Feasibility and Safety of Diffusing Alpha-Emitter Radiation Therapy for Recurrent or Unresectable Skin Cancers.

Importance: Patients with recurrent or unresectable skin cancers have limited treatment options. Diffusing alpha-emitter radiation therapy (DaRT), a novel solid tumor management strategy using alpha-particle interstitial brachytherapy, may address this challenge. Objective: To evaluate the feasibility and safety of using DaRT to manage recurrent or unresectable skin cancers. Design, Setting, and Participants: This prospective cohort study of patients who received a 2-week to 3-week treatment course and were followed up for 24 weeks after treatment during 2021 and 2022 at 2 sites in the US. Patients with malignant skin tumors or soft tissue tumors were recruited if they had limited treatment options for tumors recurrent after prior surgery or external beam radiotherapy or unresectable tumors. Intervention: Patients underwent DaRT to deliver a physical dose of 10 Gy (equivalent weighted dose of 200 CGE) to the tumor. Main Outcomes and Measures: Feasibility of the DaRT procedure was evaluated based on the ability of investigators to successfully deliver radiation to the tumor. Patients were followed up for adverse events (AEs) for 24 weeks and for tumor response by physicians' physical examination and imaging 12 weeks after device removal. Results: This study included 10 participants with recurrent or unresectable skin cancer (median [IQR] age, 72 [68-75] years; 6 males [60%]; 4 females [40%]). Six patients (60%) had recurrent disease, and 4 (40%) had tumors that were deemed unresectable. Tumors were located on the nose, chin, eyelid, scalp, neck, trunk, and extremities. Median (range) tumor volume before treatment was 2.1 cm3 (0.65-12.65 cm3). The mean (SD) prescription dose coverage of the gross tumor volume was 91% (2.8%) with all tumors having coverage of 85% or more. No device-related grade 3 AEs were noted. Common AEs were grade 1 to 2 erythema, edema, and pruritus. At 12 weeks following treatment, there was a 100% complete response rate. Nine of 10 complete responses (90%) were confirmed by CT imaging. Conclusions and Relevance: This cohort study suggests the feasibility and preliminary safety of DaRT in the management of recurrent or unresectable skin cancers. The favorable safety profile and high response rates are promising. A US trial for marketing approval based on this pilot study is under way. Trial Registration: ClinicalTrials.gov Identifier: NCT04377360.

Predicting future cancer incidence by age, race, ethnicity, and sex.

INTRODUCTION: Cancer remains a substantial burden on society. Our objective was to update projections on the number of new cancer diagnoses in the United States by age, race, ethnicity, and sex through 2040. MATERIALS AND METHODS: Population-based cancer incidence data were obtained using Surveillance, Epidemiology, and End Results (SEER) data. Population estimates were made using the 2010 US Census data population projections to calculate future cancer incidence. Trends in age-adjusted incidence rates for 23 cancer types along with total cancers were calculated and incorporated into a second projection model. RESULTS: If cancer incidence remains stable, annual cancer diagnoses are projected to increase by 29.5% from 1.86 million to 2.4 million between 2020 and 2040. This increase outpaces the projected US population growth of 12.3% over the same period. The population of older adults is projected to represent an increasing proportion of total cancer diagnoses with patients ≥65 years old comprising 69% of all new cancer diagnoses and patients ≥85 years old representing 13% of new diagnoses by 2040. Cancer diagnoses are projected to increase in racial minority groups, with a projected 44% increase in Black Americans (from 222,000 to 320,000 annually), and 86% in Hispanic Americans (from 175,000 to 326,000 annually). DISCUSSION: The landscape of cancer care will continue to change over the next several decades. The burden of disease will remain substantial, and the growing proportion of older and minority patients with cancer remains of particular interest. These projections should help guide future health policy and research priorities.

A Geriatric Assessment Intervention to Reduce Treatment Toxicity Among Older Adults With Advanced Lung Cancer: A Subgroup Analysis From a Cluster Randomized Controlled Trial.

