Effect of Acupuncture vs Sham Acupuncture or Waitlist Control on Joint Pain Related to Aromatase Inhibitors Among Women With Early-Stage Breast Cancer: A Randomized Clinical Trial.

Importance: Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors and often result in therapy discontinuation. Small studies suggest that acupuncture may decrease aromatase inhibitor-related joint symptoms. Objective: To determine the effect of acupuncture in reducing aromatase inhibitor-related joint pain. Design, Setting, and Patients: Randomized clinical trial conducted at 11 academic centers and clinical sites in the United States from March 2012 to February 2017 (final date of follow-up, September 5, 2017). Eligible patients were postmenopausal women with early-stage breast cancer who were taking an aromatase inhibitor and scored at least 3 on the Brief Pain Inventory Worst Pain (BPI-WP) item (score range, 0-10; higher scores indicate greater pain). Interventions: Patients were randomized 2:1:1 to the true acupuncture (n = 110), sham acupuncture (n = 59), or waitlist control (n = 57) group. True acupuncture and sham acupuncture protocols consisted of 12 acupuncture sessions over 6 weeks (2 sessions per week), followed by 1 session per week for 6 weeks. The waitlist control group did not receive any intervention. All participants were offered 10 acupuncture sessions to be used between weeks 24 and 52. Main Outcomes and Measures: The primary end point was the 6-week BPI-WP score. Mean 6-week BPI-WP scores were compared by study group using linear regression, adjusted for baseline pain and stratification factors (clinically meaningful difference specified as 2 points). Results: Among 226 randomized patients (mean [SD] age, 60.7 [8.6] years; 88% white; mean [SD] baseline BPI-WP score, 6.6 [1.5]), 206 (91.1%) completed the trial. From baseline to 6 weeks, the mean observed BPI-WP score decreased by 2.05 points (reduced pain) in the true acupuncture group, by 1.07 points in the sham acupuncture group, and by 0.99 points in the waitlist control group. The adjusted difference for true acupuncture vs sham acupuncture was 0.92 points (95% CI, 0.20-1.65; P = .01) and for true acupuncture vs waitlist control was 0.96 points (95% CI, 0.24-1.67; P = .01). Patients in the true acupuncture group experienced more grade 1 bruising compared with patients in the sham acupuncture group (47% vs 25%; P = .01). Conclusions and Relevance: Among postmenopausal women with early-stage breast cancer and aromatase inhibitor-related arthralgias, true acupuncture compared with sham acupuncture or with waitlist control resulted in a statistically significant reduction in joint pain at 6 weeks, although the observed improvement was of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT01535066.

Dental health status and patient-reported outcomes at baseline in patients participating in the osteonecrosis of the jaw registry study, SWOG S0702.

PURPOSE: SWOG S0702 was a cohort study of patients with cancer with bone metastases due to any cancer. Using baseline data from S0702, this report characterizes the oral health and oral health-related quality of life (OHRQoL) of patients with advanced cancer. METHODS: S0702 case report forms captured dental assessment and patient-reported outcome (PRO) data. This analysis compares PRO dental discomfort with selected clinical assessments of dental health. This analysis focuses on the 2294 patients who underwent baseline dental examination prior to study registration, but also reports on the 1235 patients for whom only OHRQol data are available. Dental characteristics including the number of teeth and the presence of gingivitis and periodontal disease were examined for correlation with PRO of oral pain, interference with eating, smiling, speech, or quality of life. RESULTS: The median age of the study participants was 62. Greater than 60% of the 2294 patients with baseline dental assessments had none to mild plaque, calculus, gingivitis, or periodontal disease, suggesting that most of this cohort had good oral hygiene. However, in each of these same categories, approximately 6% had dental findings classified as severe conditions (poor oral hygiene). There was strong evidence that the presence of periodontal disease, gingivitis, and number of teeth was correlated with lower OHRQoL across multiple domains, including pain (mouth or jaw), interference with eating, smiling and speech, and overall quality of life. CONCLUSIONS: This report characterizes the oral health and OHRQoL of patients with advanced bone metastases receiving palliative therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00874211.

Non-steroidal anti-inflammatory drug (NSAID) use is not associated with erectile dysfunction risk: results from the Prostate Cancer Prevention Trial.

