Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy

Abstract

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.

INTRODUCTION

Testicular cancer (TC) is the most common cancer among men age 18 to 39 years, with an age-adjusted 5-year relative survival of 95%.¹ This remarkable success is explained in large part by the introduction of platinum-based chemotherapy in the 1970s.² Today, the majority of patients with metastatic TC receive standard cisplatin-based chemotherapy, on the basis of international guidelines^3-5 related to prognostic groups.⁶ For two decades, this standard chemotherapy has consisted of three cycles of bleomycin, etoposide, and cisplatin (BEPX3) or four cycles of etoposide and cisplatin (EPX4) for good-risk TC or four cycles of BEP (BEPX4) for intermediate- or poor-risk TC.^7,8 Given the curative potential of these commonly used regimens, it has become increasingly important to understand the occurrence of long-term adverse health outcomes (AHOs). As recently pointed out by Oldenburg and Gietema,⁹ better characterization of AHOs may also help guide TC treatment, especially in the controversial area of whether patients with good-risk TC should receive EPX4 or BEPX3. However, no series to date has quantified the type and prevalence of long-term AHOs in large numbers of patients treated with EPX4, BEPX3, or BEPX4. Although several European studies reported toxicities in TC survivors (TCSs),^10-14 many of these investigations included older therapeutic regimens, and no study included more than 10 patients treated with EPX4.

Characterization of long-term AHOs associated with modern curative regimens is also important to develop risk-stratified, evidence-based follow-up recommendations for TCSs, who now comprise > 4% of all cancer survivors.¹⁵ Current follow-up guidelines by national and international organizations^3-5 for the prevention and treatment of long-term toxicities are limited, without broad consensus. The formulation of such guidelines, including the development of interventions to prevent or mitigate long-term effects, requires an assessment of AHOs, along with characterization of potential risk factors.^14,16,17 We aimed to provide new information on the type and prevalence of AHOs in large numbers of TCSs cured with either EP or BEP by initiating the Platinum Study, a large multicenter cohort of US and Canadian TCSs.¹⁷

METHODS

Participants

The Platinum Study was approved by Institutional Review Boards at all participating institutions. Each participant provided written informed consent allowing access to medical records since cancer diagnosis.

Eligibility criteria included: histologic/serological diagnosis of germ cell tumor (GCT), age < 55 years at diagnosis and > 18 years at enrollment, treatment with first-line cisplatin-based chemotherapy for either initial GCT or recurrence after active surveillance, no subsequent salvage chemotherapy, no radiotherapy, no antecedent chemotherapy for another primary cancer, and routine follow-up at the participating site. All participants were disease-free at the time of clinical evaluation and are referred to as TCSs.

Clinical Evaluation

TCSs underwent a brief physical examination and extensive audiometric testing, with the latter results published separately.¹⁸ Body mass index (kg/m²) was defined as normal, overweight, obese, or morbidly obese (< 25, 25 to < 30, 30 to 39, and ≥ 40 kg/m², respectively), with ≥ 30 kg/m² considered an AHO.¹⁹ Waist circumference > 102 cm defined abdominal obesity.²⁰

Patient-Reported Health Outcomes and Lifestyle Behaviors

TCSs completed a questionnaire regarding selected health outcomes that were targeted largely to those associated with cisplatin-based chemotherapy or with a TC diagnosis; in addition, lifestyle behaviors and current prescription medications were queried. Each of the following conditions was considered an AHO (definitions are listed in Appendix Table A1, online only): tinnitus, hearing impairment, peripheral neuropathy, problem with balance/vertigo/dizziness, renal disease, coronary artery disease (CAD), heart failure, cerebrovascular disease, hypertension and on prescription medication, Raynaud phenomenon, hypercholesterolemia and on prescription medication, peripheral vascular disease, thromboembolic disease, diabetes and on prescription medication, and hypogonadism with testosterone replacement. Obesity, use of psychotropic prescription medications, erectile dysfunction, and benign thyroid disease were each counted as an AHO. Chemotherapy-induced peripheral neuropathy was assessed through the European Organization for Research and Treatment of Cancer Chemotherapy-Induced Peripheral Neuropathy 20 scale²³ and the Scale for Chemotherapy-Induced Long-Term Neurotoxicity.²¹ Peripheral neuropathy was diagnosed if participants reported “quite a bit” or “very much” to relevant questions.^21,23 TCS also self-rated health as excellent, very good, good, fair, or poor.

