Dockter, Travis

Background: The rising incidence of PCNSL in the elderly represents an unmet need with an undefined standard approach [Villano Br J Cancer 2011]. High-dose methotrexate-based (HD-MTX) therapy is feasible and effective in older patients, but outcomes in this population remain poor. Despite high response rates to HD-MTX induction therapy, poor candidacy for intensive consolidative therapy results in transient disease control that may benefit from maintenance strategies [David Am J Hematol 2023]. Lenalidomide (len) has demonstrated activity in PCNSL even at low doses and represents a potential alternative to consolidation considering its extensive use in maintenance settings [Vu Br J Haematol 2019]. Anecdotal activity in PCNSL by checkpoint inhibitors such as nivolumab (nivo) has been reported [Nayak Blood 2017], and its immune response may be enhanced by len [Görgün Clin Cancer Res 2015]. A051901 evaluates the feasibility of the addition of len and nivo to rituximab (R) and HD-MTX as first line induction therapy followed by len-nivo maintenance in elderly patients with PCNSL not eligible for intensive consolidation. Study Design and Methods: This is a single-arm phase 1 multicenter US study (NCT04609046) conducted by the Alliance for Clinical Trials in Oncology with a traditional 3+3 design. Eligible patients are 18 years of age or older with untreated diffuse large B-cell lymphoma PCNSL diagnosed through brain biopsy or resection, or cerebrospinal (CSF) or vitreous fluid not considered candidates for high dose chemotherapy consolidation. This study is available to all eligible patients, regardless of race, gender, or ethnic origin. Patients must have adequate end-organ function including creatinine clearance of at least 50 mL/min. Use of systemic corticosteroids for disease control to be tapered after initiation of therapy is allowed. Induction consists of six 14-day cycles with rituximab 500 mg/m2 i.v. on day 1, HD-MTX 3g/m2 i.v. on day 2. In the most recent treatment schedule, a 5-day course of lenalidomide PO at different dose levels (dose level (DL) 1 = 10 mg, DL2 = 15 mg, DL3 = 20 mg) is initiated immediately after adequate clearance of HD-MTX. Once a maximum tolerated dose (MTD) of len is defined, a subsequent cohort will evaluate the addition of nivo 240 mg i.v. to the day 14 of the induction cycle of R-HD-MTX plus len at the MTD. Patients who present any clinical benefit from induction with at least stable disease by International PCNSL Collaborative Group response criteria are eligible for maintenance - twelve 28-day cycles of therapy with len 15 mg PO from day 1 to day 21 (regardless of dose during induction) +/- nivo 480 mg i.v. on day 1 (for those who received len and nivo during induction). The primary endpoint of the induction therapy is the MTD of len when given in combination with R-HD-MTX; the primary endpoint of maintenance is its feasibility, defined as the proportion of patients able to remain on maintenance for at least 6 cycles. As of July 2024, 16 patients have been enrolled with a maximum expected sample size of 47 patients with the assumption of 75% of patients being eligible to proceed with maintenance and 50% of those who begin maintenance not progressing in the first 6 cycles. Overall response, adverse events, progression-free and overall survival will be evaluated in all eligible patients with a focus on the outcome of patients treated at the MTD. For patients who consent to biobanking, diagnostic tissue, peripheral blood and CSF from different timepoints are collected and banked with planned exploratory analyses including whole exome sequencing, circulating tumor DNA, proteomics, metabolomics. Support: U10CA180821, U10CA180882. https://acknowledgments.alliancefound.org.