OBJECTIVE: To evaluate the associations of non-steroidal anti-inflammatory drug (NSAID) use with risk of erectile dysfunction (ED), considering the indications for NSAID use. PATIENTS AND METHODS: We analysed data from 4 726 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) without evidence of ED at baseline. Incident ED was defined as mild/moderate (decrease in normal function) or severe (absence of function). Proportional hazards models were used to estimate the covariate-adjusted associations of NSAID-related medical conditions and time-dependent NSAID use with ED risk. RESULTS: Arthritis (hazard ratio [HR] 1.56), chronic musculoskeletal pain (HR 1.35), general musculoskeletal complaints (HR 1.36), headaches (HR 1.44), sciatica (HR 1.50) and atherosclerotic disease (HR 1.60) were all significantly associated with an increased risk of mild/moderate ED, while only general musculoskeletal complaints (HR 1.22), headaches (HR 1.47) and atherosclerotic disease (HR 1.60) were associated with an increased risk of severe ED. Non-aspirin NSAID use was associated with an increased risk of mild/moderate ED (HR 1.16; P = 0.02) and aspirin use was associated with an increased risk of severe ED (HR 1.16; P = 0.03, respectively). The associations of NSAID use with ED risk were attenuated after controlling for indications for NSAID use. CONCLUSIONS: The modest associations of NSAID use with ED risk in the present cohort were probably attributable to confounding indications for NSAID use. NSAID use was not associated with ED risk.

Moving a randomized clinical trial into an observational cohort.

BACKGROUND: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a randomized, double-blind, placebo-controlled prostate cancer prevention study funded by the National Cancer Institute (NCI) and conducted by the Southwest Oncology Group (SWOG). A total of 35,533 men were assigned randomly to one of the four treatment groups (vitamin E + placebo, selenium + placebo, vitamin E + selenium, and placebo + placebo). The independent Data and Safety Monitoring Committee (DSMC) recommended the discontinuation of study supplements because of the lack of efficacy for risk reduction and because futility analyses demonstrated no possibility of benefit of the supplements to the anticipated degree (25% reduction in prostate cancer incidence) with additional follow-up. Study leadership agreed that the randomized trial should be terminated but believed that the cohort should be maintained and followed as the additional follow-up would contribute important information to the understanding of the biologic consequences of the intervention. Since the participants no longer needed to be seen in person to assess acute toxicities or to be given study supplements, it was determined that the most efficient and cost-effective way to follow them was via a central coordinated effort. PURPOSE: A number of changes were necessary at the local Study Sites and SELECT Statistical Center to transition to following participants via a Central Coordinating Center. We describe the transition process from a randomized clinical trial to the observational Centralized Follow-Up (CFU) study. METHODS: The process of transitioning SELECT, implemented at more than 400 Study Sites across the United States, Canada, and Puerto Rico, entailed many critical decisions and actions including updates to online documents such as the SELECT Workbench and Study Manual, a protocol amendment, reorganization of the Statistical Center, creation of a Transition Committee, development of materials for SELECT Study Sites, development of procedures to close Study Sites, and revision of data collection procedures and the process by which to contact participants. RESULTS: At the time of the publication of the primary SELECT results in December 2008, there were 32,569 men alive and currently active in the trial. As of 31 December 2011, 17,761 participants had been registered to the CFU study. This number is less than had been anticipated due to unforeseen difficulties with local Study Site institutional review boards (IRBs). However, from this cohort, we estimate that an additional 580 prostate cancer cases and 215 Gleason 7 or higher grade cancers will be identified. Over 109,000 individual items have been mailed to participants. Active SELECT ancillary studies have continued. The substantial SELECT biorepository is available to researchers; requests to use the specimens are reviewed for feasibility and scientific merit. As of April 2012, 12 proposals had been approved. LIMITATIONS: The accrual goal of the follow-up study was not met, limiting our power to address the study objectives satisfactorily. The CFU study is also dependent on a number of factors including continued funding, continued interest of investigators in the biorepository, and the continued contribution of the participants. Our experience may be less pertinent to investigators who wish to follow participants in a treatment trial or participants in prevention trials in other medical areas. CONCLUSIONS: Extended follow-up of participants in prevention research is important to study the long-term effects of the interventions, such as those used in SELECT. The approach taken by SELECT investigators was to continue to follow participants centrally via an annual questionnaire and with a web-based option. The participants enrolled in the CFU study represent a large, well-characterized, generally healthy cohort. The CFU has enabled us to collect additional prostate and other cancer endpoints and longer follow-up on the almost 18,000 participants enrolled. The utility of the extensive biorepository that was developed during the course of the SELECT is enhanced by longer follow-up.

