis as a teachable moment to introduce and promote lifestyle changes.

Radiotherapy is a mainstay of cancer treatment, used in either a curative or palliative manner to treat approximately 50% of patients with cancer. Normal tissue toxicity limits the doses used in standard radiation therapy protocols and impedes improvements in radiotherapy efficacy. Damage to surrounding normal tissues can produce reactions ranging from bothersome symptoms that negatively affect quality of life to severe life-threatening complications. Improved ways of predicting, before treatment, the risk for development of normal tissue toxicity may allow for more personalized treatment and reduce the incidence and severity of late effects. There is increasing recognition that the cause of normal tissue toxicity is multifactorial and includes genetic factors in addition to radiation dose and volume of exposure, underlying comorbidities, age, concomitant chemotherapy or hormonal therapy, and use of other medications. An understanding of the specific genetic risk factors for normal tissue response to radiation has the potential to enhance our ability to predict adverse outcomes at the treatment-planning stage. Therefore, the field of radiogenomics has focused upon the identification of genetic variants associated with normal tissue toxicity resulting from radiotherapy. Innovative analytic methods are being applied to the discovery of risk variants and development of integrative predictive models that build on traditional normal tissue complication probability models by incorporating genetic information. Results from initial studies provide promising evidence that genetic-based risk models could play an important role in the implementation of precision medicine for radiation oncology through enhancing the ability to predict normal tissue reactions and thereby improve cancer treatment.

Testicular cancer survivors are at increased risk of cardiovascular disease after cisplatin-based chemotherapy. Among 787 testicular cancer survivors, the Framingham Risk Score for cardiovascular disease was elevated among less educated and less vigorously active patients, but did not differ by chemotherapy regimen (4 cycles of EP [etoposide and cisplatin] or 3–4 cycles of BEP [bleomycin, etoposide, and cisplatin]). Follow-up and counseling in high-risk subgroups is recommended. BACKGROUND: Testicular cancer survivors (TCSs) are at increased risk of cardiovascular disease (CVD) after cisplatin-based chemotherapy (CBCT). Identifying at-risk survivors would allow early intervention, but risk prediction tools such as the Framingham Risk Score (FRS) have not been applied to TCSs given modern chemotherapy. METHODS: TCSs > 1 year post-CBCT were evaluated. Associations between FRS and clinical, socioeconomic, and lifestyle measures and treatment regimen (4 cycles, etoposide and cisplatin [EP × 4]); 3 or 4 cycles, bleomycin plus EP (BEP × 3, BEP × 4) were analyzed with general linear multivariable models. Controls from the National Health and Nutrition Examination Survey were matched 1:1 to TCSs by age, race, and education with differences in mean FRS evaluated with 2-sided t tests. RESULTS: Of 787 TCSs (median age, 37.3 years; median follow-up, 4.2 years), 284, 342, and 161 received EP × 4, BEP × 3, or BEP × 4, respectively. TCSs had higher median systolic blood pressure (126 vs. 119 mm Hg; P < .001), but fewer were smokers (8.4% vs. 28.2%; P < .001) than controls. In multivariable analysis, no significant differences in FRS between EP × 4, BEP × 3, and BEP × 4 were observed, but less than college education (P < .001) and lack of vigorous exercise (P = .006) were associated with higher FRS. Mean FRS did not differ between TCSs and controls (6.8% vs. 7.3%; P = .67). CONCLUSION: This is the first study to apply the office-based FRS to TCSs. Chemotherapy regimen (BEP × 3 vs. EP × 4) was not associated with FRS, but less educated and less vigorously active patients had higher FRS, and present a high-risk subgroup for intense follow-up and counseling.