Introduction: More older adults die from lung cancer worldwide than breast, prostate, and colorectal cancers combined. Current lung cancer treatments may prolong life, but can also cause considerable treatment-related toxicity. Objective: This study is a secondary analysis of a cluster-randomized clinical trial which evaluated whether providing a geriatric assessment (GA) summary and GA-guided management recommendations can improve grade 3-5 toxicity among older adults with advanced lung cancer. Methods: We analyzed participants aged ≥70 years(y) with stage III & IV (advanced) lung cancer and ≥1 GA domain impairment starting a new cancer treatment with high-risk of toxicity within the National Cancer Institute's Community Oncology Research Program. Community practices were randomized to the intervention arm (oncologists received GA summary & recommendations) versus usual care (UC: no summary or recommendations given). The primary outcome was grade 3-5 toxicity through 3 months post-treatment initiation. Secondary outcomes included 6-month (mo) and 1-year overall survival (OS), treatment modifications, and unplanned hospitalizations. Outcomes were analyzed using generalized linear mixed and Cox proportional hazards models with practice site as a random effect. Trial Registration: NCT02054741. Results & Conclusion: Among 180 participants with advanced lung cancer, the mean age was 76.3y (SD 5.1), 39.4% were female and 82.2% had stage IV disease. The proportion of patients who experienced grade 3-5 toxicity was significantly lower in the intervention arm vs UC (53.1% vs 71.6%, P=0.01). More participants in the intervention arm received lower intensity treatment at cycle 1 (56.3% vs 35.3%; P<0.01). Even with a cycle 1 dose reduction, OS at 6mo and 1 year was not significantly different (adjusted hazard ratio [HR] intervention vs. UC: 6mo HR=0.90, 95% CI: 0.52-1.57, P=0.72; 1 year HR=0.89, 95% CI: 0.58-1.36, P=0.57). Frequent toxicity checks, providing education and counseling materials, and initiating direct communication with the patient's primary care physician were among the most common GA-guided management recommendations. Providing a GA summary and management recommendations can significantly improve tolerability of cancer treatment among older adults with advanced lung cancer.

Radiation Therapy in Older Adults With Cancer: A Critical Modality in Geriatric Oncology.

Radiation therapy (RT) is a commonly used modality in the treatment of older adults with cancer, and RT represents an attractive oncologic treatment option, providing a noninvasive local therapy with limited systemic side effects. The Journal of Clinical Oncology (JCO) recently published a special series on Geriatric Oncology providing a comprehensive overview of multiple treatment modalities available to older adults with cancer. The purpose of this short review is to highlight the importance of RT in the treatment of older adults and encourage multidisciplinary participation in their care.

Association between Prior Malignancy Exclusion Criteria and Age Disparities in Cancer Clinical Trials.

Prior malignancy exclusion criteria (PMEC) are often utilized in cancer clinical trials; however, the incidence of PMEC and the association of PMEC with trial participant age disparities remain poorly understood. This study aimed to identify age disparities in oncologic randomized clinical trials as a result of PMEC. Using a comprehensive collection of modern phase III cancer clinical trials obtained via ClinicalTrials.gov, we assessed the incidence and covariates associated with trials excluding patients with prior cancers within 5+ years from registration (PMEC-5). Using the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database, we further sought to determine the correlation between PMEC-5 and age disparities. PMEC-5 were used in 41% of all trials, with higher PMEC-5 utilization among industry-supported trials as well as trials evaluating a targeted therapy. Comparing trial patient median ages with population-matched median ages by disease site and time-period, we assessed the association between PMEC-5 and age disparities among trial participants. PMEC-5 were independently associated with heightened age disparities, which further worsened with longer exclusionary timeframes. Together, PMEC likely contribute to age disparities, suggesting that eligibility criteria modernization through narrower PMEC timeframes may work toward reducing such disparities in cancer clinical trial enrollment.

Disparities in older adult accrual to cancer trials: Analysis from the alliance for clinical trials in oncology (A151736).