TCSs reported the average time per week engaged in various physical activities during the past year.²⁴ Total kilocalories per week were estimated by summing metabolic equivalent (MET) –hours for each physical activity and multiplying by the participant’s weight (kilograms). Kilocalories per week were calculated for vigorous (≥ 6 METs) and moderate (3 to < 6 METs) physical activities.²⁵

Data Collection From Medical Records

Study staff were trained in person to abstract data according to a standard protocol using forms adapted from prior studies.^26-31 Data included GCT diagnosis, and for each cytotoxic drug: name, dose, date(s) of administration, number of cycles, and cumulative dose. All data were entered into the eClinical system.³²

Comparison Cohort

Matched controls for selected comparisons were chosen from the National Health and Nutrition Examination Survey (NHANES) using two consecutive data sets (2009 to 2012), following methods applied by the St Jude’s Lifetime Cohort.³³ Controls (restricted to men without cancer) were matched 1:1 on race, age (within 5 years), educational level, and fasting status at blood collection.

Statistical Analysis

Data were summarized with medians (ranges) for continuous variables and proportions for categorical variables. To evaluate associations of clinical, demographic, and behavioral risk factors with AHO number, multinomial logistic regression, including all clinically relevant variables known to affect health outcomes, estimated the adjusted (multivariable) odds ratios (ORs), 95% CIs, and P values. For comparisons with NHANES controls, multinomial or binary logistic regression estimated the relative odds of TCSs having one of the following: elevated body mass index; waist circumference ≥ 102 cm; self-reported hypertension; elevated fasting total cholesterol (≥ 240 mg/dL), LDL ≥ 160 mg/dL, or triglyceride concentration ≥ 150 mg/dL; decreased fasting HDL (< 40 mg/dL); smoking status (ever, current); alcohol consumption > 2 d/wk; and self-reported health. Comparisons with lipid values were restricted to participants who fasted for at least 8 hours before venipuncture (N = 131 TCSs, N = 131 controls). All tests were two-tailed (α = 0.05). The Mantel 1df χ² test for trend was used to determine the association between AHO number and self-rating of health. Data were analyzed with SAS statistical software program (SAS Institute Inc, Cary, NC).

RESULTS

Study Subjects

Of 1,024 eligible subjects, 952 (93.0%) consented to participate. Reasons for nonparticipation included lack of interest (n = 27), time commitment (n = 17), travel (n = 14), and miscellaneous concerns (n = 14). Participants and nonparticipants were similar in terms of age at TC diagnosis (P = .52), age at assessment (P = .40), and race (P = .25). Of all patients, 950 were seen in clinic as part of a scheduled follow-up visit and two were seen because of concern regarding recurrence. No patients were seen for treatment-related adverse effects.

Population Characteristics

Chemotherapy consisted largely of BEPX3 (38.2%), EPX4 (30.9%), and BEPX4 (17.9%; Table 1). Median age at clinical evaluation was 37 years (range, 19 to 68 years), and median time since chemotherapy completion was 4.3 years (range, 1.0 to 29.9 years). Most (85.8%) TCSs were white,³⁵ married or cohabitating (61.5%), and had at least a college education (64.0%). Clinical and sociodemographic characteristics were comparable for EPX4 and BEPX3 (P > .05), except for race and educational status (each P < .01).

Table 1.

Clinical and Sociodemographic Characteristics of 952 Survivors of Cisplatin-Treated Germ Cell Tumors by Treatment Regimen

More than 70% of TCSs were overweight (42.4%) or obese (30.9%; Table 2). Only 8.3% of participants currently smoked; 11.4% consumed two or more alcoholic drinks daily, and 69.0% engaged in weekly vigorous-intensity physical activity. Physical examination findings and health behaviors were similar for EPX4 and BEPX3 (P > .05), except for smoking status (P < .01).

Table 2.

