Southeast Clinical Oncology Research Consortium

Management of refractory chronic low back pain (CLBP) includes a range of treatments (eg, physical therapy, injections, ablations, neurostimulation, surgery) with varying utilization and effectiveness. This pragmatic randomized controlled trial (RCT) evaluated the effectiveness of one treatment option, percutaneous 60-day peripheral nerve stimulation (PNS), compared to usual care with standard interventional management for CLBP. Two hundred thirty patients with CLBP were randomized in a 1:1 ratio to Group 1 (percutaneous 60-day PNS) or Group 2 (physician-directed usual care with standard interventional management). The Primary Clinical Endpoint evaluated the proportion of participants with ≥50% reductions in CLBP at 3 months post-treatment compared to baseline. At the Primary Endpoint, a greater proportion of participants receiving percutaneous 60-day PNS (55%; n = 112; 95% confidence interval [CI] = 45-65) experienced ≥50% pain relief compared to usual care with standard interventional management (26%; n = 110; 95% CI = 17-34; P < .001). Concordant with the Primary Endpoint, percutaneous 60-day PNS also produced greater improvements in patient-centric secondary endpoints, including disability, pain interference, health-related quality of life, and analgesic consumption. Reductions in pain and resulting improvements in function were sustained through 6 months with percutaneous 60-day PNS. This prospective multicenter pragmatic RCT met its Primary Clinical Endpoint and found that more participants with CLBP reported pain relief at 3 months after receiving percutaneous 60-day PNS as compared to usual care with standard interventional management. Participants treated with 60-day PNS showed greater reductions in pain and more substantial improvements in functional outcomes through 6 months. NCT04246281; Primary funding: Department of Defense (DoD), with additional funding needed to complete the study provided by the study's sponsor, SPR.The protocol is available on ClinicalTrials.gov. The statistical analysis plan and results will be made available within 12 months of the study's completion.

BackgroundThe benefit of regional nodal irradiation in the treatment of breast cancer is well established for patients with pathologically positive axillary nodes, but whether it is also beneficial for patients whose nodes become pathologically tumor free (ypN0) after neoadjuvant chemotherapy remains unclear.MethodsWe evaluated whether regional nodal irradiation improves outcomes in patients with biopsy-proven, node-positive breast cancer who reach ypN0 status after neoadjuvant chemotherapy. Patients with breast cancer with a clinical stage of T1 to T3 (tumor size, ≤2 cm to >5 cm), N1, and M0 (indicating spread to one to three axillary lymph nodes but no distant metastasis) who had ypN0 status after neoadjuvant chemotherapy were randomly assigned to receive regional nodal irradiation or no regional nodal irradiation. The primary end point was the interval of freedom from invasive breast cancer recurrence or death from breast cancer (invasive breast cancer recurrence–free interval). Secondary end points included the locoregional recurrence–free interval, the distant recurrence–free interval, disease-free survival, and overall survival. Safety was also assessed.ResultsA total of 1641 patients were enrolled in the trial; 1556 were included in the primary-event analysis: 772 in the irradiation group and 784 in the no-irradiation group. After a median follow-up of 59.5 months, 109 primary end-point events (50 in the irradiation group and 59 in the no-irradiation group) had occurred. Regional nodal irradiation did not significantly increase the invasive breast cancer recurrence–free interval (hazard ratio, 0.88; 95% confidence interval, 0.60 to 1.28; P=0.51). Point estimates of survival free from the primary end-point events were 92.7% in the irradiation group and 91.8% in the no-irradiation group. Regional nodal irradiation did not increase the locoregional recurrence–free interval, the distant recurrence–free interval, disease-free survival, or overall survival. No deaths related to the protocol-specified therapy were reported, and no unexpected adverse events were observed. Grade 4 adverse events occurred in 0.5% of patients in the irradiation group and 0.1% of those in the no-irradiation group.ConclusionsThe addition of adjuvant regional nodal irradiation did not decrease the risk of invasive breast cancer recurrence or death from breast cancer in patients who had negative axillary nodes after neoadjuvant chemotherapy. (Funded by the National Institutes of Health; NSABP B-51–Radiation Therapy Oncology Group 1304 ClinicalTrials.gov number, NCT01872975.)

