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.

Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or without prior-bevacizumab treatment.

OBJECTIVE: To examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa). METHODS: This phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naïve and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI). RESULTS: Between March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2-9) and 6 (5-9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0-6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031). CONCLUSIONS: The bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.

Randomized Double-Blind Placebo-Controlled Biomarker Modulation Study of Vitamin D Supplementation in Premenopausal Women at High Risk for Breast Cancer (SWOG S0812).

Observational studies have reported an inverse association between vitamin D intake and breast cancer risk. We examined whether vitamin D supplementation in high-risk premenopausal women reduces mammographic density (MD), an established breast cancer risk factor. We conducted a multicenter randomized double-blind placebo-controlled trial in premenopausal women at high risk for breast cancer [5-year risk ≥ 1.67%, lifetime risk ≥ 20%, lobular carcinoma in situ, prior stage 0-II breast cancer, hereditary breast cancer syndrome, or high MD (heterogeneously/extremely dense)], with a baseline serum 25-hydroxyvitamin D [25(OH)D] ≤ 32 ng/mL. Participants were randomized to 12 months of vitamin D3 20,000 IU/week or matching placebo. The primary endpoint was change in MD from baseline to 12 months using the Cumulus technique. Secondary endpoints included serial blood biomarkers [25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)D), insulin-like growth factor (IGF)-1, IGF-binding protein-3] and MD change at 24 months. Among 208 women randomized, median age was 44.6 years, 84% were white, 33% had baseline 25(OH)D < 20 ng/mL, and 78% had high baseline MD. Comparing the active and placebo groups at 12 months, MD changes were small and did not significantly differ. Mean MD changes at 12 and 24 months were -0.3% and -1.2%, respectively, in the active arm and +1.5% and +1.6% with placebo (P > 0.05). We observed a mean change in serum 25(OH)D of +18.9 versus +2.8 ng/mL (P < 0.01) and IGF-1 of -9.8 versus -1.8 ng/mL (P = 0.28), respectively. At 12 months, MD was positively correlated with serum IGF-1 and IGF-1/IGFBP-3 (P < 0.01). This trial does not support the use of vitamin D supplementation for breast cancer risk reduction.

Omega-3 fatty acid use for obese breast cancer patients with aromatase inhibitor-related arthralgia (SWOG S0927).

PURPOSE: Although aromatase inhibitors (AIs) prolong survival in post-menopausal breast cancer (BC) patients, AI-associated arthralgia can lead to discontinuation. Obese patients have higher rates of AI arthralgia than non-obese patients, but treatment options are limited. Omega-3 fatty acid (O3-FA) treatment for AI arthralgia has produced mixed results. METHODS: We performed an exploratory analysis of SWOG S0927, a multicenter randomized placebo-controlled trial of O3-FA use for AI arthralgia. Post-menopausal women with stage I-III BC taking an AI were randomized to 24 weeks of O3-FAs or placebo. Brief Pain Inventory (BPI) questionnaires and fasting serum were collected at baseline, 12, and 24 weeks. The BPI assessment included worst pain, average pain, and pain interference scores (range 0-10). RESULTS: Among the 249 participants, 139 had BMI < 30 kg/m2 (56%) and 110 had BMI ≥ 30 kg/m2 (44%). Among obese patients, O3-FA use was associated with significantly lower BPI worst pain scores at 24 weeks compared with placebo (4.36 vs. 5.70, p = 0.02), whereas among non-obese patients, there was no significant difference in scores between treatment arms (5.27 vs. 4.58, p = 0.28; interaction p = 0.05). Similarly, O3-FA use was associated with lower BPI average pain and pain interference scores at 24 weeks compared with placebo among obese patients, but no significant difference between treatment arms in non-obese patients (interaction p = 0.005 and p = 0.01, respectively). CONCLUSIONS: In obese BC patients, O3-FA use was associated with significantly reduced AI arthralgia compared to placebo.

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.

Two-Year Trends of Taxane-Induced Neuropathy in Women Enrolled in a Randomized Trial of Acetyl-L-Carnitine (SWOG S0715).