Assessment of financial screening and navigation capabilities at National Cancer Institute community oncology clinics.

BACKGROUND: Cancer-related financial hardship is a side effect of cancer diagnosis and treatment, and affects both patients and caregivers. Although many oncology clinics have increased financial navigation services, few have resources to proactively provide financial counseling and assistance to families affected by cancer before financial hardship occurs. As part of an ongoing randomized study testing a proactive financial navigation intervention, S1912CD, among sites of the National Cancer Institute Community Oncology Research Program (NCORP), we conducted a baseline survey to learn more about existing financial resources available to patients and caregivers. METHODS: The NCORP sites participating in the S1912CD study completed a required 10-question survey about their available financial resources and an optional 5-question survey that focused on financial screening and navigation workflow and challenges prior to starting recruitment. The proportion of NCORP sites offering financial navigation services was calculated and responses to the optional survey were reviewed to determine current screening and navigation practices and identify any challenges. RESULTS: Most sites (96%) reported offering financial navigation for cancer patients. Sites primarily identified patients needing financial assistance through social work evaluations (78%) or distress screening tools (76%). Sites revealed challenges in addressing financial needs at the outset and through diagnosis, including lack of proactive screening and referral to financial navigation services as well as staffing challenges. CONCLUSIONS: Although most participating NCORP sites offer some form of financial assistance, the survey data enabled identification of gaps and challenges in providing services. Utilizing community partners to deliver comprehensive financial navigation guidance to cancer patients and caregivers may help meet needs while reducing site burden.

Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial.

Importance: A key issue for the adjuvant treatment of patients with melanoma is the assessment of the effect of treatment on relapse, survival, and quality of life (QOL). Objective: To compare QOL in patients with resected melanoma at high risk for relapse who were treated with adjuvant pembrolizumab vs standard of care with either ipilimumab or high-dose interferon α 2b (HDI). Design, Setting, and Participants: The S1404 phase 3 randomized clinical trial was conducted by the SWOG Cancer Research Network at 211 community/academic sites in the US, Canada, and Ireland. Patients were enrolled from December 2015 to October 2017. Data analysis for this QOL substudy was completed in March 2022. Overall, 832 patients were evaluable for the primary QOL end point. Interventions: Patients were randomized (1:1) to treatment with adjuvant pembrolizumab vs standard of care with ipilimumab/HDI. Main Outcomes and Measures: Quality of life was assessed for patients at baseline and cycles 1, 3, 5, 7, and 9 after randomization using the Functional Assessment of Cancer Therapy (FACT) Biological Response Modifiers (FACT-BRM), FACT-General, Functional Assessment of Chronic Illness Therapy-Diarrhea, and European QOL 5-Dimension 3-Level scales. The primary end point was the comparison by arm of cycle 3 FACT-BRM trial outcome index (TOI) scores using linear regression. Linear-mixed models were used to evaluate QOL scores over time. Regression analyses included adjustments for the baseline score, disease stage, and programmed cell death ligand 1 status. A clinically meaningful difference of 5 points was targeted. Results: Among 1303 eligible patients (median [range] age, 56.7 [18.3-86.0] years; 524 women [40.2%]; 779 men [59.8%]; 10 Asian [0.8%], 7 Black [0.5%], 44 Hispanic [3.4%], and 1243 White [95.4%] individuals), 1188 (91.1%) had baseline FACT-BRM TOI scores, and 832 were evaluable at cycle 3 (ipilimumab/HDI = 267 [32.1%]; pembrolizumab = 565 [67.9%]). Evaluable patients were predominantly younger than 65 years (623 [74.9%]) and male (779 [58.9%]). Estimates of FACT-BRM TOI cycle 3 compliance did not differ by arm (ipilimumab/HDI, 96.0% vs pembrolizumab, 98.3%; P = .25). The adjusted cycle 3 FACT-BRM TOI score was 9.6 points (95% CI, 7.9-11.3; P < .001) higher (better QOL) for pembrolizumab compared with ipilimumab/HDI, exceeding the prespecified clinically meaningful difference. In linear-mixed models, differences by arm exceeded 5 points in favor of pembrolizumab through cycle 7. In post hoc analyses, FACT-BRM TOI scores favored the pembrolizumab arm compared with the subset of patients receiving ipilimumab (difference, 6.0 points; 95% CI, 4.1-7.8; P < .001) or HDI (difference, 17.0 points; 95% CI, 14.6-19.4; P < .001). Conclusions and Relevance: This secondary analysis of a phase 3 randomized clinical trial found that adjuvant pembrolizumab improved QOL vs treatment with adjuvant ipilimumab or HDI in patients with high-risk resected melanoma. Trial Registration: ClinicalTrials.gov identifier: NCT02506153.