Objective: To assess the effect of a practice-level preoperative frailty screening and optimization toolkit (OPTI-Surg) on postoperative functional recovery and complications in elderly cancer patients undergoing major surgery. Background: Frailty is common in older adults. It increases the risk of poor postoperative functional recovery and complications. The potential for a practice-level screening/optimization intervention to improve outcomes is unknown. Methods: Thoracic, gastrointestinal, and urologic oncological surgery practices within the National Cancer Institute Community Oncology Research Program (NCORP) were randomized 1:1:1 to usual care (UC), OPTI-Surg, or OPTI-Surg with an implementation coach. OPTI-Surg consisted of the Edmonton Frail Scale and guided recommendations for referral interventions. Patients 70 years old or above undergoing curative intent surgery were eligible. The primary outcome was 8 weeks postoperative function (kcal/wk). The key secondary outcome was complications within 90 days. Mixed models were used to compare UC to the 2 OPTI-Surg arms combined. Results: From July 2019 to September 2022, 325 patients were enrolled in 29 practices. One hundred ninety-nine (64 UC, 135 OPTI-Surg) and 279 (78 UC, 201 OPTI-Surg) were evaluable for primary and secondary analysis, respectively. UC and OPTI-Surg patients did not significantly differ in total caloric expenditure (2.2 UC, 2.0 OPTI-Surg) after adjusting for baseline function (P=0.53). UC and OPTI-Surg patients did not significantly differ in postoperative complications (25.6% UC, 35.3% OPTI-Surg, P=0.5). Conclusions: Frailty assessment was successfully performed, but the OPTI-Surg intervention did not improve postoperative function nor reduce postoperative complications compared with UC. Future analysis will explore practice-level factors associated with toolkit implementation and the differences between the coaching and noncoaching arms.

Background: Music therapy (MT) offers benefits of improved symptom relief and quality of life at the end of life, but its impact on hospice patients and caregivers needs more research. Objective: To assess the impact of MT intervention on symptom burden and well-being of hospice patients and caregivers. Methods: A total of 18 hospice patients, selected based on scores ≥4 on the revised Edmonton Symptom Assessment System (ESAS-r) items on pain, depression, anxiety, or well-being, participated in MT sessions provided by a board-certified music therapist. Over a period of 2-3 weeks, 3-4 MT sessions were conducted for each. Patient Quality of life (QOL) was assessed using the Linear Analogue Self-Assessment (LASA). Depression and anxiety were measured with the Patient Health Questionnaire-4 (PHQ-4). For the 7 caregivers enrolled, stress levels were measured using the Pearlin role overload measure and LASA. Results: Patients reported a reduction in symptom severity and emotional distress and an increase in QOL. All patients endorsed satisfaction with music therapy, describing it as particularly beneficial for stress relief, relaxation, spiritual support, emotional support, and well-being. Scores on overall QOL and stress were worse for caregivers. Conclusion: This study provides evidence that MT reduces symptom burden and enhances the quality of life for hospice patients. Hospice patients and their caregivers endorsed satisfaction with MT. Given the benefits observed, integrating MT into hospice care regimens could potentially improve patient and caregiver outcomes. Larger studies should be conducted to better assess the impact of MT in this population.

Importance Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)–positive/ERBB2 (formerly HER2)–negative breast cancer. However, the combination has not been tested in early-stage disease. Objective To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone. Design, Setting, and Participants A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or >66%)/ERBB2-negative breast cancer were included. All analyses were based on data frozen on March 2, 2023. Interventions Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively. Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery. Main Outcomes and Measures The primary outcome was the endocrine-sensitive disease rate (ESDR). A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression). Results Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled. Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively. Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression. The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively. Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%. PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors. A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], −90.4% [−95.2 to −81.9%] vs −76.7% [−89.0 to −55.6%]; P < .001), but not luminal A tumors. Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%. Conclusions and Relevance In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer. Aromatase inhibition remains the standard-of-care NET. Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation. Trial Registration ClinicalTrials.gov Identifier: NCT01953588