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling side effect of taxanes. Acetyl-L-carnitine (ALC) was unexpectedly found to increase CIPN in a randomized trial. We investigated the long-term patterns of CIPN among patients in this trial. Methods: S0715 was a randomized, double-blind, multicenter trial comparing ALC (1000 mg three times a day) with placebo for 24 weeks in women undergoing adjuvant taxane-based chemotherapy for breast cancer. CIPN was measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale at weeks 12, 24, 36, 52, and 104. We examined NTX scores over two years using linear mixed models for longitudinal data. Individual time points were examined using linear regression. Regression analyses included stratification factors and the baseline score as covariates. All statistical tests were two-sided. Results: Four-hundred nine subjects were eligible for evaluation. Patients receiving ALC had a statistically significantly (P = .01) greater reduction in NTX scores (worse CIPN) of -1.39 points (95% confidence interval [CI] = -2.48 to -0.30) than the placebo group. These differences were particularly evident at weeks 24 (-1.68, 95% CI = -3.02 to -0.33), 36 (-1.37, 95% CI = -2.69 to -0.04), and 52 (-1.83, 95% CI = -3.35 to -0.32). At 104 weeks, 39.5% on the ALC arm and 34.4% on the placebo arm reported a five-point (10%) decrease from baseline. For both treatment groups, 104-week NTX scores were statistically significantly different compared with baseline (P < .001). Conclusions: For both groups, NTX scores were reduced from baseline and remained persistently low. Twenty-four weeks of ALC therapy resulted in statistically significantly worse CIPN over two years. Understanding the mechanism of this persistent effect may inform prevention and treatment strategies. Until then, the potential efficacy and harms of commonly used supplements should be rigorously studied.

Feasibility of Patient Reporting of Symptomatic Adverse Events via the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in a Chemoradiotherapy Cooperative Group Multicenter Clinical Trial.

PURPOSE: To assess the feasibility of measuring symptomatic adverse events (AEs) in a multicenter clinical trial using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). METHODS AND MATERIALS: Patients enrolled in NRG Oncology's RTOG 1012 (Prophylactic Manuka Honey for Reduction of Chemoradiation Induced Esophagitis-Related Pain during Treatment of Lung Cancer) were asked to self-report 53 PRO-CTCAE items representing 30 symptomatic AEs at 6 time points (baseline; weekly ×4 during treatment; 12 weeks after treatment). Reporting was conducted via wireless tablet computers in clinic waiting areas. Compliance was defined as the proportion of visits when an expected PRO-CTCAE assessment was completed. RESULTS: Among 226 study sites participating in RTOG 1012, 100% completed 35-minute PRO-CTCAE training for clinical research associates (CRAs); 80 sites enrolled patients, of which 34 (43%) required tablet computers to be provided. All 152 patients in RTOG 1012 agreed to self-report using the PRO-CTCAE (median age 66 years; 47% female; 84% white). Median time for CRAs to learn the system was 60 minutes (range, 30-240 minutes), and median time for CRAs to teach a patient to self-report was 10 minutes (range, 2-60 minutes). Compliance was high, particularly during active treatment, when patients self-reported at 86% of expected time points, although compliance was lower after treatment (72%). Common reasons for noncompliance were institutional errors, such as forgetting to provide computers to participants; patients missing clinic visits; Internet connectivity; and patients feeling "too sick." CONCLUSIONS: Most patients enrolled in a multicenter chemoradiotherapy trial were willing and able to self-report symptomatic AEs at visits using tablet computers. Minimal effort was required by local site staff to support this system. The observed causes of missing data may be obviated by allowing patients to self-report electronically between visits, and by using central compliance monitoring. These approaches are being incorporated into ongoing studies.

Opportunities and challenges in incorporating ancillary studies into a cancer prevention randomized clinical trial.