Physical Examination Findings and Health Behaviors for 952 Survivors of Cisplatin-Treated Germ-Cell Tumors by Treatment Regimen

AHOs

Overall, 79.6% TCSs reported at least one AHO, and 20.1%, 15.0%, 10.1%, and 12.5% reported two, three, four, or five or more AHOs, respectively (Table 3). Median number of AHOs after EPX4 or BEPX3 was two, with 34.3% and 35.1% of TCSs reporting three or more AHOs, respectively. The type and prevalence of individual AHOs after EPX4 and BEPX3 were similar (P > .05), except 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). Among all TCSs, the most common AHOs were tinnitus (37.1%), self-reported hearing impairment (31.5%), obesity (30.9%), and peripheral neuropathy (27.0%). Both peripheral neuropathy and tinnitus and/or hearing impairment were reported by one in six (16.4%) TCSs. Current prescription medication use for hypertension, hypercholesterolemia, and diabetes was noted by 11.6%, 10.5%, and 3.1% of TCSs, respectively. After BEPX4, the type and prevalence of AHOs were similar to EPX4 and BEPX3, with the exception of erectile dysfunction (20.0%).

Table 3.

Numbers and Types of Self-Reported AHOs Among 952 Cisplatin-Treated Germ Cell Tumor Survivors

Number of AHOs was inversely associated with self-rating of health (Fig 1), with the latter declining as AHO numbers increased (P < .001). Among 194 TCSs with no AHOs, 80.4%, 18.6%, and 1.0% self-reported health as excellent/very good, good, or fair/poor. In contrast, among 119 TCSs with five or more AHOs, the comparable percentages were 26.9%, 56.3%, and 16.8%, respectively.

Fig 1.

Proportion of testicular cancer survivors (TCSs) with excellent, very good, good, fair, and poor self-reported health by number of adverse health outcomes (AHOs). P value for association of number of AHOs with self-reported health was < .01 (Mantel 1df χ² test of trend). Self-reported health was not indicated by one participant with one to two AHOs and one participant with three to four AHOs.

Increasing age at clinical evaluation was associated with significantly increased risks of one to two, three to four, or five or more AHOs, compared with no AHOs (OR, 1.22, 1.50, and 1.87, respectively), whereas vigorous physical activity was associated with significantly decreased AHOs (OR, 0.62, 0.51, and 0.41, respectively; Table 4). Cumulative bleomycin dose was significantly associated with five or more AHOs (OR, 1.44 [95% CI, 1.20 to 1.71] per 90,000 IU), with nonsignificant risks of the same magnitude (OR, 1.40 [95% CI, 0.95 to 2.05] per 100 mg/m²) for cumulative cisplatin dose. When AHOs were limited to those previously linked to cisplatin (peripheral neuropathy, hearing loss, tinnitus), ORs (per 100 mg/m²) for one (n = 288), two (n = 185), and three (n = 84) AHOs compared with no AHOs were 1.14 (95% CI, 0.87 to 1.49; P = .34), 1.48 (95% CI, 1.11 to 1.97; P = .01), and 1.46 (95% CI, 1.002 to 2.13; P = .05), respectively (footnote, Table 4). For Raynaud syndrome, the OR (per 100 mg/m² of cisplatin) was 1.0 (95% CI, 0.77 to 1.29), and for bleomycin, the OR (per 90,000 IU) was 1.31 (95% CI, 1.16 to 1.47).

Table 4.

Multinomial Logistic Regression Analyses of AHOs in 915 Survivors of Cisplatin-Treated Germ Cell Tumors

Statistically significant risk factors for three to four AHOs also included noncollege graduate (OR, 1.88), nonmarried status (OR, 1.85), and current (OR, 3.05) or former smoking (OR, 1.61). These characteristics were also associated with significantly increased risks of five or more AHOs (OR, 2.57, 1.89, 3.73, and 1.76, respectively).

Compared with matched NHANES controls, TCS had significantly higher risks of elevated concentrations of fasting total cholesterol (OR, 4.76) and LDL cholesterol (OR = 2.42) but lower risks of increased fasting HDL cholesterol (OR, 0.38; P = .001; Table 5). TCSs had significantly higher self-reported health and were less likely to be current (OR, 0.22; P < .001) or ever smokers (OR, 0.64; P < .001).