BACKGROUND: Older adults are under-represented in cancer clinical trials. However, it remains unclear which types of trials under-enroll aging patients. We aimed to identify associations between trial characteristics and disparate enrollment of older adults onto trials sponsored by the Alliance for Clinical Trials in Oncology (Alliance). METHODS: Actual age ≥ 65 percentage and trial data were extracted from the Alliance closed study list. Each trial, based on its cancer type and years of enrollment, was assigned an expected age ≥ 65 percentage extracted from the Surveillance, Epidemiology, and End Results (SEER) US population-based database. Enrollment disparity difference (EDD), the difference between the expected age ≥ 65 percentage and the actual age ≥ 65 percentage, was calculated for each trial. Linear regression determined trial variables associated with larger EDDs and variables with an overall association p-value <0.20 were included in a multivariable fixed-effects linear model. RESULTS: The median age of 66,708 patients across 237 trials was 60 years (range 18-102). The average actual age ≥ 65 percentage enrolled per trial was lower than each trial's expected age ≥ 65 percentage average (39% vs. 58%; EDD 19, 95% CI 17.1-21.3%, p < 0.0001). In multivariable analyses, non-genitourinary (GU) cancer types (p < 0.001), trimodality+ trials (estimate 8.78, 95%CI 2.21-15.34, p = 0.009), and phase 2 trials (estimate 4.43 95% CI -0.06-8.91; p = 0.05) were all associated with larger EDDs. CONCLUSIONS: Disparate enrollment of older adults is not equal across cancer trials. Future strategies to improve older adult inclusion should focus on trial types associated with the highest disparate enrollment.

The association of age with acute toxicities in NRG oncology combined modality lower GI cancer trials.

PURPOSE: Expected toxicity from chemoradiation (CRT) is an important factor in treatment decisions but is poorly understood in older adults with lower gastrointestinal (GI) malignancies. Our objective was to compare acute adverse events (AAEs) of older and younger adults with lower GI malignancies treated on NRG studies. METHODS: Data from 6 NRG trials, testing combined modality therapy in patients with anal or rectal cancer, were used to test the hypothesis that older age was associated with increased AAEs. AAEs and compliance with protocol-directed therapy were compared between patients aged ≥70 and < 70. Categorical variables were compared across age groups using the chi-square test. The association of age on AAEs was evaluated using a covariate-adjusted logistic regression model, with odds ratio (OR) reported. To adjust for multiple comparisons, a p-value <0.01 was considered statistically significant. RESULTS: There were 2525 patients, including 380 patients ≥70 years old (15%) evaluable. Older patients were more likely to have worse baseline performance status (PS 1 or 2) (23% vs. 16%, p = 0.001), but otherwise baseline characteristics were similar. Older patients were less likely to complete their chemotherapy (78% vs. 87%, p < 0.001), but had similar RT duration. On univariate analysis, older patients were more likely to experience grade ≥ 3 GI AAEs (36% vs. 23%, p < 0.001), and less likely to experience grade ≥ 3 skin AAEs (8% vs. 14%, p = 0.002). On multivariable analysis, older age was associated with grade ≥ 3 GI AAE (OR 1.93, 95% CI: 1.52, 2.47, p < 0.001) after adjusting for sex, race, PS, and disease site. CONCLUSIONS: Older patients with lower GI cancers who underwent CRT were less likely to complete chemotherapy and had higher rates of grade 3+ GI AAEs. These results can be used to counsel older adults prior to treatment and manage expected toxicities throughout pelvic CRT.

Cryoablation Without Excision for Low-Risk Early-Stage Breast Cancer: 3-Year Interim Analysis of Ipsilateral Breast Tumor Recurrence in the ICE3 Trial.