Background: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged

Purpose To provide new information on adverse health outcomes (AHOs) in testicular cancer survivors (TCSs) after four cycles of etoposide and cisplatin (EPX4) or three or four cycles of bleomycin, etoposide, cisplatin (BEPX3/BEPX4). Methods Nine hundred fifty-two TCSs > 1 year postchemotherapy underwent physical examination and completed a questionnaire. Multinomial logistic regression estimated AHOs odds ratios (ORs) in relation to age, cumulative cisplatin and/or bleomycin dose, time since chemotherapy, sociodemographic factors, and health behaviors. Results Median age at evaluation was 37 years; median time since chemotherapy was 4.3 years. Chemotherapy consisted largely of BEPX3 (38.2%), EPX4 (30.9%), and BEPX4 (17.9%). None, one to two, three to four, or five or more AHOs were reported by 20.4%, 42.0%, 25.1%, and 12.5% of TCSs, respectively. Median number after EPX4 or BEPX3 was two (range, zero to nine and zero to 11, respectively; P > .05) and two (range, zero to 10) after BEPX4. When comparing individual AHOs for EPX4 versus BEPX3, Raynaud phenomenon (11.6% v 21.4%; P < .01), peripheral neuropathy (29.2% v 21.4%; P = .02), and obesity (25.5% v 33.0%; P = .04) differed. Larger cumulative bleomycin doses (OR, 1.44 per 90,000 IU) were significantly associated with five or more AHOs. Increasing age was a significant risk factor for one to two, three to four, or five or more AHOs versus zero AHOs (OR, 1.22, 1.50, and 1.87 per 5 years, respectively; P < .01); vigorous physical activity was protective (OR, 0.62, 0.51, and 0.41, respectively; P < .05). Significant risk factors for three to four and five or more AHOs included current (OR, 3.05 and 3.73) or former (OR, 1.61 and 1.76) smoking ( P < .05). Self-reported health was excellent/very good in 59.9% of TCSs but decreased as AHOs increased ( P < .001). Conclusion Numbers of AHOs after EPX4 or BEPX3 appear similar, with median follow-up of 4.3 years. A healthy lifestyle was associated with reduced number of AHOs.

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.

Although elevated risks of pancreatic cancer have been observed in long-term survivors of Hodgkin lymphoma (HL), no prior study has assessed the risk of second pancreatic cancer in relation to radiation dose and specific chemotherapeutic agents.We conducted an international case-control study within a cohort of 19 882 HL survivors diagnosed from 1953 to 2003 including 36 cases and 70 matched controls.Median ages at HL and pancreatic cancer diagnoses were 47 and 60.5 years, respectively; median time to pancreatic cancer was 19 years. Pancreatic cancer risk increased with increasing radiation dose to the pancreatic tumor location (Ptrend = 0.005) and increasing number of alkylating agent (AA)-containing cycles of chemotherapy (Ptrend = 0.008). The odds ratio (OR) for patients treated with both subdiaphragmatic radiation (≥10 Gy) and ≥6 AA-containing chemotherapy cycles (13 cases, 6 controls) compared with patients with neither treatment was 17.9 (95% confidence interval 3.5-158). The joint effect of these two treatments was significantly greater than additive (P = 0.041) and nonsignificantly greater than multiplicative (P = 0.29). Especially high risks were observed among patients receiving ≥8400 mg/m(2) of procarbazine with nitrogen mustard or ≥3900 mg/m(2) of cyclophosphamide.Our study demonstrates for the first time that both radiotherapy and chemotherapy substantially increase pancreatic cancer risks among HL survivors treated in the past. These findings extend the range of nonhematologic cancers associated with chemotherapy and add to the evidence that the combination of radiotherapy and chemotherapy can lead to especially large risks.

Advances in Hodgkin lymphoma (HL) treatment have dramatically improved prognosis, with 5-year relative survival now over 80% in the United States (US) and Europe. However, subsequent malignancies, often occurring as late adverse effects of treatment, are a leading cause of morbidity and mortality

IntroductionAnnually, 1.4 million women worldwide are diagnosed with breast cancer (BC) and are at risk for another common malignancy: non–small-cell lung cancer (NSCLC). No large population-based study has examined subsequent survival.MethodsWomen with histologically confirmed NSCLC after BC (BC-NSCLC, n = 3529) were identified in SEER-18 registries (1988–2009). Clinicopathologic characteristics and survival outcomes were compared among women with first primary NSCLC (NSCLC-1, n = 151,628). Cox regression analyses were adjusted for patient, BC, and NSCLC factors.ResultsBC-NSCLC was diagnosed at earlier stages (34% localized, 30% regional, 36% distant) than NSCLC-1 (22%, 28%, and 50%, respectively; p < 0.0001). For localized and regional BC-NSCLC, surgical resection rates were higher than NSCLC-1 (72% versus 69% [p < 0.01] and 56% versus 46% [p < 0.0001]), respectively). Radiotherapy was given less often for BC-NSCLC than NSCLC-1 (localized: 15% versus 18%, p < 0.004; regional: 38% versus 49%, p < 0.0001). Median overall survival (OS) after localized, regional, and distant BC-NSCLC was 5.1 years, 1.9 years, and 5.8 months, respectively. For NSCLC-1, median OS was 4.6 years, 1.5 years, and 4.6 months, respectively. BC history did not affect OS for localized NSCLC, and OS was modestly greater after regional (p = 0.016) and distant (p < 0.0001) BC-NSCLC compared with NSCLC-1. BC radiotherapy to the ipsilateral chest did not unfavorably influence OS.ConclusionsBC survivors are more likely to be diagnosed with earlier stage NSCLC versus first primary NSCLC patients, perhaps reflecting heightened surveillance compared with the general population. In contrast to prior studies of NSCLC in survivors of lymphopoietic malignancies, BC history does not appear to adversely affect OS after NSCLC.