12130 Background: Cancer-related fatigue (CRF) is one of the most common and debilitating symptoms reported by cancer patients, significantly impairing quality of life (QoL) across physical, functional, emotional, and social domains. Despite its prevalence, limited data exist quantifying how rapid changes in CRF after a single chemotherapy cycle influence QoL. We aim to evaluate if rapid clinically meaningful changes in CRF post chemotherapy impact QoL in breast cancer patients. Methods: This Phase III RCT (NCT03367572) enrolled chemotherapy-naïve breast cancer patients across 21 NCORP practices receiving high/moderate emetogenic chemotherapy. CRF was assessed at baseline and post chemotherapy cycle 1 (n = 1,262) using a four-day home diary, with maximum fatigue change as the primary outcome. For analysis, the CRF variable was dichotomized into two categories: a clinically significant increase (≥3 points) and less than a 3-point increase. QOL was measured with FACT-G and its subscales: emotional (EWB), functional (FWB), physical (PWB), and social (SWB). ANCOVA and Cohen’s d effect size (ES) evaluated whether clinically meaningful CRF changes predicted QOL changes across cycles. Results: Among 1,262 patients with valid fatigue scores, 74.8% experienced increased CRF after cycle 1, with 53.2% reporting a ≥3-point increase and a mean increase of 2.9 points for the group. Clinically significant increases in CRF strongly impacted quality of life (QOL), as reflected in FACT-G Total Score changes post-cycle 1 (≥3: −12.4 vs &lt; 3: −4.7; mean difference: 7.7, p &lt; 0.001, ES: 0.74), exceeding the clinically meaningful threshold of &gt; 5 points. Analysis of the subscales revealed PWB with the largest changes of 4.8 (≥3: −X vs &lt; 3: −X; p &lt; 0.001, ES: 1.00). FWB changes were 2.1 (≥3: −X vs &lt; 3: −X; p≤0.0001, ES: 0.48) and EWB changes were 0.7 (≥3: −X vs &lt; 3: −X; p &lt; 0.001, ES: 0.26). CRF did not significantly impact SWB. Notably, many of these subscale changes surpassed the clinically meaningful threshold of &gt; 2 points. Conclusions: This study underscores the rapid onset and significant impact of CRF on QoL in breast cancer patients receiving chemotherapy. Clinically meaningful increases in CRF, even after a single chemotherapy cycle, were predictive of substantial declines in QoL, particularly in physical and functional well-being. These results emphasize the urgent need for targeted fatigue management strategies, such as tailored interventions addressing physical and functional domains, to improve patient outcomes. Clinical trial information: NCT03367572 .

Cancer-related cognitive impairment is a broad term encompassing subtle cognitive problems to more severe impairment. The severity of this impairment is influenced by host, disease, and treatment factors, and the impairment affects patients before, during, and following cancer treatment. The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee (SxQoL SC) convened a clinical trial planning meeting to review the state of the science on cancer-related cognitive impairment and develop phase II/III intervention trials aimed at improving cognitive function in cancer survivors with non-central nervous system disease and longitudinal studies to understand the trajectory of cognitive impairment and contributing factors. Participants included experts in the field of cancer-related cognitive impairment, members of the SxQoL SC, patient advocates, representatives from all 7 NCI Community Oncology Research Program research bases, and the NCI. Presentations focused on the following topics: measurement, lessons learned from pediatric and geriatric oncology, biomarker and mechanism endpoints, longitudinal study designs, and pharmacological and behavioral intervention trials. Panel discussions provided guidance on priority cognitive assessments, considerations for remote assessments, inclusion of relevant biomarkers, and strategies for ensuring broad inclusion criteria. Three clinical trial planning meeting working groups (longitudinal studies as well as pharmacological and behavioral intervention trials) convened for 1 year to discuss and report on top priorities and to design studies. The meeting experts concluded that sufficient data exist to advance phase II/III trials using selected pharmacological and behavioral interventions for the treatment of cancer-related cognitive impairment in the non-central nervous system setting, with recommendations included herein.