S1417CD: A Prospective Multicenter Cooperative Group-Led Study of Financial Hardship in Metastatic Colorectal Cancer Patients.

BACKGROUND: Financial toxicity is a growing problem in oncology, but no prior studies have prospectively measured the financial impact of cancer treatment in a diverse national cohort of newly diagnosed cancer patients. S1417CD was the first cooperative group-led multicenter prospective cohort study to evaluate financial hardship in metastatic colorectal cancer (mCRC) patients. METHODS: Patients aged 18 years or older within 120 days of mCRC diagnosis completed quarterly questionnaires for 12 months. We estimated the cumulative incidence of major financial hardship (MFH), defined as 1 or more of increased debt, new loans from family and/or friends, selling or refinancing home, or 20% or more income decline. We evaluated the association between patient characteristics and MFH using multivariate cox regression and the association between MFH and quality of life using linear regression. RESULTS: A total of 380 patients (median age = 59.9 years) were enrolled; 77.7% were White, 98.0% insured, and 56.5% had annual income of $50 000 or less. Cumulative incidence of MFH at 12 months was 71.3% (95% confidence interval = 65.7% to 76.1%). Age, race, marital status, and income (split at $50 000 per year) were not statistically significantly associated with MFH. However, income less than $100 000 and total assets less than $100 000 were both associated with greater MFH. MFH at 3 months was associated with decreased social functioning and quality of life at 6 months. CONCLUSIONS: Nearly 3 out of 4 mCRC patients experienced MFH despite access to health insurance. These findings underscore the need for clinic and policy solutions that protect cancer patients from financial harm.

Comparison of Acupuncture vs Sham Acupuncture or Waiting List Control in the Treatment of Aromatase Inhibitor-Related Joint Pain: A Randomized Clinical Trial.

Importance: Aromatase inhibitors (AIs) have proven efficacy for the treatment of hormone-sensitive breast cancer; however, arthralgias (pain and stiffness) contribute to nonadherence with therapy for more than 50% of patients. Objective: To examine the effect of acupuncture in reducing AI-related joint pain through 52 weeks. Design, Setting, and Participants: A randomized clinical trial was conducted at 11 sites in the US from May 1, 2012, to February 29, 2016, with a scheduled final date of follow-up of September 5, 2017, to compare true acupuncture (TA) with sham acupuncture (SA) or waiting list control (WC). Women with early-stage breast cancer were eligible if they were taking an AI and scored 3 or higher on the Brief Pain Inventory Worst Pain (BPI-WP) item (score range, 0-10; higher scores indicate greater pain). Analysis was conducted for data received through May 3, 2021. Interventions: Participants were randomized 2:1:1 to the TA (n = 110), SA (n = 59), or WC (n = 57) group. The TA and SA protocols were composed of 6 weeks of intervention at 2 sessions per week (12 sessions overall), followed by 6 additional weeks of intervention with 1 session per week. Participants randomized to WC received no intervention. All participants were offered 10 acupuncture sessions to be used between weeks 24 and 52. Main Outcomes and Measures: In this long-term evaluation, the primary end point was the 52-week BPI-WP score, compared by study group using linear regression, adjusted for baseline pain and stratification factors. Results: Among 226 randomized women (mean [SD] age, 60.7 [8.6] years; 87.7% White; mean [SD] baseline BPI-WP score, 6.7 [1.5]), 191 (84.5%) completed the trial. In a linear regression, 52-week mean BPI-WP scores were 1.08 (95% CI, 0.24-1.91) points lower in the TA compared with the SA group (P = .01) and were 0.99 (95% CI, 0.12-1.86) points lower in the TA compared with the WC group (P = .03). In addition, 52-week BPI pain interference scores were statistically significantly lower in the TA compared with the SA group (difference, 0.58; 95% CI, 0.00-1.16; P = .05). Between 24 and 52 weeks, 12 (13.2%) of TA, 6 (11.3%) of SA, and 5 (10.6%) of WC patients reported receipt of acupuncture. Conclusions and Relevance: In this randomized clinical trial, women with AI-related joint pain receiving 12 weeks of TA had reduced pain at 52 weeks compared with controls, suggesting long-term benefits of this therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01535066.