BACKGROUND Despite improved cure rates for bone and soft tissue sarcomas, to the authors' knowledge, no large population-based study to date has evaluated long-term cause-specific mortality in patients diagnosed in the adolescent and young adult (AYA) age range (15 years-39 years). METHODS A total of 28,844 survivors of AYA bone and soft tissue sarcoma, who accrued 113,206 person-years of follow-up, were identified in the population-based Surveillance, Epidemiology, and End Results program. Standardized mortality ratios (SMR) and absolute excess risks (AER) (per 10,000 person-years) were calculated to evaluate associations with histology (chemotherapy-sensitive subtypes: Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma vs all other subtypes), age, and initial therapy. RESULTS All-cause mortality in survivors of AYA sarcoma was found to be significantly increased compared with that of the general population (SMR, 1.76; 95% confidence interval [95% CI], 1.60-1.92 [AER of 19]), and persisted for > 20 years (SMR, 1.39; 95% CI, 1.04-1.82 [AER of 20]). Significant excess mortality was observed for both second malignant neoplasms (SMR, 2.05; 95% CI, 1.71-2.43 [AER of 7]) and noncancer causes (SMR, 1.66; 95% CI, 1.49-1.85 [AER of 19]). Significant excess deaths occurred among patients with chemotherapy-sensitive (SMR, 2.76; 95% CI, 2.20-3.41 [AER of 32]) and nonchemosensitive (SMR, 1.63; 95% CI, 1.47-1.80 [AER of 17]) subtypes. Significantly elevated noncancer mortality in the former group included cardiovascular disease (SMR, 2.33) and infections (SMR, 15.6), whereas significant excess deaths in the latter group included diabetes (SMR, 2.40) and infections (SMR, 2.77). CONCLUSIONS Survivors of AYA bone and soft tissue sarcoma experience significant long-term mortality due to second malignant neoplasms and noncancer causes. Further research is needed to develop preventive and surveillance guidelines in this understudied population to prevent and reduce long-term excess mortality. Cancer 2014;120:2334–2342. © 2014 American Cancer Society.

Platinum-based chemotherapy continues to be linked with the subsequent development of various solid tumours. In a large analytical study of >5,800 survivors of testicular cancer, Groot and colleagues observed statistically significant dose-dependent increases in gastrointestinal cancer incidence after platinum-based chemotherapy, providing evidence for a potential dose-dependent relationship.