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 and conducted by SWOG (Southwest Oncology Group). A total of 35,533 men were assigned randomly to one of four treatment groups (vitamin E + placebo, selenium + placebo, vitamin E + selenium, placebo + placebo). At the time of the trial's development, NIH had invested substantial resources in evaluating the potential benefits of these antioxidants. To capitalize on the knowledge gained from following a large cohort of healthy, aging males on the effects of selenium and/or vitamin E, ancillary studies with other disease endpoints were solicited. METHODS: Four ancillary studies were added. Each drew from the same population but had independent objectives and an endpoint other than prostate cancer. These studies fell into two categories: those prospectively enrolling and following participants (studies of Alzheimer's disease and respiratory function) and those requiring a retrospective medical record review after a reported event (cataracts/age-related macular degeneration and colorectal screening). An examination of the challenges and opportunities of adding ancillary studies is provided. The impact of the ancillary studies on adherence to SELECT was evaluated using a Cox proportional hazards model. RESULTS: While the addition of ancillary studies appears to have improved participant adherence to the primary trial, this did not come without added complexity. Activation of the ancillary studies happened after the SELECT randomizations had begun resulting in accrual problems to some of the studies. Study site participation in the ancillary trials varied greatly and depended on the interest of the study site principal investigator. Procedures for each were integrated into the primary trial and all monitoring was done by the SELECT Data and Safety Monitoring Committee. The impact of the early closure of the primary trial was different for each of the ancillary trials. CONCLUSIONS: The ancillary studies allowed study sites to broaden the research opportunities for their participants. Their implementation was efficient because of the established infrastructure of the primary trial. Implementation of these ancillary trials took substantial planning and coordination but enriched the overall primary trial. TRIAL REGISTRATION: NCT00006392-S0000 : Selenium and Vitamin E in Preventing Prostate Cancer (SELECT) (4 October 2000). NCT00780689-S0000A :  Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADVISE) (25 June 2002). NCT00784225-S0000B : Vitamin E and/or Selenium in Preventing Cataract and Age-Related Macular Degeneration in Men on SELECT SWOG-S0000 (SEE) (31 October 2008). NCT00706121-S0000D : Effect of Vitamin E and/or Selenium on Colorectal Polyps in Men Enrolled on SELECT Trial SWOG-S0000 (ACP) (26 June 2008). NCT00063453-S0000C : Vitamin E and/or Selenium in Preventing Loss of Lung Function in Older Men Enrolled on SELECT Clinical Trial SWOG-S0000 (26 June 2003).

Effect of long-term vitamin E and selenium supplementation on urine F2-isoprostanes, a biomarker of oxidative stress.

BACKGROUND: Cigarette smoking generates reactive oxidant species and contributes to systemic oxidative stress, which plays a role in the pathophysiology of chronic diseases. Nutrients with antioxidant properties, including vitamin E and selenium, are proposed to reduce systemic oxidative burden and thus to mitigate the negative health effects of reactive oxidant species. OBJECTIVE: Our objective was to determine whether long-term supplementation with vitamin E and/or selenium reduces oxidative stress in smokers, as measured by urine 8-iso-prostaglandin F2-alpha (8-iso-PGF2α). DESIGN: We measured urine 8-iso-PGF2α with competitive enzyme linked immunoassay (ELISA) in 312 male current smokers after 36 months of intervention in a randomized placebo-controlled trial of vitamin E (400IU/d all rac-α-tocopheryl acetate) and/or selenium (200µg/d L-selenomethionine). We used linear regression to estimate the effect of intervention on urine 8-iso-PGF2α, with adjustments for age and race. RESULTS: Compared to placebo, vitamin E alone lowered urine 8-iso-PGF2α by 21% (p=0.02); there was no effect of combined vitamin E and selenium (intervention arm lower by 9%; p=0.37) or selenium alone (intervention arm higher by 8%; p=0.52). CONCLUSIONS: Long-term vitamin E supplementation decreases urine 8-iso-PGF2α among male cigarette smokers, but we observed little to no evidence for an effect of selenium supplementation, alone or combined with vitamin E.

Randomized Multicenter Placebo-Controlled Trial of Omega-3 Fatty Acids for the Control of Aromatase Inhibitor-Induced Musculoskeletal Pain: SWOG S0927.

PURPOSE: Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors (AIs) and can result in decreased quality of life and discontinuation of therapy. Omega-3 fatty acids (O3-FAs) can be effective in decreasing arthralgia resulting from rheumatologic conditions and reducing serum triglycerides. PATIENTS AND METHODS: Women with early-stage breast cancer receiving an AI who had a worst joint pain/stiffness score ≥ 5 of 10 using the Brief Pain Inventory-Short Form (BPI-SF) were randomly assigned to receive either O3-FAs 3.3 g or placebo (soybean/corn oil) daily for 24 weeks. Clinically significant change was defined as ≥ 2-point drop from baseline. Patients also completed quality-of-life (Functional Assessment of Cancer Therapy-Endocrine Symptoms) and additional pain/stiffness assessments at baseline and weeks 6, 12, and 24. Serial fasting blood was collected for lipid analysis. RESULTS: Among 262 patients registered, 249 were evaluable, with 122 women in the O3-FA arm and 127 in the placebo arm. Compared with baseline, the mean observed BPI-SF score decreased by 1.74 points at 12 weeks and 2.22 points at 24 weeks with O3-FAs and by 1.49 and 1.81 points, respectively, with placebo. In a linear regression adjusting for the baseline score, osteoarthritis, and taxane use, adjusted 12-week BPI-SF scores did not differ by arm (P = .58). Triglyceride levels decreased in patients receiving O3-FA treatment and remained the same for those receiving placebo (P = .01). No between-group differences were seen for HDL, LDL, or C-reactive protein. CONCLUSION: We found a substantial (> 50%) and sustained improvement in AI arthralgia for both O3-FAs and placebo but found no meaningful difference between the groups.