Association Between Health-Related Quality of Life and Progression-Free Survival in Patients With Advanced Cancer: A Secondary Analysis of SWOG Clinical Trials.

PURPOSE: Health-related quality of life (HRQOL) is an established prognostic factor for mortality; however, it is unclear if HRQOL is predictive of time to disease progression, a particularly meaningful outcome for patients. We examined the association between HRQOL and progression-free survival (PFS) in SWOG Cancer Research Network clinical trials. METHODS: For this secondary analysis, we reviewed all completed SWOG clinical trials to identify those for patients with advanced cancer that incorporated Functional Assessment of Cancer Therapy (FACT) questionnaires at baseline. FACT-Trial Outcome Index (FACT-TOI) was the primary independent variable. Associations between FACT-TOI and other FACT subscores with PFS and overall survival were evaluated via log-rank test and multivariable Cox regression analysis. RESULTS: Three clinical trials met our inclusion criteria: S0027 and S9509 for advanced non-small-cell lung cancer and S0421 for hormone-refractory prostate cancer. Of the 1,527 enrolled patients, 1,295 (85%) had both HRQOL and survival outcomes data available and were included in this analysis. In univariable analysis, we observed a statistically significant gradient effect in all three trials, with higher baseline FACT-TOI scores corresponding to better PFS (S0027, P < .001; S9509, P = .02; and S0421, P < .001). In multivariable analysis, FACT-TOI was significantly associated with PFS in S0027 (hazard ratio [HR] = 0.64; 95% CI, 0.42 to 1.00) but not in S9509 (HR = 0.77; 95% CI, 0.56 to 1.05) or S042 (HR = 0.86; 95% CI, 0.73 to 1.01). FACT-TOI was significantly associated with overall survival in multivariable analysis (P < .005 in all three trials). CONCLUSION: The association between baseline FACT-TOI scores and survival underscores their potential as a stratification factor in clinical trials.

Transparency and reproducibility in data analysis: the Prostate Cancer Prevention Trial.

With the analysis of complex, messy data sets, the statistics community has recently focused attention on "reproducible research," namely research that can be readily replicated by others. One standard that has been proposed is the availability of data sets and computer code. However, in some situations, raw data cannot be disseminated for reasons of confidentiality or because the data are so messy as to make dissemination impractical. For one such situation, we propose 2 steps for reproducible research: (i) presentation of a table of data and (ii) presentation of a formula to estimate key quantities from the table of data. We illustrate this strategy in the analysis of data from the Prostate Cancer Prevention Trial, which investigated the effect of the drug finasteride versus placebo on the period prevalence of prostate cancer. With such an important result at stake, a transparent analysis was important.

Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

CONTEXT: The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer. OBJECTIVE: To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS: A total of 35,533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34,887 men who were randomly assigned to 1 of 4 treatment groups: 8752 to receive selenium; 8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011. INTERVENTIONS: Oral selenium (200 µg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years. MAIN OUTCOME MEASURES: Prostate cancer incidence. RESULTS: This report includes 54,464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination. CONCLUSION: Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00006392.