Platinum is detectable in the plasma years after completion of cisplatin treatment. Although it has been hypothesized that circulating platinum contributes to the severity and persistence of cisplatin’s adverse effects, results have been inconsistent due to the lack of an effective pharmacokinetic model that takes into account time since therapy and the use of relatively small patient cohorts. Here, we report the largest pharmacokinetic study to date of 1,013 testicular cancer survivors (TCS) assessed 1-35 years after completion of cisplatin-based chemotherapy, and perform a genome-wide association study (GWAS) to assess genetic contributions to our pharmacokinetic phenotype computed from serum platinum levels. Eligible TCS given 300 or 400 (± 15 mg/m2) cisplatin underwent extensive audiometric testing and clinical examination, as well as completed questionnaires at the time of follow-up. We then built an empirical pharmacokinetic model by considering time since treatment and cumulative cisplatin dose received, fitting the data to a power (log-log linear) model as a log-log transformation linearized relationship with time. This power model was used to generate a residual platinum value (RPtV) that likely correlates with the area under concentration-time curve. Using linear regression, we found positive associations between RPtV and several clinically relevant phenotypes including the cumulative burden of morbidity for cisplatin-induced toxicities (β = 0.08, p = 8.42x10-3), peripheral sensory neuropathy (β = 0.14, p = 5.45x10-3), Raynaud’s phenomenon (β = 0.09, p = 0.04), hypercholesterolemia (β = 0.22, p = 0.02), LDL-cholesterol (β = 2.67x10-3, p = 0.01), luteinizing hormone (β = 0.02, p = 0.01), and age at clinical examination (β = 0.02, p = 2.04x10-7). Multinomial regression indicated that these associations are much more prominent in patients designated with high RPtV (> 1 standard deviation above the mean). In addition, we found a strong negative association with creatinine clearance (β = -9.04x10-3, p = 1.03 x10-10). GWAS implicated two SNPs that met genome-wide significance: rs78225733 (p = 6.9 x 10-9) in a gene desert on chromosome 12 and rs45623132 (p = 1.1 x 10-8), which is intronic to meningioma 1 (MN1). Taken together, our novel pharmacokinetic model indicates serum platinum levels are associated with several cisplatin-induced toxicities and comorbidities, and that finding methods by which to reduce circulating platinum once patients have been cured of their disease could be an effective strategy to improve their overall quality of life. Citation Format: Matthew R. Trendowski, Omar El-Charif, Zepeng Mu, Mark J. Ratain, Heather Wheeler, Paul C. Dinh, Darren R. Feldman, Shirin Ardeshir-Rouhani-Fard, Robert J. Hamilton, David J. Vaughn, Chunkit Fung, Taisei Mushiroda, Lawrence H. Einhorn, Lois B. Travis, M. Eileen Dolan. Pharmacokinetic modeling of serum platinum reveals extent of long-term exposure and associated comorbidities after cisplatin treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3904.

e23085 Background: Patients given cisplatin-based chemotherapy (CBC) experience HL and tinnitus. However, the impact of these toxicities on psychosocial and physical functioning in cancer survivors has not been systematically evaluated. Methods: Eligible testicular cancer survivors (TCS) aged ≤ 55 y at diagnosis and given first-line CBC at Indiana U., completed comprehensive questionnaires. The validated 25-item Hearing Handicap Inventory for Adults (HHIA) quantified emotional (13 items) and social difficulties (12 items) related to HL. The validated 20-item Tinnitus Primary Function Questionnaire (TPFQ) assessed domains affected by tinnitus, i.e., concentration, emotion, hearing, sleep (5 items each). For each HHIA scale, TCS were grouped into 3 standard handicap levels: 0–16% (none/minimal), 18-42% (mild/moderate), and 44-100% (significant). Proportions of social vs. emotional handicap were compared with a McNemar’s test. For TPFQ, each scale score is continuous (0: [no interference] to 100% [total interference by tinnitus]) and computed as the mean of 5 items. TPFQ measures were compared by signed-rank tests (P < 0.05 was significant). Results: Of 43 TCS (median age: 35 y, range 20–74 y; median time since chemotherapy completion: 7 y, range 2-27 y), 95% were white, and 70% had at least a college degree. Median cumulative cisplatin dose was 300 (range 200-600 mg/m2). The most commonly administered regimen was bleomycin, etoposide and cisplatin; 23 (53.5%) reported HL, and 25 (58%) had tinnitus. Of TCS with HL, 25% had some degree of related handicap (total HHIA scale: 20% and 5% for mild/moderate and significant handicap, respectively). More TCS had social vs. emotional handicap (33.3% vs. 14.3%, P = 0.13). Tinnitus had significantly greater interference with emotion (median: 14, range 0-84) compared to concentration [(median 6, range 0-41), p = 0.04)], and sleep [(median: 0, range (0-78), p = 0.001)]. Other comparisons were not significant. Conclusions: Cisplatin-related HL has a considerably greater negative impact on social vs. emotional measures, and affected TCS may benefit from hearing aids. TCS experiencing significant issues related to emotion due to tinnitus may benefit from interventions to lessen their impact.