Deep learning-based mammographic evaluations could noninvasively assess response to breast cancer chemoprevention. We evaluated change in a convolutional neural network-based breast cancer risk model applied to mammograms among women enrolled in SWOG S0812, which randomly assigned 208 premenopausal high-risk women to receive oral vitamin D3 20 000 IU weekly or placebo for 12 months. We applied the convolutional neural network model to mammograms collected at baseline (n = 109), 12 months (n = 97), and 24 months (n = 67) and compared changes in convolutional neural network-based risk score between treatment groups. Change in convolutional neural network-based risk score was not statistically significantly different between vitamin D and placebo groups at 12 months (0.005 vs 0.002, P = .875) or at 24 months (0.020 vs 0.001, P = .563). The findings are consistent with the primary analysis of S0812, which did not demonstrate statistically significant changes in mammographic density with vitamin D supplementation compared with placebo. There is an ongoing need to evaluate biomarkers of response to novel breast cancer chemopreventive agents.

Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. Circulating EVs are protected from degradation, making them attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease-vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EVISF) were isolated via ultracentrifugation and characterized by nanoparticle tracking analysis, immunogold labeling, and flow cytometry. Mass spectrometry and proteomic analyses were performed on EVISF cargo. EVISF were 40-150 nm in size and expressed CD63, CD9, and CD81. Using a model of cerebral amyloidosis (e.g. APPswe,PSEN1dE9 mice), we found protein concentration increased but protein diversity decreased with A deposition. Genotype, age, and Aβ deposition modulated proteostasis- and immunometabolic-related pathways. Changes in the microglial EVISF proteome were sexually dimorphic and associated with a differential response of plaque associated microglia. We found that female APP/PS1 mice have more amyloid plaques, less plaque associated microglia, and a less robust- and diverse- EVISF microglial proteome. Thus, in vivo microdialysis is a novel technique for collecting EVISF and offers a unique opportunity to explore the role of EVs in AD.

PURPOSEResistance to immune checkpoint inhibition (ICI) in advanced non–small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types.METHODSIn this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity.RESULTSOf 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC.CONCLUSIONThis randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.

3607 Background: Through mining The Cancer Genome Atlas (TCGA) data and a large set of transcriptomes of CRC in GEO, we constructed 15 metagenes reflecting the transcriptomic impact of major driver genes of CRC. Independent of any clinical information, we used metagenes as features to further develop an ML model, then tested it using gene expression (GE) data from C-07 and C-08. Methods: We carried out a prospectively designed and double-blind study to evaluate the clinical utility of the ML model in the adjuvant setting. Samples were classified as Sig+ or Sig-. Association of signatures with recurrence free interval were tested using log-rank test, and significance was set at P&lt;0.05. Cox regression models were used to estimate hazard ratios in univariate and multivariate models and for significance testing in multivariate models. Clinical variables included in multivariate models were nodal status, age, sex, and T stage. Results: We tested the ML model for its ability to predict oxaliplatin benefit in all C-07 pts with available GE data (n=846). Sig+ pts received significant benefit from oxaliplatin (HR=0.68, 95% CI=0.48-0.95, p=0.025) but Sig- did not (Sig- HR=1.05, 95% CI=0.72-1.53, p=0.79), however, the int p value showed only a trend for significance (int p=0.091). Sig+ remained significant for oxaliplatin benefit in multivariate analysis (HR=0.67, 95% CI=0.48-0.95, p=0.024). When we combined all C-07 pts (C-07 FULV-trtd n=298, FLOX n=304) with C-08 FOLFOX-treated pts (n=226) the Sig+ was significantly associated with oxaliplatin benefit (HR=0.65, 95% CI=0.48-0.89, p=0.0065) with a significant int p=0.03. We also tested the signature for association with bev benefit in C-08 (n=438), using a different cut off. Sig+ showed only a trend for an association with bev benefit (HR=0.63, 95% CI=0.35-1.12, p=0.11). To increase the power to detect bev benefit, we also tested the signature for association with bev benefit in all C-08 patients and C-07 pts treated with FLOX. The Sig+ group received significant benefit from bev (HR=0.58, 95% CI=0.36-0.94, p=0.025) but the Sig- group did not (HR=1.02, 95% CI=0.64-1.63, p=0.94), however, the int p was not significant (p=0.101). The model also showed an association with prognosis within the FULV treatment arm in C-07 (HR=1.51, 95% CI=1.07-2.14, p=0.018) and the FOLFOX+bev arm in C-08 (HR=0.55, 95% CI=0.30-1.01, p=0.049). Conclusions: Although our study is not optimally powered, our analyses indicate that the ML model was predictive for oxaliplatin benefit in stage II and III CC and may be useful for detecting bev benefit. Importantly, the Sig- population is candidate for omitting oxaliplatin (de-escalation) in adjuvant setting but will require further validation. Support: PA DOH, U10CA-180868, -180822, -196067, Genentech, Sanofi; NSABP. Clinical trial information: 00096278, 00004931.