Table 5.

Comparison of Physical Examination Findings, Lipid Profiles, and Health Behaviors in 952 Survivors of Cisplatin-Treated Germ Cell Tumors with a Matched Normative Population

DISCUSSION

The Platinum Study represents the largest cohort to date of TCSs treated with EPX4, BEPX3, and BEPX4 with an assessment of the prevalence and type of AHOs. A new finding includes that more than one third of TCSs at a median age of 37 years reported three or more AHOs, with similar prevalence and type after EPX4 and BEPX3, except for peripheral neuropathy, Raynaud phenomenon, and obesity. Factors consistently associated with increased numbers of AHOs included age at clinical evaluation, current smoking, lower educational attainment, and nonmarried status. Weekly vigorous physical activity was noteworthy for its uniformly inverse association with AHOs. Self-reported health was excellent/very good in 59.9% of TCSs, but decreased as AHOs increased (P < .001). These and other new findings are discussed below.

AHOs: Quantification and Type by Treatment Regimen

Prior studies of BEP included a median of 126 patients (range, 25 to 287), and EPX4 could not be separately evaluated because fewer than 10 patients received the latter regimen.^10,11,37-39 Of four small US-based investigations,^40-43 a limited number of AHOs was addressed in one series (143 patients)⁴¹ but also included treatments with carboplatin-based and other non–cisplatin-based regimens and excluded established cisplatin complications (eg, neuropathy).

Both ototoxicity and cisplatin-induced peripheral neuropathy were reported by one in six TCSs, a combination of symptoms that to our knowledge have not yet been jointly evaluated. This finding is particularly noteworthy, because preliminary genetic analyses among our patients show that peripheral neuropathy–associated genes demonstrate a striking enrichment for significant gene-level associations with ototoxicity (P < 2.2 × 10⁻¹⁶).⁴⁴ Understanding the extent to which various cisplatin-related adverse effects may share underlying genetic architecture provides an inroad into delineating the underlying pathophysiology of symptom constellations and the eventual development of preventive strategies.⁴⁵

The highly significant association between increasing age at clinical evaluation and number of AHOs reflects in part comorbidities acquired with advancing age, apart from cisplatin-related toxicities (Appendix Table A2, online only). Although no independent effect of time since chemotherapy was observed, this likely reflects the relatively short follow-up duration and commensurate weighting of results by acute-onset toxicities. Among survivors of childhood cancer with substantially longer follow-up,⁴⁶ the number of AHOs indeed increases with time. In addition, an important question not only for TCS but also for other patients receiving cisplatin-based chemotherapy with long-term survival is the extent to which the severity of selected acute-onset toxicities, such as hearing loss, may be accelerated during the aging process.¹⁸

The significant association between cumulative cisplatin dose and the number of cisplatin-related AHOs extends existing evidence that cisplatin contributes to the development of peripheral neuropathy^38,39 and ototoxicity,^18,37,38 with dose-dependent relationships noted previously for each individually.^18,37,38 However, for other AHOs, such as hypogonadism, orchiectomy likely partly contributes, although evidence suggests that this outcome may be accentuated in patients administered cisplatin-based chemotherapy.⁴⁷ Raynaud phenomenon is a known toxicity of bleomycin³⁹ and may be associated with cisplatin.³⁸ Although we found no association with cumulative cisplatin dose and Raynaud phenomenon, risk was significantly elevated by 1.3-fold per 90,000-IU increase in bleomycin dose, a finding consistent in part with Glendenning et al,³⁹ who evaluated risk in 180,000-IU increments (OR, 2.9 per 180,000-IU increase; P < .001).

AHOs and Self-Reported Health

The extent to which increasing numbers of AHOs significantly and negatively affect self-reported health is noteworthy and underscores the importance of patient-reported outcomes in survivorship research. Norwegian TCSs had lowered Short Form-36 Physical Component summary scores⁴⁸ and increased risks of anxiety disorders, which were associated with peripheral neuropathy, compared with age-adjusted normative data.⁴⁹ Dahl et al¹⁴ reported that neurotoxic adverse effects, anxiety/depression, and musculoskeletal issues were associated with poor quality of life. Fleer et al⁵⁰ found that chronic disease was also a quality-of-life correlate, although an association with number of conditions was not evaluated.