11573 Background: No large, population-based U.S. study has comprehensively examined SMN and HMN risks after TC, taking into account initial therapy and focusing on recent decades. Methods: Standardized incidence ratios (SIR) for SMN and HMN stratified by site and time since TC diagnosis were calculated for 24,900 TCS (median age, TC diagnosis: 33 y) reported to population-based cancer registries in the NCI SEER program (1973-2014). TCS were initially given CHEM (n=6,340), RT (n=9,058), or SURG (n=8,995), with each group accruing 80,700, 156,735, and 128,039 person-years (PY) of follow-up, respectively. Results: During 372,709 PY of follow-up, 1,625 TCS developed SMN and 228 developed HMN, including 107 lymphomas, 92 leukemias, and 29 plasma cell dyscrasias. Among all TCS, overall risk of SMN was increased by 1.06-fold (95% CI 1.01-1.1). Risks of SMN were increased after RT (SIR 1.1, 95% CI 1.06-1.2) and CHEM (SIR 1.3, 95% CI 1.1-1.4); but not after SURG (SIR 0.8). After CHEM, significant excesses of SMN of the pancreas (SIR 2.2), soft tissue (SIR 4.0), kidney (SIR 1.7), thyroid (SIR 3.3) occurred; after RT, significantly elevated risks for SMN of the stomach (SIR 1.7), rectum/sigmoid (SIR 1.4), pancreas (SIR 2.7), soft tissue (SIR 2.2), bladder (SIR 1.5), and thyroid (SIR 2.0) were observed. The 30 year cumulative incidence of SMN after SURG, CHEM, and RT was 8.9% (95% CI 7.8-9.9), 10.1% (95% CI 8.8-11.5) and 17.0% (95% CI 15.8-18.2), respectively. Significantly increased risks of leukemia followed CHEM (SIR 2.7) and SURG (SIR 1.8) and were driven by increased risks for acute myeloid leukemia, with significant excesses restricted to 1-10 y and 1-5 y after TC diagnosis, respectively; nonsignificant 2-fold excesses occurred 1-10 y after RT. Risks for lymphoma and plasma cell dyscrasias were not elevated (1.02 and 1.27, respectively). Conclusions: In the largest population-based study of U.S. TCS to date, we report significant 6% excesses of SMN and 2-fold increased risks of leukemias. Efforts to minimize CHEM exposure and decrease doses/field size of RT in TC should continue. TCS should be educated about cancer prevention and screening.

e16058 Background: We aim to provide new information on cisplatin-related AHOs and employment status in TCS and evaluate impact on SRH. Methods: 1,815 TCS ³1 year post-chemotherapy underwent physical exam, audiometry, renal function evaluation, and completed questionnaires. Therapy data were obtained from medical records. A cumulative burden of morbidity score (CBMPt) assessed the number and severity of platinum-related AHOs (peripheral sensory neuropathy (PSN), hearing loss, tinnitus, and renal function) with grading per CTCAE v4.03. Multivariable regression assessed relations between CBMPt score, individual AHOs and employment status as well as SRH, adjusting for sociodemographic/clinical factors. Unemployment in TCS was compared with subjects in the Behavioral Risk Factor Surveillance System (BRFSS) of similar age/race/ethnicity. Results: Almost 1 in 10 TCS were either on disability leave (2.4%) or unemployed (6.8%) at a median age of 37 yr (median follow-up: 4 yr). TCS with tinnitus (OR = 3.1, grade 3 vs. 0, P = 0.04), renal dysfunction (OR = 13.5, grade 3 vs. 0, P = 0.01), or pain (OR = 7.2 and 40.9, grade 2 or 3 vs. 0, respectively; P < 0.001 each) had significantly greater odds of disability leave vs. full-time employment after adjusting for sociodemographic/clinical factors; pain was strongly correlated with PSN (Pearson r2= 0.40; P < 0.001). CBMPt score was associated with disability leave (OR = 1.5, P = 0.04), but not with unemployment. A significantly higher percentage of TCS were unemployed vs. BRFSS norms (e.g. 3.6% of TCS age 35-39 vs. 2.0% in BRFSS). PSN (OR = 2.2, grade 3 vs. 0, P = 0.02), self-reported hearing loss (OR = 1.8, grade 2/3 vs. 0, P = 0.04), and pain (OR = 2.8 and 8.5, grade 2 or 3 vs. 0, respectively; P < 0.01 each) were each associated with increased odds of unemployment vs. full-time employment. Cisplatin-related AHOs and pain were associated with significantly worse SRH (P < 0.05). Conclusions: Our findings have new, important implications regarding productivity loss and socioeconomic costs in TCS. Survivorship care strategies should include inquiries about employment status, and every effort made to assist affected TCS in returning to the work force.