370 Background: Mounting evidence suggests tailored preparation targeting geriatric vulnerabilities can improve functional outcomes after major surgery in older adults. Although many surgeons express interest in surgical optimization of older patients, few practices have the time or expertise to deliver geriatric prehabilitation before surgery. This study investigated the effectiveness of OPTI-Surg, a frailty prehabilitation toolkit, for improving surgical outcomes. In this abstract, we report adherence to the OPTI-Surg toolkit in the intervention arm. Methods: Thoracic (T), gastrointestinal (GI), and urologic (GU) oncological surgery practices affiliated with NCI’s Community Oncology Research Program (NCORP) were randomized 1:1:1, stratified by practice type, to usual care (control), OPTI-Surg toolkit, or OPTI-Surg with an implementation coach. The toolkit was implemented at the practice level and consisted of the 12-item Edmonton Frail Scale (EFS) and guided recommendations for interventions including referrals directed at identified vulnerabilities. Eligible patients were ≥70 years old and undergoing curative intent surgery for T, Gl, or GU cancers. Results: From July 2019 to October 2021, 155 patients were enrolled in the OPTI-Surg intervention arm. The EFS was administered to 153 (98.7%) of the enrolled patients, 143 of whom went on to have surgery. Overall, 134 (93.7%) surgical patients had at least one deficit identified on the EFS assessment and 55 (41.0%) of these patients received a recommended referral intended to optimize surgical outcomes. Among the 55 patients who received referrals, 44 (80.0%) followed through on the referral. Individual deficit rates were highest for medication use, general health status, and functional performance, and referrals were most frequently made for deficits in continence and functional independence (Table). Conclusions: In the OPTI-Surg geriatric surgical optimization trial, implementation of the frailty screening with the EFS assessment was successful. Rates of recommended referrals for patients with identified deficits, however, were low. When referred, most patients followed through for targeted prehabilitation. Clinical trial information: NCT03857620 .[Table: see text]

1541 Background: Frailty is common in older adults undergoing major cancer surgery. Mounting evidence indicates multimodal interventions to optimize patient functional status by addressing vulnerabilities associated with frailty before surgery result in decreased complications and enhanced functional recovery. This study tested the effectiveness of OPTI-Surg, a surgical prehabilitation toolkit for improving surgical care and outcomes in older patients undergoing major cancer surgery. Here, we report results from the planned futility interim analysis (IA). Methods: Thoracic (T), gastrointestinal (GI), and urologic (GU) oncological surgery practices affiliated with NCI’s Community Oncology Research Program were randomized 1:1:1, stratified by practice type, to usual care (control), OPTI-Surg toolkit, or OPTI-Surg with an implementation coach. The toolkit was implemented at the practice level. It consisted of the 12-item Edmonton Frail Scale and guided recommendations for interventions directed at identified vulnerabilities. Eligible patients were adults ≥70 years old undergoing curative intent surgery for lung, gastrointestinal, or urologic cancers. Primary outcome was 8-week post-operative function (weekly caloric expenditure) derived from the validated Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire. A linear mixed model was used to compare usual care to the 2 OPTI-Surg arms combined, controlling for baseline function. Results: From July 2019 to October 2021, 225 patients, 50% of the total accrual goal, were enrolled from 29 practices, triggering the IA. Study was suspended to new patient accrual March to June 2020 due to the COVID-19 pandemic. There were no differences in demographics by arm (mean age 76.2 years; 46.4% women; 79.6% white; 20.4% lung resection, 69.8% major GI surgery, 9.8% total cystectomy). Of the 225 patients, 140 (47 Usual Care, 93 OPTI-Surg) were evaluable for the IA. There was no significant difference in post-operative function between OPTI-Surg and usual care (mean decrease of 0.59 kCal/week for OPTI-Surg patients and 0.19 kCal/week for usual care patients, p = 0.762, intraclass correlation = 0.033). Based on the futility analysis, the DSMB recommended closure of recruitment on September 16, 2022. Conclusions: Implementation of the OPTI-Surg toolkit did not significantly improve functional outcomes 8 weeks after surgery for patients aged 70 and older undergoing major cancer surgery compared to usual care. Future analysis of implementation and ethnographic data may identify reasons why significant differences between the intervention and usual care arms were not observed, potentially including disruptions due to the COVID-19 pandemic. Clinical trial information: NCT03857620 .