A randomized controlled trial of vitamin E and selenium on rate of decline in lung function.

BACKGROUND: The intake of nutrients with antioxidant properties is hypothesized to augment antioxidant defenses, decrease oxidant damage to tissues, and attenuate age-related rate of decline in lung function. The objective was to determine whether long-term intervention with selenium and/or vitamin E supplements attenuates the annual rate of decline in lung function, particularly in cigarette smokers. METHODS: The Respiratory Ancillary Study (RAS) tested the single and joint effects of selenium (200 µg/d L-selenomethionine) and vitamin E (400 IU/day all rac-α-tocopheryl acetate) in a randomized double-blind placebo-controlled trial. At the end of the intervention, 1,641 men had repeated pulmonary function tests separated by an average of 3 years. Linear mixed-effects regression models estimated the effect of intervention on annual rate of decline in lung function. RESULTS: Compared to placebo, intervention had no main effect on either forced expiratory volume in the first second (FEV1) or forced expiratory flow (FEF25-75). There was no evidence for a smoking by treatment interaction for FEV1, but selenium attenuated rate of decline in FEF25-75 in current smokers (P = 0.0219). For current smokers randomized to selenium, annual rate of decline in FEF25-75 was similar to the annual decline experienced by never smokers randomized to placebo, with consistent effects for selenium alone and combined with vitamin E. CONCLUSIONS: Among all men, there was no effect of selenium and/or vitamin E supplementation on rate of lung function decline. However, current smokers randomized to selenium had an attenuated rate of decline in FEF25-75, a marker of airflow. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00241865 .

Age-related cataract in men in the selenium and vitamin e cancer prevention trial eye endpoints study: a randomized clinical trial.

IMPORTANCE: Observational studies suggest a role for dietary nutrients such as vitamin E and selenium in cataract prevention. However, the results of randomized clinical trials of vitamin E supplements and cataract have been disappointing and are not yet available for selenium. OBJECTIVE: To test whether long-term supplementation with selenium and vitamin E affects the incidence of cataract in a large cohort of men. DESIGN, SETTING, AND PARTICIPANTS: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) Eye Endpoints Study was an ancillary study of the Southwest Oncology Group-coordinated SELECT, a randomized placebo-controlled 4-arm trial of selenium and vitamin E conducted among 35,533 men, 50 years and older for African American participants and 55 years and older for all other men, at 427 participating sites in the United States, Canada, and Puerto Rico. A total of 11,267 SELECT participants from 128 SELECT sites participated in the SELECT Eye Endpoints ancillary study. INTERVENTIONS: Individual supplements of selenium (200 µg per day from L-selenomethionine) and vitamin E (400 IU per day of all rac-α-tocopheryl acetate). MAIN OUTCOMES AND MEASURES: Incident cataract was defined as a lens opacity, age related in origin, and responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-reports confirmed by medical record review. Cataract extraction was defined as the surgical removal of an incident cataract. RESULTS: During a mean (SD) of 5.6 (1.2) years of treatment and follow-up, 389 cases of cataract were documented. There were 185 cataracts in the selenium group and 204 in the no selenium group (hazard ratio, 0.91; 95 % CI, 0.75-1.11; P = .37). For vitamin E, there were 197 cases in the treated group and 192 in the placebo group (hazard ratio, 1.02; 95 % CI, 0.84-1.25; P = .81). Similar results were observed for cataract extraction. CONCLUSIONS AND RELEVANCE: These data from a large cohort of apparently healthy men indicate that long-term daily supplementation with selenium and/or vitamin E is unlikely to have a large beneficial effect on age-related cataract. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00784225.

Multilevel modeling and value of information in clinical trial decision support.