Purpose To provide dosimetric data for an epidemiologic study on the risk of second primary esophageal cancer among breast cancer survivors, by reconstructing the radiation dose incidentally delivered to the esophagus of 414 women treated with radiation therapy for breast cancer during 1943-1996 in North America and Europe. Methods and Materials We abstracted the radiation therapy treatment parameters from each patient's radiation therapy record. Treatment fields included direct chest wall (37% of patients), medial and lateral tangentials (45%), supraclavicular (SCV, 64%), internal mammary (IM, 44%), SCV and IM together (16%), axillary (52%), and breast/chest wall boosts (7%). The beam types used were 60 Co (45% of fields), orthovoltage (33%), megavoltage photons (11%), and electrons (10%). The population median prescribed dose to the target volume ranged from 21 Gy to 40 Gy. We reconstructed the doses over the length of the esophagus using abstracted patient data, water phantom measurements, and a computational model of the human body. Results Fields that treated the SCV and/or IM lymph nodes were used for 85% of the patients and delivered the highest doses within 3 regions of the esophagus: cervical (population median 38 Gy), upper thoracic (32 Gy), and middle thoracic (25 Gy). Other fields (direct chest wall, tangential, and axillary) contributed substantially lower doses (approximately 2 Gy). The cervical to middle thoracic esophagus received the highest dose because of its close proximity to the SCV and IM fields and less overlying tissue in that part of the chest. The location of the SCV field border relative to the midline was one of the most important determinants of the dose to the esophagus. Conclusions Breast cancer patients in this study received relatively high incidental radiation therapy doses to the esophagus when the SCV and/or IM lymph nodes were treated, whereas direct chest wall, tangentials, and axillary fields contributed lower doses.

Background: The increased risk of gastrointestinal (GI) cancers after Hodgkin's lymphoma (HL) is well established. However, no large population-based study has described the actuarial survival after subsequent GI cancers in HL survivors (HL-GI). Patients and methods: For 209 patients with HL-GI cancers (105 colon, 35 stomach, 30 pancreas, 21 rectum, and 18 esophagus) and 484 165 patients with first primary GI cancers (GI-1), actuarial survival was compared, accounting for age, gender, race, GI cancer stage, radiation for HL, and other variables. Results: Though survival of HL patients who developed localized stage colon cancer was similar to that of the GI-1 group, overall survival (OS) of HL patients with regional or distant stage colon cancer was reduced [hazard ratio, (HR)=1.46, P=0.01]. The HL survivors with regional or distant stage colon cancer in the transverse segment had an especially high risk of mortality (HR: 2.7, P=0.001 for OS). For localized stomach cancer, OS was inferior among HL survivors (HR=3.46, P=0.006). Conclusions: The HL patients who develop GI cancer experience significantly reduced survival compared with patients with a first primary GI cancer. Further research is needed to explain the inferior survival of HL patients and to define selection criteria for cancer screening in HL survivors.

Purpose Cisplatin is widely used but highly ototoxic. Effects of cumulative cisplatin dose on hearing loss have not been comprehensively evaluated in survivors of adult-onset cancer. Patients and Methods Comprehensive audiological measures were conducted on 488 North American male germ cell tumor (GCT) survivors in relation to cumulative cisplatin dose, including audiograms (0.25 to 12 kHz), tests of middle ear function, and tinnitus. American Speech-Language-Hearing Association criteria defined hearing loss severity. The geometric mean of hearing thresholds (0.25 to 12 kHz) summarized overall hearing status consistent with audiometric guidelines. Patients were sorted into quartiles of hearing thresholds of age- and sex-matched controls. Results Increasing cumulative cisplatin dose (median, 400 mg/m2; range, 200 to 800 mg/m2) was significantly related to hearing loss at 4, 6, 8, 10, and 12 kHz (P trends, .021 to < .001): every 100 mg/m2 increase resulted in a 3.2-dB impairment in age-adjusted overall hearing threshold (4 to 12 kHz; P < .001). Cumulative cisplatin doses > 300 mg/m2 were associated with greater American Speech-Language-Hearing Association–defined hearing loss severity (odds ratio, 1.59; P = .0066) and worse normative-matched quartiles (odds ratio, 1.33; P = .093) compared with smaller doses. Almost one in five (18%) patients had severe to profound hearing loss. Tinnitus (40% patients) was significantly correlated with reduced hearing at each frequency (P < .001). Noise-induced damage (10% patients) was unaffected by cisplatin dose (P = .59). Hypertension was significantly related (P = .0066) to overall hearing threshold (4 to 12 kHz) in age- and cisplatin dose–adjusted analyses. Middle ear deficits occurred in 22.3% of patients but, as expected, were not related to cytotoxic drug dosage. Conclusion Follow-up of adult-onset cancer survivors given cisplatin should include routine inquiry for hearing status and tinnitus, referral to audiologists as clinically indicated, and hypertension control. Patients should be urged to avoid noise exposure, ototoxic drugs, and other factors that further damage hearing.