BACKGROUND: The ICE3 trial is designed to evaluate the safety and efficacy of breast cryoablation, enabling women older than 60 years with low-risk early-stage breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks. METHODS: The ICE3 trial is a prospective, multi-center, single-arm, non-randomized trial including women age 60 years or older with unifocal, ultrasound-visible invasive ductal carcinoma size 1.5 cm or smaller and classified as low to intermediate grade, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Ipsilateral breast tumor recurrence (IBTR) at 5 years was the primary outcome. A 3-year interim analysis of IBTR was performed, and the IBTR probability was estimated using the Kaplan-Meier method. RESULTS: Full eligibility for the study was met by 194 patients, who received successful cryoablation per protocol. The mean age was 75 years (range, 55-94 years). The mean tumor length was 8.1 mm (range, 8-14.9 mm), and the mean tumor width was 7.4 mm (range, 2.8-14 mm). During a mean follow-up period of 34.83 months, the IBTR rate was 2.06% (4/194 patients). Device-related adverse events were reported as mild in 18.4% and moderate in 2.4% of the patients. No severe device-related adverse events were reported. More than 95% of the patients and 98% of the physicians reported satisfaction with the cosmetic results at the clinical follow-up evaluation. CONCLUSIONS: Breast cryoablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Further study within a clinical trial or registry is needed to confirm cryoablation as a viable alternative to surgical excision for appropriately selected low-risk patients.

Evolution and Current Status of the Multidisciplinary Management of Locally Advanced Rectal Cancer.

The management of locally advanced rectal cancer has grown in both complexity and quality since the first proctectomy. What once was a malignancy with a fairly consistent treatment algorithm for decades, a recent paradigm shift in the care of these patients has led to a more personalized, multidisciplinary approach with variations in timing, sequence, duration, and potential exclusion of multimodality therapies. This review summarizes the most important evidence behind these developing overarching concepts to provide a context for this paradigm shift.

Weathering the Storm: Managing Older Adults With Breast Cancer Amid COVID-19 and Beyond.

Caring for older patients with breast cancer presents unique clinical considerations because of preexisting and competing comorbidity, the potential for treatment-related toxicity, and the consequent impact on functional status. In the context of the COVID-19 pandemic, treatment decision making for older patients is especially challenging and encourages us to refocus our treatment priorities. While we work to avoid treatment delays and maintain therapeutic benefit, we also need to minimize the risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposures, myelosuppression, general chemotherapy toxicity, and functional decline. Herein, we propose multidisciplinary care considerations for the aging patient with breast cancer, with the goal to promote a team-based, multidisciplinary treatment approach during the COVID-19 pandemic and beyond. These considerations remain relevant as we navigate the "new normal" for the approximately 30% of breast cancer patients aged 70 years and older who are diagnosed in the United States annually and for the thousands of older patients living with recurrent and/or metastatic disease.

Survival After Robotic-assisted Prostatectomy for Localized Prostate Cancer: An Epidemiologic Study.

BACKGROUNDS: To determine the potential survival benefit associated with robotic-assisted laparoscopic prostatectomy (RALP) compared to open radical prostatectomy (ORP) for prostate cancer. SUMMARY OF BACKGROUND DATA: RALP has become the dominant surgical approach for localized disease in the absence of randomized clinical evidence and despite of the factor that RALP is more expensive than ORP. METHODS: We performed a cohort study involving patients who underwent RALP and ORP for localized prostate cancer at the Commission on Cancer- accredited hospitals in the United States. Overall survival was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. An interrupted time-series analysis using the surveillance, epidemiology, and end results program database was also performed. RESULTS: From 2010 to 2011, 37,645 patients received RALP and 12,655 patients received ORP. At a median follow-up of 60.7 months, RALP was associated with improved overall survival by both univariate [hazard ratio (HR), 0.69; P < 0.001] and multivariate analysis (HR, 0.76; P < 0.001) compared with ORP. Propensity score-matched analysis demonstrated improved 5-year all-cause mortality (3.9% vs 5.5%, HR, 0.73; P < 0.001) for RALP. The interrupted time-series analysis demonstrated the adoption of robotic surgery coincided with a systematic improvement in the 5-year cancer-specific survival rate of 0.17% (95% confidence interval, 0.06-0.25) per year after 2003 (P = 0.004 for change of trend), as compared to the time before adoption of RALP (1998-2003, annual percentage change, 0.01%; 95% confidence interval, -0.06 to 0.08). Sensitivity analysis suggested that the results from the interrupted time-series analysis were consistent with the improvement in the all-cause mortality demonstrated in the survival analysis (P = 0.87). CONCLUSIONS: In this epidemiologic analysis, RALP was associated with a small but statistically significant improvement in 5-year all-cause mortality compared to ORP for localized prostate cancer. This is the first time in the literature to report a survival benefit with RALP. Our findings have significant quality and cost implications, and provide assurance regarding a dominant adoption of more expensive technology in the absence of randomized controlled trials.