Cardiovascular Disease

Two European investigations^10,11 evaluated cardiovascular disease incidence and risk factors in at least 300 cisplatin-treated TCSs (Appendix Table A3, online only). Among 390 TCSs treated with BEP (n = 168), carboplatin-based regimens (n = 138), or cisplatin, vinblastine, bleomycin (n = 19), a 6.7% incidence of cardiovascular events was reported (median follow-up, 9.7 years),¹¹ although results were not stratified by treatment. Haugnes et al¹⁰ reported a CAD prevalence of 6.2% among 364 TCSs receiving BEP (n = 160; median follow-up, 19 years). The substantially lower CAD prevalence here likely reflects the shorter follow-up, younger attained age, and differences in underlying risk factors (eg, diet, activity) between US and European populations.⁵¹

Compared with NHANES controls, TCSs were 2.4- to 4.8-fold more likely to demonstrate significantly elevated fasting LDL and total cholesterol. Use of lipid-lowering medications (10.5%) was only slightly lower than in TCSs (14.0%) evaluated by Haugnes et al¹⁰ (median age, 49 years). Although antihypertensive medication use in the Norwegian study was 26.0%,¹⁰ use in our patients (11.6%) is comparable to the British cohort (13.3%; median follow-up age, 41 years).¹¹

AHOs and Health-Related Behaviors and Sociodemographic Factors

To our knowledge, the association of physical activity on the subsequent development of AHOs in TCSs has not been assessed in US^40-42 or European^10-13 studies. Two US studies^42,43 reported that 19% to 25% of TCSs continued to smoke after diagnosis, but associations with AHOs were not evaluated. The low prevalence of smoking here may reflect in part TCS management at large cancer centers, many of which have smoking cessation programs.

TCSs with lower educational levels and those who were unmarried experienced greater numbers of AHOs, associations that to our knowledge have not been previously examined in other US^40-43 and European^10-13 TCS studies. In the Childhood Cancer Survivor Study,⁵² lower educational attainment was significantly associated (OR, 2.0) with at least one adverse health status domain. In contrast, for adult-onset cancer survivors, to our knowledge there are no data addressing the effect of sociodemographic parameters on AHOs, although these characteristics have been evaluated in terms of influence on cancer diagnosis, treatment, and survival. For example, lower socioeconomic level and single status are associated with cancer diagnoses at more advanced stages, receipt of less-aggressive treatment, and increased cancer-specific and all-cause mortality.^53-55

Strengths and Limitations

A major strength of our study is that our estimate of the type and prevalence of AHOs is based on the largest number of TCSs to date treated with EPX4, BEPX3, and BEPX4, with results stratified by regimen. Other strengths include the high participation rate (93%), physical examinations, medical chart abstraction, assessment of AHOs and health behaviors, and estimation of risk without the confounding effect of radiotherapy. Although our investigation included many AHOs, it was largely focused on cisplatin-related toxicities and thus did not include psychosocial/mental health outcomes or pulmonary toxicity. Because bleomycin is avoided in patients at high risk for lung toxicity, we do not expect the low prevalence of clinically significant pulmonary toxicity to materially affect our overall conclusions.⁵⁶ Nonetheless, our results should be considered a minimal estimate of AHO number, without an assessment of severity and with a relatively short median follow-up time. Furthermore, some toxicities may be underestimated; for example, in our prior report,¹⁸ self-reported hearing loss was 31.5% compared with 80% hearing deficits detected by objective audiometric evaluation. As in previous studies of TCSs^14,40,42 and adult survivors of childhood cancer,^57,58 AHOs were largely self-reported, without baseline data before treatment. Any cross-sectional design has potential inherent limitations and does not allow us to infer causation of evaluated risk factors to AHOs and determine the exact prevalence, although prospective data collection is planned. Moreover, our AHO estimates represent the long-term effects of EPX4, BEPX3, and BEPX4 as administered at major cancer centers; thus, our results may not be generalizable to community-based settings.