Association of Fatigue and Outcomes in Advanced Cancer: An Analysis of Four SWOG Treatment Trials.

PURPOSE: Patient-reported outcomes may be associated with cancer outcomes. We evaluated clinically significant fatigue (CSF), overall survival, adverse events (AEs), and quality of life (QOL) during cancer treatment. METHODS: We compared outcomes in four phase II or III chemotherapy trials, two advanced non-small-cell lung cancer and two advanced hormone-refractory prostate cancer, with or without baseline CSF. CSF was defined as a rating of two or greater on the Functional Assessment of Cancer Therapy fatigue question or a European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 fatigue symptom score of 50% or greater. Survival was compared according to CSF using Kaplan-Meier estimates and Cox regression models. Differences in AE rates by CSF were assessed via chi-squared tests, and QOL changes from baseline to 3 months via linear regression. RESULTS: Of 1,994 participants, 1,907 (median age 69 years, range: 32-91) had complete baseline QOL survey data, with 52% reporting CSF at baseline. For the two hormone-refractory prostate cancer studies, baseline CSF was associated with higher mortality rates, with adjusted hazard ratios of (95% CI, P value) 1.32 (1.13 to 1.55, P < .001) and 1.31 (1.02 to 1.67, P = .03) and with increased incidence of grade 3-5 constitutional (16.5% v 9.4%, P = .002; 13.9% v 6.3%, P = .002) and neurologic (11.7% v 6.1%, P = .006; 9.0% v 3.9%, P = .01) AEs, respectively. Baseline CSF was associated with a higher mortality rate in one non-small-cell lung cancer study: hazard ratio 1.44 and 1.04 to 2.00, P = .03. CONCLUSION: Oncology trial participants with baseline CSF had poorer survival and experienced more AEs than participants without CSF. This indicates fatigue as an important baseline prognostic factor in oncology treatment trials.

Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer.

IMPORTANCE: Osteonecrosis of the jaw (ONJ) affects patients with cancer and metastatic bone disease (MBD) treated with bone-modifying agents (BMAs), yet the true incidence is unknown. OBJECTIVE: To define the cumulative incidence of ONJ at 3 years in patients receiving zoledronic acid for MBD from any malignant neoplasm. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, prospective observational cohort study (SWOG Cancer Research Network S0702) included patients with MBD with either limited or no prior exposure to BMAs and a clinical care plan that included use of zoledronic acid within 30 days of registration. Medical, dental, and patient-reported outcome forms were submitted at baseline and every 6 months. Follow-up was 3 years. Osteonecrosis of the jaw was defined using established criteria. Data were collected from January 30, 2009, to December 13, 2013, and analyzed from August 24, 2018, to August 6, 2020. INTERVENTIONS/EXPOSURES: Cancer treatments, BMAs, and dental care were administered as clinically indicated. MAIN OUTCOMES AND MEASURES: Cumulative incidence of confirmed ONJ, defined as an area of exposed bone in the maxillofacial region present for more than 8 weeks with no concurrent radiotherapy to the craniofacial region. Risk factors for ONJ were also examined. RESULTS: The SWOG S0702 trial enrolled 3491 evaluable patients (1806 women [51.7%]; median age, 63.1 [range, 2.24-93.9] years), of whom 1120 had breast cancer; 580, myeloma; 702, prostate cancer; 666, lung cancer; and 423, other neoplasm. A baseline dental examination was performed in 2263 patients (64.8%). Overall, 90 patients developed confirmed ONJ, with cumulative incidence of 0.8% (95% CI, 0.5%-1.1%) at year 1, 2.0% (95% CI, 1.5%-2.5%) at year 2, and 2.8% (95% CI, 2.3%-3.5%) at year 3; 3-year cumulative incidence was highest in patients with myeloma (4.3%; 95% CI, 2.8%-6.4%). Patients with planned zoledronic acid dosing intervals of less than 5 weeks were more likely to experience ONJ than patients with planned dosing intervals of 5 weeks or more (hazard ratio [HR], 4.65; 95% CI, 1.46-14.81; P = .009). A higher rate of ONJ was associated with fewer total number of teeth (HR, 0.51; 95% CI, 0.31-0.83; P = .006), the presence of dentures (HR, 1.83; 95% CI, 1.10-3.03; P = .02), and current smoking (HR, 2.12; 95% CI, 1.12-4.02; P = .02). CONCLUSIONS AND RELEVANCE: As the findings show, the cumulative incidence of ONJ after 3 years was 2.8% in patients receiving zoledronic acid for MBD. Cancer type, oral health, and frequency of dosing were associated with the risk of ONJ. These data provide information to guide stratification of risk for developing ONJ in patients with MBD receiving zoledronic acid.