PURPOSE Patients with bulky stage I/II classic Hodgkin lymphoma (cHL) are typically treated with chemotherapy followed by radiation. Late effects associated with radiotherapy include increased risk of second cancer and cardiovascular disease. We tested a positron emission tomography (PET)–adapted approach in patients with bulky, early-stage cHL, omitting radiotherapy in patients with interim PET-negative (PET−) disease and intensifying treatment in patients with PET-positive (PET+) disease. METHODS Eligible patients with bulky disease (mass > 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray) received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by interim fluorodeoxyglucose PET (PET2). Patients with PET2–, defined as 1-3 on the 5-point scale, received four additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Patients with PET2+ received four cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone followed by 30.6 Gy involved-field radiation. RESULTS Of 94 evaluable patients, 53% were female with median age 30 years (range, 18-58 years). Eight-five (90%) had stage II disease, including 48 (51%) with stage IIB/IIBE. Seventy-eight (78%) were PET2– and 21 (22%) were PET2+. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia and one developing sepsis. The primary end point of 3-year progression-free survival (PFS) was 93.1% in PET2– and 89.7% in PET2+ patients. Three-year overall survival was 98.6% and 94.4%, respectively. The estimated hazard ratio comparing PFS of patients with PET2+ and patients with PET2− was 1.03 (85% upper bound 2.38) and was significantly less than the null hypothesis of 4.1 (one-sided P = .04). CONCLUSION Our study of PET-adapted therapy in bulky stage I/II cHL met its primary goal and was associated with an excellent 3-year PFS rate of 92.3% in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.

PURPOSE Bone marrow biopsies (BMB) are performed before/after therapy to confirm complete response (CR) in patients with lymphoma on clinical trials. We sought to establish whether BMB add value in assessing response or predict progression-free survival (PFS) or overall survival (OS) outcomes in follicular lymphoma (FL) subjects in a large, multicenter, multitrial cohort. METHODS Data were pooled from seven trials of 580 subjects with previously untreated FL through Alliance for Clinical Trials in Oncology (Alliance) and SWOG Cancer Research Network (SWOG) completing enrollment from 2008 to 2016. RESULTS Only 5/580 (0.9%) had positive baseline BMB, CR on imaging, and subsequent positive BMB ( P < .0001). Therefore, BMB were irrelevant to response in 99% of subjects. A sensitivity analysis of 385 FL subjects treated on an Eastern Cooperative Oncology Group study was included. In the Eastern Cooperative Oncology Group cohort, 5/385 (1.3%) had BMB that affected response assessment. Since some subjects do not undergo confirmatory BMB, we performed a landmark survival analysis from first radiologic CR with data from 580 subjects from Alliance and SWOG. Of subjects with CR on imaging (n = 187), PFS and OS were not significantly different among those with negative BMB to confirm CR (n = 47) versus those without repeat BMB (n = 140; PFS: adjusted hazard ratio, 1.10, 95% CI, 0.62 to 1.94, log-rank P = .686; OS: hazard ratio, 0.59, 95% CI, 0.23 to 1.53, log-rank P = .276). CONCLUSION We conclude that BMB add little value to response assessment in subjects with FL treated on clinical trials and we recommend eliminating BMB from clinical trial requirements. BMB should also be removed from diagnostic guidelines for FL except in scenarios in which it may change management including confirmation of limited stage and assessment of cytopenias. This would reduce cost, patient discomfort, resource utilization, and potentially remove a barrier to trial enrollment.