Second malignant neoplasms (SMNs) are a potentially life-threatening late effect of testicular cancer (TC) and its therapy. Although the increased risk for developing solid tumors among TC survivors is largely attributed to radiotherapy, chemotherapy may also be associated with excess risks. However, the baseline risks of developing site-specific SMNs in TC survivors have not yet been quantified, nor have interactions between treatments and other risk factors been elucidated. Studies to date report overall relative risks ranging from 1.4- to 2.8-fold for SMN in TC survivors, with significantly elevated risks apparent for more than 35 years. Analytic investigations show relationships between increasing radiation dose and/or field size and solid tumor risk. Small excess risks of leukemia follow treatment with either chemotherapy or radiotherapy. Recently, concern has been expressed about the increased risk of SMN from radiation exposure during imaging surveillance for recurrence. A small number of studies have examined this issue, generating inconclusive results. Given the current changes in TC treatment that result in lower radiation doses, in the future solid tumors will likely have a considerably lower impact on the lives of TC survivors, although diligent follow-up will be required to accurately quantify long-term risks and to ascertain risks associated with chemotherapy.

Purpose Cisplatin-induced neurotoxicity and ototoxicity (NTX) are important adverse effects after chemotherapy for testicular cancer (TC). Although serum platinum is measurable years after therapy, its impact on NTX has not been evaluated. Patients and Methods In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Serum platinum was quantified by inductively coupled plasma mass spectrometry. Patient-reported outcomes were evaluated with the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), regarding the extent of symptom bother as 0, “not at all”; 1, “a little”; 2, “quite a bit”; or 3, “very much.” Summing the six symptom scores yielded a total SCIN score of 0 to 18. Categorizing total SCIN scores into quartiles yielded similar-sized groups with increasing symptoms. Multivariate ordinal logistic regression analyses evaluated associations between NTX and long-term serum platinum levels, adjusting for cisplatin dose, dosing schedule, and age. Results At Survey I, a significant four- to five-fold association with total SCIN score emerged for the highest serum platinum quartile (odds ratio [OR], 4.69; 95% CI, 1.82 to 12.08). Paresthesias and Raynaud's syndrome (hands and feet) showed significant two- to four-fold increased risks with the highest platinum quartile. At Survey II, total SCIN score remained significantly associated with the highest platinum quartile (OR, 4.28; 95% CI, 1.36 to 13.48). Paresthesias (hands and feet) and tinnitus showed significant three- to four-fold increased risks for the highest platinum quartile. Cumulative cisplatin dose was not associated with total SCIN score or individual SCIN symptoms in multivariate analyses. Conclusion Here we document a significant relationship between increasing levels of residual serum platinum and NTX severity after adjusting for initial cisplatin dose.