Caregivers of adults with cancer often report a different understanding of the patient's prognosis than the oncologist. We examine the associations of caregiver-oncologist prognostic concordance with caregiver depressive symptoms, distress, and quality of life (QoL). We also explore whether these relationships differed by caregiver environment mastery, an individual's sense of control, and effectiveness in managing life situations. We used data from a national geriatric assessment cluster-randomized trial (URCC 13070) that recruited patients aged 70 years and older with incurable cancer considering any line of cancer treatment at community oncology practices, their caregivers, and their oncologists. At enrollment, caregivers and oncologists estimated the patient's prognosis (0-6 months, 7-12 months, 1-2 years, 2-5 years, and >5 years; identical responses were concordant). Caregivers completed the Ryff's environmental mastery at enrollment. At 4-6 weeks, caregivers completed the Patient Health Questionnaire-2 (depressive symptoms), distress thermometer, and 12-Item Short-Form Health Survey (quality of life [QoL]). We used generalized estimating equations in models adjusted for covariates. We then assessed the moderation effect of caregiver mastery. Of 411 caregiver-oncologist dyads (mean age = 66.5 years), 369 provided responses and 28% were concordant. Prognostic concordance was associated with greater caregiver depressive symptoms (β = 0.30; p = .04) but not distress or QoL. A significant moderation effect for caregiver depressive symptoms was found between concordance and mastery (p = .01). Specifically, among caregivers with low mastery (below median), concordance was associated with greater depressive symptoms (β = 0.68; p = .003). Caregiver-oncologist prognostic concordance was associated with caregiver depressive symptoms. We found a novel moderating effect of caregiver mastery on the relationship between concordance and caregiver depressive symptoms. Caregiver-oncologist prognostic concordance is associated with greater caregiver depressive symptoms, particularly in those with low caregiver mastery. When discussing prognosis with caregivers, physicians should be aware that prognostic understanding may affect caregiver psychological health and should assess their depressive symptoms. In addition, while promoting accurate prognostic understanding, physicians should also identify strengths and build resilience among caregivers.

Diet has been associated with survival in patients with stage I to III colorectal cancer, but data on patients with metastatic colorectal cancer are limited. To examine the association between diet quality and overall survival among individuals with metastatic colorectal cancer. This was a prospective cohort study of patients with metastatic colorectal cancer who were enrolled in the Cancer and Leukemia Group B (Alliance) and Southwest Oncology Group 80405 trial between October 27, 2005, and February 29, 2012, and followed up through January 2018. Participants completed a validated food frequency questionnaire within 4 weeks after initiation of first-line treatment for metastatic colorectal cancer. Diets were categorized according to the Alternative Healthy Eating Index (AHEI), Alternate Mediterranean Diet (AMED) score, Dietary Approaches to Stop Hypertension (DASH) score, and Western and prudent dietary patterns derived using principal component analysis. Participants were categorized into sex-specific quintiles. Multivariable hazard ratios (HRs) and 95% CIs for overall survival. In this cohort study of 1284 individuals with metastatic colorectal cancer, the median age was 59 (interquartile range [IQR]: 51-68) years, median body mass index was 27.2 (IQR, 24.1-31.4), 521 (41%) were female, and 1102 (86%) were White. There were 1100 deaths during a median follow-up of 73 months (IQR, 64-87 months). We observed an inverse association between the AMED score and risk of death (HR quintile 5 vs quintile 1, 0.83; 95% CI, 0.67-1.04; P = .04 for trend), but the point estimates were not statistically significant. None of the other diet scores or patterns were associated with overall survival. In this prospective analysis of patients with metastatic colorectal cancer, diet quality assessed at initiation of first-line treatment for metastatic disease was not associated with overall survival.