Randomized phase II study of a home-based walking intervention for radiation-related fatigue among older patients with breast cancer.

BACKGROUND: Fatigue is a common side effect of radiation therapy and can dramatically affect the quality of life in older cancer patients. We compared a home-based graduated walking intervention with a fixed walking recommendation.recommendation to exercise to determine the effects of these interventions during adjuvant radiotherapy (RT) on older women with breast cancer. METHODS: A randomized phase 2 trial in women ≥65 years, with stage 0-3 breast cancer. Prior to initiating breast RT, women were randomized to a Home-Based Graduated Walking Program (HBGWP) or a fixed walking recommendation. The primary outcome of fatigue was measured by the Total Disruption Index (TDI) of the Fatigue Symptom Inventory (FSI). Secondary outcomes including a short physical performance battery (SPPB) and questionnaires on exercise, physical function, fatigue (PROMIS Fatigue), and fatigue-related symptoms were collected at 3 time points. The primary goal was to compare the change in TDI between arms at the end of RT. Random coefficients models were used to determine the association between arm, fatigue, and exercise over time. Linear regression models were used to describe the change in outcome variables between visits. RESULTS: Median age of the 54 participants (27 per arm) was 69 years (range 65-84). The baseline characteristics were similar between study arms. The number of minutes walking per week increased in both arms (mean 21 min/wk. baseline to 83 min/wk. end of RT, p < 0.01) and physical function improved over time in both arms (median 10.5 at baseline to 12 at end of RT, p < 0.01).There was no significant difference in change in TDI between arms (2.7 ± 9.9 vs. 1.8 ± 14.0, p = 0.61)between baseline and end of RT. However, in our linear regression model increasing walking over time was associated with statistically significant lower levels of fatigue (-2.44+/- 1.04, p = 0.04), but not in posthoc subgroup analyses. CONCLUSION: The HBGWP did not decrease fatigue more than the fixed recommendation to exercise. Both the graduated intervention and fixed recommendation lead to increased walking which was associated with lower fatigue in this study of older adult breast cancer patients.

Performance Status Restriction in Phase III Cancer Clinical Trials.

BACKGROUND: Patients with good performance status (PS) tend to be favored in randomized clinical trials (RCTs), possibly limiting the generalizability of trial findings. We aimed to characterize trial-related factors associated with the use of PS eligibility criteria and analyze patient accrual breakdown by PS. METHODS: Adult, therapeutic, multiarm phase III cancer-specific RCTs were identified through ClinicalTrials.gov. PS data were extracted from articles. Trials with a PS restriction ECOG score ≤1 were identified. Factors associated with PS restriction were determined, and the use of PS restrictions was analyzed over time. RESULTS: In total, 600 trials were included and 238,213 patients had PS data. Of those trials, 527 studies (87.8%) specified a PS restriction cutoff, with 237 (39.5%) having a strict inclusion criterion (ECOG PS ≤1). Enrollment criteria restrictions based on PS (ECOG PS ≤1) were more common among industry-supported trials (P<.001) and lung cancer trials (P<.001). Nearly half of trials that led to FDA approval included strict PS restrictions. Most patients enrolled across all trials had an ECOG PS of 0 to 1 (96.3%). Even among trials that allowed patients with ECOG PS ≥2, only 8.1% of those enrolled had a poor PS. Trials of lung, breast, gastrointestinal, and genitourinary cancers all included <5% of patients with poor PS. Finally, only 4.7% of patients enrolled in trials that led to subsequent FDA approval had poor PS. CONCLUSIONS: Use of PS restrictions in oncologic RCTs is pervasive, and exceedingly few patients with poor PS are enrolled. The selective accrual of healthier patients has the potential to severely limit and bias trial results. Future trials should consider a wider cancer population with close toxicity monitoring to ensure the generalizability of results while maintaining patient safety.