BACKGROUND: Clinical trials are the main method for evaluating safety and efficacy of medical interventions and have produced many advances in improving human health. The Women's Health Initiative overturned a half-century of harmful practice in hormone therapy, the National Lung Screening Trial identified the first successful lung cancer screening tool and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial overturned decades-long assumptions. While some trials identify unforeseen safety issues or harms, many fail to demonstrate efficacy. Large trials require substantial resources; to ensure reliable outcomes, we must seek ways to improve the predictive information used as the basis of trials. RESULTS: Here we demonstrate a modeling framework for linking knowledge of underlying biological mechanism to evaluate the expectation of trial outcomes. Key features include the ability to propagate uncertainty in biological mechanism to uncertainty in trial outcome and mechanisms for identifying knowledge gaps most responsible for unexpected outcomes. The framework was used to model the effect of selenium supplementation for prostate cancer prevention and parallels the Selenium and Vitamin E Cancer Prevention Trial that showed no efficacy despite suggestive data from secondary endpoints in the Nutritional Prevention of Cancer trial and found increased incidence of high-grade prostate cancer in certain subgroups. CONCLUSION: Using machine learning methods, we identified the parameters of the model that are most predictive of trial outcome and found that the top four are directly related to the rates of reactions producing methylselenol and transporting extracellular selenium into the cell as selenide. This modeling process demonstrates how the approach can be used in advance of a large clinical trial to identify the best targets for conducting further research to reduce the uncertainty in the trial outcome.

Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial.

BACKGROUND: In vitro, animal, and ecological studies suggest that inadequate vitamin D intake could increase prostate cancer risk, but results of biomarker-based longitudinal studies are inconsistent. METHODS: Data for this case (n = 1,731) and cohort (n = 3,203) analysis are from the Selenium and Vitamin E Cancer Prevention Trial. Cox proportional hazard models were used to test whether baseline plasma vitamin D (25-hydroxy) concentration, adjusted for season of blood collection, was associated with the risk of total and Gleason score 2-6, 7-10, and 8-10 prostate cancer. RESULTS: There were U-shaped associations of vitamin D with total cancer risk: compared with the first quintile, HRs were 0.83 [95% confidence interval (CI), 0.66-1.03; P = 0.092], 0.74 (95% CI, 0.59-0.92; P = 0.008), 0.86 (95% CI, 0.69-1.07; P = 0.181), and 0.98 (95% CI, 0.78-1.21; P = 0.823), for the second through fifth quintiles, respectively. For Gleason 7-10 cancer, corresponding HRs were 0.63 (95% CI, 0.45-0.90; P = 0.010), 0.66 (95% CI, 0.47-0.92; P = 0.016), 0.79 (95% CI, 0.56-1.10; P = 0.165), and 0.88 (95% CI, 0.63-1.22; P = 0.436). Among African American men (n = 250 cases), higher vitamin D was associated with reduced risk of Gleason 7-10 cancer only: in the a posteriori contrast of quintiles 1-2 versus 3-5, the HR was 0.55 (95% CI, 0.31-0.97; P = 0.037), with no evidence of dose-response or a U-shaped association. CONCLUSIONS: Both low and high vitamin D concentrations were associated with increased risk of prostate cancer, and more strongly for high-grade disease. IMPACT: The optimal range of circulating vitamin D for prostate cancer prevention may be narrow. Supplementation of men with adequate levels may be harmful. Cancer Epidemiol Biomarkers Prev; 23(8); 1494-504. ©2014 AACR.

Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk.

BACKGROUND: The Selenium and Vitamin E Cancer Prevention Trial found no effect of selenium supplementation on prostate cancer (PCa) risk but a 17% increased risk from vitamin E supplementation. This case-cohort study investigates effects of selenium and vitamin E supplementation conditional upon baseline selenium status. METHODS: There were 1739 total and 489 high-grade (Gleason 7-10) PCa cases and 3117 men in the randomly selected cohort. Proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for effects of supplementation within quintiles of baseline toenail selenium. Cox proportional hazards models were used to estimate hazard ratios, and all statistical tests are two-sided. RESULTS: Toenail selenium, in the absence of supplementation, was not associated with PCa risk. Selenium supplementation (combined selenium only and selenium + vitamin E arms) had no effect among men with low selenium status (<60th percentile of toenail selenium) but increased the risk of high-grade PCa among men with higher selenium status by 91% (P = .007). Vitamin E supplementation (alone) had no effect among men with high selenium status (≥40th percentile of toenail selenium) but increased the risks of total, low-grade, and high-grade PCa among men with lower selenium status (63%, P = .02; 46%, P = .09; 111%, P = .008, respectively). CONCLUSIONS: Selenium supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status. Vitamin E increased the risk of PCa among men with low selenium status. Men should avoid selenium or vitamin E supplementation at doses that exceed recommended dietary intakes.