Abstract Introduction: The ALTERNATE trial randomized postmenopausal women with ER Allred 6-8 HER2- breast cancer to 6 months of NET with anastrozole (A), fulvestrant (F) or the combination (A+F). Biopsies were taken preNET and after 4-weeks(wks). Patients with Ki67 values &gt;10% at 4-wks were offered triage to neoadjuvant chemotherapy. Patients with on-treatment Ki67 ≤ 10% who completed NET underwent surgery and Ki67 was reassessed. The primary endpoint was endocrine-sensitive disease rate (ESDR). ESD is defined as pCR or PEPI-0 residual disease (pT1-2, pN0, Ki67 ≤ 2.7%). We previously reported that the ESDR difference between the F-containing arms and the A arm was not &gt;10% (ASCO 2020) and that baseline RNA-seq-based intrinsic subtypes predicted outcomes overall (SABCS 2021). Herein we describe relationships between PAM50 intrinsic subtype and Ki67 values by treatment arm because comparative drug effectiveness in adjuvant endocrine therapy studies in ER+ HER2- breast cancer can be predicted by the degree of Ki67 suppression (PMC3518447). Methods: 743 of the 1297 eligible patients (A: 264; F: 231; A+F: 248) had RNA extracted from preNET frozen tumor biopsies with &gt;50% tumor content and subjected to RNA seq. Intrinsic subtypes were then assigned as LumA, LumB, and NonLum (Basal or HER2-E) using open-source PAM50-based informatics. Differences in the proportion with wk4 Ki67 &gt; 10%, % change in wk4 ki67, and surgical CCCA (Ki67 ≤ 2.7%) rate (sxCCCA) between treatments and by intrinsic subtype was assessed using stratified logistic regression, Wilcoxon rank sum test, and Fisher’s exact test, respectively. Analysis of sxCCCA excluded those who failed to complete NET for reasons other than disease progression or early Ki67 &gt;10%. Results: Amongst the 358 LumA cases there were no significant differences in Ki67-based endpoints between treatments. Among the 292 LumB cases, the wk4 ki67 &gt; 10% rate was lower with A+F (19.4%) than A (43%) (P=0.0002) and was somewhat lower in F (31%) versus A (P=0.076). The % change in wk4 Ki67 in LumB cases, adjusted for baseline Ki67, showed markedly superior suppression for A+F versus A (-90% vs. -77%; P=&lt;0.0001) and versus F (-90% vs. -80%; P=0.0026). Furthermore sxCCCA rates were significantly higher with A+F than A (53% vs. 25% P = &lt;0.0001) and somewhat higher for F (37%) than A (p=0.068), indicating that superior antiproliferative effects for A+F persist after 6 months on therapy. Lack of Ki67 suppression in response to treatment was observed in the majority of 43 NonLum samples regardless of treatment. Conclusion: The combination of A+F was significantly more effective than either drug alone for the control of LumB breast cancer cell proliferation. This suggests that A+F may be a more effective adjuvant endocrine therapy than A alone in LumB disease. The lower Ki67 suppression with A alone also suggests that poorer outcome in some LumB tumors may be due to insufficient ER targeting rather than ER-independent tumor growth Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG), NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. (MJE) CPRIT RR140033, P50-CA186784, P50-CA58223, U01-CA214125, U24-CA210954, Gift from Ralph and Lisa Eads, McNair Scholarship. ClinicalTrials.gov Identifier: NCT01953588 Citation Format: Matthew J. Ellis, Meenakshi Anurag, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard Gibbs, Souzan Sanati, Kiran Vij, Mark Watson, Travis Dockter, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erica Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J. Hieken, Yang Wang, A. Marilyn Leitch, Gary W. Unzeitig, Eric Winer, Anna Weiss, Kelly Hunt, Ann H. Partridge, Charles M. Perou, Vera Suman, Cynthia X. Ma, Lisa A. Carey. The effect of intrinsic subtype on inhibition of tumor growth by anastrozole vs. fulvestrant vs. the combination: Results from the Alliance neoadjuvant endocrine therapy (NET) ALTERNATE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT026.

6602 Background: Treatment advances have greatly improved survival and quality of life among blood cancer patients, yet significant financial costs are a growing concern. Methods: We conducted an observational, prospective survey in 2019-2020 to estimate the self-reported prevalence of financial difficulty among multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients and identify sociodemographic correlates of financial difficulty. Patients with an MM or CLL diagnosis >/= 18 years of age were recruited from NCI NCORP sites of care. Financial difficulty was measured in a previously validated single question from the EORTC QLQ C30 and a composite measure of five questions from the EORTC QLQ C30. Results: 521 MM and CLL patients were registered to the study, 416 patients were administered all or part of the patient survey, for an overall response rate of 79.8%. 16.8% of respondents reported experiencing financial difficulty in response to the single item question and 58.6% reported experiencing financial difficulty in response to the composite measure. Respondents reporting financial difficulty to both measures had reported household incomes of less than $60,000, identified their highest education levels as a high school diploma or GED, had more than one medical comorbidity and used an expensive oral chemotherapeutic agent to treat their blood cancer. Conclusions: Blood cancer patients treated at NCI NCORP sites are experiencing financial difficulties. Results of this study aim to inform physician, site of care and policy efforts to improve access among cancer patients. Clinical trial information: NCT03870633. [Table: see text]