BACKGROUND: Radiotherapy with its advantage of organ preservation has been used to treat laryngeal cancer (LC) for several decades. However, the impact of radiation on overall survival (OS) in a large population-based study has not been evaluated to date. METHODS: The authors analyzed all patients who had localized and/or regional glottic and supraglottic cancer in the Surveillance, Epidemiology, and End Results Program by comparing treatment trends and OS for the periods 1988 to 1993, 1994 to 1999, and 2000 to 2006. Kaplan-Meier and logistic regression analyses were conducted to evaluate OS and the influence of patient demographics on treatment received. RESULTS: Among 13,808 patients with LC, radiotherapy use increased over the 3 periods for localized glottic cancer (LGC) (94%, 97%, and 98% during 1988-1993, 1994-1999, and 2000-2006, respectively; P < .001); for regional glottic cancer (RGC) (53%, 66%, and 75%, respectively; P < .001), for localized supraglottic cancer (LSGC) (61%, 83%, and 94%, respectively), and for regional supraglottic cancer (RSGC) (43%, 55%, and 78%, respectively; P < .001). No significant decrease in 5-year OS was observed during the 3 periods (LGC: 73%, 76%, and 78%, respectively; RGC: 57%, 51%, and 56%, respectively; LSGC: 33%, 35%, and 39%, respectively; and RSGC: 36%, 36%, and 43%, respectively). Blacks were significantly less likely to receive radiotherapy than whites (odds ratio: LGC, 0.42; RGC, 0.76; RSGC, 0.68; all P < .05). Those in the lowest tertile of median household income, compared with highest tertile, received radiotherapy less frequently (odds ratio: LGC, 0.42; RGC, 0.57; RSGC, 0.57; all P < .001). CONCLUSIONS: The current results indicated that the increased use of radiation with its advantage of speech preservation had no adverse impact on the survival of patients with LC. Black race and low income status had significant, inverse relations with the receipt of radiotherapy. Cancer 2012;. © 2011 American Cancer Society.

As a result of therapeutic advances, there is a growing population of survivors of both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). A thorough understanding of the late effects of cancer and its treatment, including the risk of developing a second malignancy and non-neoplastic complications, most notably cardiac disease, is essential for the proper long-term follow-up care of these patients. For HL survivors cured in the past 5 decades, a large body of literature describes a range of long-term effects, many of which are related to extent of treatment. These studies form the basis for many of the follow-up recommendations developed for HL survivors. As HL therapy continues to evolve, however, with an emphasis toward treatment reduction, in particular for early-stage disease, it will be important to rigorously observe this new generation of patients long term to document and quantify late effects associated with modern treatments. Although data on late effects after NHL therapy have recently emerged, the formulation of structured follow-up plans for this heterogeneous group of survivors is challenging, given the highly variable natural history, treatments, and overall prognosis. However, the chemotherapy and radiation therapy approaches for some types of NHL are similar to that for HL; thus, some of the follow-up guidelines for patients with HL may also be transferrable to selected survivors of NHL. Additional work focused on treatment-related complications after NHL will facilitate the development of follow-up programs, as well as treatment refinements to minimize late effects in patients with various types of NHL.

Purpose The prognostic significance of age at testicular cancer (TC) diagnosis, socioeconomic status (SES), race, and marital status on TC-specific mortality is not well-characterized. In a cancer that is so curable, it is important to identify any influence that confers an increased risk of TC-specific mortality. Patients and Methods Using multivariate cause-specific Cox regression models that accounted for competing risks, hazard ratios (HRs) were calculated for 10-year TC-specific mortality among 27,948 patients with TC reported to the Surveillance, Epidemiology and End Results program (1978 to 2006). Independent predictors were age at diagnosis, SES, race, marital status, extent of disease (EOD), calendar year of diagnosis, radiotherapy, and retroperitoneal lymph node dissection (RPLND). Results Compared with younger patients, diagnostic age 40+ was associated with increased mortality (seminoma, HR, 2.00, P < .001; nonseminoma, HR, 2.09; P < .001; most evident in metastatic disease, HR, 8.62; P < .001; HR, 6.35; P < .001, respectively). Unmarried men had two-to three-fold excess mortality compared to married men (HR, 2.97; P < .001; HR, 1.54; P < .001, respectively). Among nonseminoma patients, decreasing SES (P trend < .001) and nonwhite race (HR, 2.11; P < .001) increased mortality. Diagnosis after 1987 resulted in reduced mortality compared to earlier calendar years (HR, 0.58; P = .001; HR, 0.74; P = .001, respectively). Lack of RPLND was associated with seven-fold increase in death (P < .001). Conclusion TC-specific mortality is doubled among US patients diagnosed with seminoma or nonseminoma after age 40, even when initial treatment and EOD are taken into account. Among men with nonseminoma, nonwhite race and lower SES also significantly increase TC-specific mortality. Additional research is needed, enabling the development of interventional strategies and preventive approaches, as applicable.