Design, data linkage, and implementation considerations in the first cooperative group led study assessing financial outcomes in cancer patients and their informal caregivers.

BACKGROUND: Few studies have assessed the financial impact of cancer diagnosis on patients and caregivers in diverse clinical settings. S1417CD, led by the SWOG Cancer Research Network, is the first prospective longitudinal cohort study assessing financial outcomes conducted in the NCI Community Oncology Research Program (NCORP). We report our experience navigating design and implementation barriers. METHODS: Patients age ≥ 18 within 120 days of metastatic colorectal cancer diagnosis were considered eligible and invited to identify a caregiver to participate in an optional substudy. Measures include 1) patient and caregiver surveys assessing financial status, caregiver burden, and quality of life and 2) patient credit reports obtained from the credit agency TransUnion through a linkage requiring social security numbers and secure data transfer processes. The primary endpoint is incidence of treatment-related financial hardship, defined as one or more of the following: debt accrual, selling or refinancing home, ≥20% income decline, or borrowing money. Accrual goal was n = 374 patients in 3 years. RESULTS: S1417CD activated on Apr 1, 2016 and closed on Feb 1, 2019 after reaching its accrual goal sooner than anticipated. A total of 380 patients (median age 59.7 years) and 155 caregivers enrolled across 548 clinical sites. Credit data were not obtainable for 76 (20%) patients due to early death, lack of credit, or inability to match records. CONCLUSIONS: Robust accrual to S1417CD demonstrates patients' and caregivers' willingness to improve understanding of financial toxicity despite perceived barriers such as embarrassment and fears that disclosing financial status could influence treatment recommendations.

Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

CONTEXT: Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer. OBJECTIVE: To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer. INTERVENTIONS: Oral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years. MAIN OUTCOME MEASURES: Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer. RESULTS: As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group. CONCLUSION: Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00006392.

Smoking, Sex, and Non-Small Cell Lung Cancer: Steroid Hormone Receptors in Tumor Tissue (S0424).

Background: To what extent steroid hormones contribute to lung cancer in male and female never smokers and smokers is unclear. We examined expression of hormone receptors in lung tumors by sex and smoking. Methods: Patients with primary non-small cell lung cancer were recruited into an Intergroup study in the United States and Canada, led by SWOG (S0424). Tumors from 813 cases (450 women and 363 men) were assayed using immunohistochemistry for estrogen receptor (ER)-α, ER-ß, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Linear regression was used to examine differences in expression by sex and smoking status. Cox proportional hazard models were used to estimate survival associated with the receptors. All statistical tests were two-sided. Results: In ever smokers, postmenopause and oral contraceptive use were associated with lower nuclear ER-ß (P = .02) and total (nuclear + cytoplasmic) PR expression (P = .02), respectively. Women had lower cytoplasmic ER-α (regression coefficient [ß], or differences in H-scores = -15.8, P = .003) and nuclear ER-ß (ß = -12.8, P = .04) expression than men, adjusting for age, race, and smoking. Ever smokers had both higher cytoplasmic ER-α (ß = 45.0, P < .001) and ER-ß (ß = 25.9, P < .001) but lower total PR (ß = -42.1, P < .001) than never smokers. Higher cytoplasmic ER-α and ER-ß were associated with worse survival (hazard ratio = 1.73, 95% confidence interval [CI] = 1.15 to 2.58, and HR = 1.59, 95% CI = 1.08 to 2.33, respectively; quartiles 4 vs 1). Conclusions: Lower expression of nuclear ER-ß in women supports the estrogen hypothesis in lung cancer etiology. Increasing cytoplasmic ER-α and ER-ß and decreasing PR protein expression may be mechanisms whereby smoking disrupts hormone pathways.