Phase III prostate cancer chemoprevention trials.

Chemoprevention refers to the use of pharmacologic interventions to delay, prevent, or reverse carcinogenesis with the ultimate goal of reducing cancer incidence. Two large, population-based, phase 3 prostate cancer prevention trials reported that 5-alpha reductase inhibitors significantly reduce prostate cancer risk. However, this class of agents were also associated with increased detection of high-grade prostate cancer. Another large, phase 3 prostate cancer prevention clinical trial showed no benefit for long-term supplementation with the trace element Se, given in the form of selenomethionine, or vitamin E, either individually or in combination. Paradoxically, a significant increase in prostate cancer was observed among men randomized to receive vitamin E alone. A great deal of progress had been made in the field of prostate cancer prevention over the past decade. Future studies will focus on prevention of disease progression in men on Active Surveillance, immunotherapy, mechanistically based drug combinations, and novel biomarkers of risk and benefit.

Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial.

BACKGROUND: Studies of dietary ω-3 fatty acid intake and prostate cancer risk are inconsistent; however, recent large prospective studies have found increased risk of prostate cancer among men with high blood concentrations of long-chain ω-3 polyunsaturated fatty acids ([LCω-3PUFA] 20:5ω3; 22:5ω3; 22:6ω3]. This case-cohort study examines associations between plasma phospholipid fatty acids and prostate cancer risk among participants in the Selenium and Vitamin E Cancer Prevention Trial. METHODS: Case subjects were 834 men diagnosed with prostate cancer, of which 156 had high-grade cancer. The subcohort consisted of 1393 men selected randomly at baseline and from within strata frequency matched to case subjects on age and race. Proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between fatty acids and prostate cancer risk overall and by grade. All statistical tests were two-sided. RESULTS: Compared with men in the lowest quartiles of LCω-3PUFA, men in the highest quartile had increased risks for low-grade (HR = 1.44, 95% CI = 1.08 to 1.93), high-grade (HR = 1.71, 95% CI = 1.00 to 2.94), and total prostate cancer (HR = 1.43, 95% CI = 1.09 to 1.88). Associations were similar for individual long-chain ω-3 fatty acids. Higher linoleic acid (ω-6) was associated with reduced risks of low-grade (HR = 0.75, 95% CI = 0.56 to 0.99) and total prostate cancer (HR = 0.77, 95% CI = 0.59 to 1.01); however, there was no dose response. CONCLUSIONS: This study confirms previous reports of increased prostate cancer risk among men with high blood concentrations of LCω-3PUFA. The consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis. Recommendations to increase LCω-3PUFA intake should consider its potential risks.

Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is common and leads to suboptimal treatment. Acetyl-L-carnitine (ALC) is a natural compound involved in neuronal protection. Studies have suggested ALC may be effective for the prevention and treatment of CIPN. PATIENTS AND METHODS: A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) -Taxane scale at 12 weeks. Secondary objectives included changes in 24-week end points, functional status (FACT-Trial Outcome Index [TOI]), fatigue (Functional Assessment of Chronic Illness Therapy [FACIT] -Fatigue), and NTX grade. RESULTS: A total of 409 patients were evaluable (208 received ALC; 201, placebo). In a multivariate linear regression, week-12 scores were 0.9 points lower (more CIPN) with ALC than placebo (95% CI, -2.2 to 0.4; P = .17), whereas week-24 scores were 1.8 points lower with ALC (95% CI, -3.2 to -0.4; P = .01). Patients receiving ALC were more likely to have a > 5-point decrease in FACT-NTX scores (38% v 28%; P = .05), and FACT-TOI scores were 3.5 points lower with ALC (P = .03). Grade 3 to 4 neurotoxicity was more frequent in the ALC arm (eight v one). No differences between arms were observed for FACIT-Fatigue or other toxicities. Serum carnitine level increased with ALC but remained stable with placebo. CONCLUSION: There was no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks. This is the first study to our knowledge showing that a nutritional supplement increased CIPN. Patients should be discouraged from using supplements without proven efficacy.

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.