In conclusion, at a median follow-up of 4.3 years, the prevalence and type of AHOs among TCSs receiving EPX4, BEPX3, or BEPX4 appear largely similar, although a strong influence of increasing age is apparent. Because alterations in the successful TC regimens are unlikely, our results underscore the importance of continued follow-up of TCSs to determine the extent to which AHOs might increase as the cohort matures.⁹ Similarly, ongoing genetic research to broaden our understanding of the biologic basis and causal pathways of cisplatin-associated AHOs^44,45,59 is needed to form the foundation for the development of preventive and interventional strategies. Although increasing numbers of AHOs were associated with a significant decline in self-reported health, more TCSs rated their health as excellent, very good, or good compared with NHANES controls.

In view of our observed associations, health care providers should promote a healthy lifestyle among TCSs, including tobacco cessation, physical activity, and weight control. Future prospective studies should aim to identify high-risk groups who develop life-threatening conditions that can be reduced by follow-up management.

Appendix

Table A1.

Definitions of Adverse Health Outcomes in the Platinum Study

Table A2.

Number of Adverse Health Outcomes in 952 Cisplatin-Treated Germ-Cell Tumor Survivors According to Clinical and Sociodemographic Characteristics and Health Behaviors

Table A3.

Prevalence of CVD Risk Factors in Testicular Cancer Survivors Managed with Chemotherapy or Surgery in Selected Clinical Studies

AUTHOR CONTRIBUTIONS

Conception and design: Howard D. Sesso, Lawrence H. Einhorn, Lois B. Travis

Financial support: Lois B. Travis

Administrative support: Lois B. Travis

Provision of study materials or patients: Chunkit Fung, Darren R. Feldman, Robert J. Hamilton, David J. Vaughn, Clair J. Beard, Christian K. Kollmannsberger, Lawrence H. Einhorn, Lois B. Travis

Collection and assembly of data: Chunkit Fung, Darren R. Feldman, Ryan Cook, Sandra Althouse, Lois B. Travis

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Chunkit Fung

Stock or Other Ownership: GlaxoSmithKline

Consulting or Advisory Role: Janssen Scientific Affairs, Dendreon, Bayer HealthCare Pharmaceuticals, Novartis

Research Funding: Astellas Pharma (Inst)

Howard D. Sesso

No relationship to disclose

Annalynn M. Williams

No relationship to disclose

Sarah L. Kerns

No relationship to disclose

Patrick Monahan

No relationship to disclose

Mohammad Abu Zaid

No relationship to disclose

Darren R. Feldman

Consulting or Advisory Role: Bayer HealthCare Pharmaceuticals, Gilead Sciences (I), Seattle Genetics

Research Funding: Novartis, Seattle Genetics

Robert J. Hamilton

Honoraria: Janssen Pharmaceuticals, AbbVie, Bayer HealthCare Pharmaceuticals, Astellas Pharma

Consulting or Advisory Role: Bayer HealthCare Pharmaceuticals

Research Funding: Janssen Pharmaceuticals

David J. Vaughn

Consulting or Advisory Role: Astellas Pharma

Clair J. Beard

No relationship to disclose

Christian K. Kollmannsberger

Honoraria: Pfizer, Novartis, Bristol-Myers Squibb

Consulting or Advisory Role: Pfizer, Novartis, Seattle Genetics, Bristol-Myers Squibb

Ryan Cook

No relationship to disclose

Sandra Althouse

No relationship to disclose

Shirin Ardeshir-Rouhani-Fard

No relationship to disclose

Steve E. Lipshultz

Leadership: Tenet Healthcare

Consulting or Advisory Role: Clinigen Group, Axio Research

Travel, Accommodations, Expenses: ProCardio European Commission/Hemlholtz Zentrum, IMCO (International Meeting on Cardiology), Regeneron Pharmaceuticals, EuroMeds, British Society for Cardiovascular Research Pharmacology, National Cancer Research Institute

Other Relationship: Elsevier, BioMed Central

Lawrence H. Einhorn

Stock or Other Ownership: Amgen, Biogen Idec

Consulting or Advisory Role: Celgene

Sophie D. Fossa

No relationship to disclose

Lois B. Travis

No relationship to disclose