Association of Antioxidant Supplement Use and Dementia in the Prevention of Alzheimer's Disease by Vitamin E and Selenium Trial (PREADViSE).

Importance: Oxidative stress is an established dementia pathway, but it is unknown if the use of antioxidant supplements can prevent dementia. Objective: To determine if antioxidant supplements (vitamin E or selenium) used alone or in combination can prevent dementia in asymptomatic older men. Design, Setting, and Participants: The Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADViSE) trial began as a double-blind randomized clinical trial in May 2002, which transformed into a cohort study from September 2009 to May 2015. The PREADViSE trial was ancillary to the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized clinical trial of the same antioxidant supplements for preventing prostate cancer, which closed in 2009 owing to findings from a futility analysis. The PREADViSE trial recruited 7540 men, of whom 3786 continued into the cohort study. Participants were at least 60 years old at study entry and were enrolled at 130 SELECT sites, and Cox proportional hazards models were used in a modified intent-to-treat analysis to compare hazard rates among the study arms. Interventions: Participants were randomized to vitamin E, selenium, vitamin E and selenium, or placebo. While taking study supplements, enrolled men visited their SELECT site and were evaluated for dementia using a 2-stage screen. During the cohort study, men were contacted by telephone and assessed using an enhanced 2-stage cognitive screen. In both phases, men were encouraged to visit their physician if the screen results indicated possible cognitive impairment. Main Outcomes and Measures: Dementia case ascertainment relied on a consensus review of the cognitive screens and medical records for men with suspected dementia who visited their physician for an evaluation or by review of all available information, including a functional assessment screen. Results: The mean (SD) baseline age of the 7540 participants was 67.5 (5.3) years, with 3936 (52.2%) reporting a college education or better, 754 (10.0%) reporting black race, and 505 (6.7%) reporting Hispanic ethnicity. Dementia incidence (325 of 7338 men [4.4%]) was not different among the 4 study arms. A Cox model, which adjusted incidence for participant demographic information and baseline self-reported comorbidities, yielded hazard ratios of 0.88 (95% CI, 0.64-1.20) for vitamin E, 0.83 (0.60-1.13) for selenium, and 1.00 (0.75-1.35) for the combination compared with placebo. Conclusions and Relevance: Neither supplement prevented dementia. To our knowledge, this is the first study to investigate the long-term association of antioxidant supplement use and dementia incidence among asymptomatic men.

Colorectal Adenomas in Participants of the SELECT Randomized Trial of Selenium and Vitamin E for Prostate Cancer Prevention.

Selenium and vitamin E micronutrients have been advocated for the prevention of colorectal cancer. Colorectal adenoma occurrence was used as a surrogate for colorectal cancer in an ancillary study to the Selenium and Vitamin E Cancer Prevention Trial (SELECT) for prostate cancer prevention. The primary objective was to measure the effect of selenium (as selenomethionine) on colorectal adenomas occurrence, with the effect of vitamin E (as α-tocopherol) supplementation on colorectal adenoma occurrence considered as a secondary objective. Participants who underwent lower endoscopy while in SELECT were identified from a subgroup of the 35,533 men randomized in the trial. Adenoma occurrence was ascertained from the endoscopy and pathology reports for these procedures. Relative Risk (RR) estimates and 95% confidence intervals (CI) of adenoma occurrence were generated comparing those randomized to selenium versus placebo and to vitamin E versus placebo based on the full factorial design. Evaluable endoscopy information was obtained for 6,546 participants, of whom 2,286 had 1+ adenomas. Apart from 21 flexible sigmoidoscopies, all the procedures yielding adenomas were colonoscopies. Adenomas occurred in 34.2% and 35.7%, respectively, of participants whose intervention included or did not include selenium. Compared with placebo, the RR for adenoma occurrence in participants randomized to selenium was 0.96 (95% CI, 0.90-1.02; P = 0.194). Vitamin E did not affect adenoma occurrence compared with placebo (RR = 1.03; 95% CI, 0.96-1.10; P = 0.38). Neither selenium nor vitamin E supplementation can be recommended for colorectal adenoma prevention. Cancer Prev Res; 10(1); 45-54. ©2016 AACR.