Brain metastases (BrM) are among the most common neurologic complications of cancer. In fact, up to 40% of patients with a metastatic malignant tumor will develop BrM during their lifetime. 1 Historically, patients with BrM have been excluded from clinical trials due to concerns about poor prognosis and increased risk of neurologic toxic effects. 2 This has resulted in a scarcity of evidence for the efficacy of systemic therapies in the central nervous system (CNS). Our objective was to determine the proportion of phase 3 clinical trials investigating a systemic therapy intervention for patients with metastatic breast cancer, lung cancer, and melanoma that included patients with BrM and/or evaluated CNS-specific end points.Methods | A search was conducted on January 19, 2020, using the online, publicly accessible ClinicalTrials.gov database to identify eligible studies. Details regarding search terms, inclusion/exclusion criteria, and statistical methods are outlined in the Supplement. Patient consent was waived due to the deidentified nature of the data analyzed. The Sunnybrook Health Sciences Centre Research Ethics Board determined that ethical review was not required for the use of publicly available data.

This systematic review examines the proportion of patients with leptomeningeal disease included in phase 3 randomized clinical trials for patients with metastatic breast cancer, lung cancer, and melanoma.

Introduction: Leptomeningeal disease (LMD) is a late complication of metastatic cancer that significantly limits patient survival. LMD is most prevalent in patients with melanoma, lung, and breast cancer, with incidence reaching 24.1% among those treated for brain metastases with both surgery and radiotherapy. As systemic treatment advances in oncology continue to improve patient survival, the incidence of LMD is expected to rise. This necessitates increased efforts to identify effective LMD therapies. Further, recent reporting of focal LMD in asymptomatic patients indicates that unique categories of LMD exist which may not necessarily portend a dismal prognosis. Unfortunately, exclusion of these patients from clinical trials has resulted in a paucity of high-quality evidence to guide management in this patient population. We therefore conducted a systematic review to determine the proportion and characteristics of phase III randomized clinical trials in breast cancer, lung cancer, and melanoma that included patients with LMD and/or included LMD-specific outcomes. Methods: The online ClinicalTrials.gov database was searched on December 22, 2020 for eligible phase III randomized control trials. No time limits were applied. The 1619 search results were screened by two independent reviewers for randomized, multi-arm therapeutic trials in advanced breast cancer, lung cancer, or melanoma. Results: 245 trials were included in this review, 75/245 (30.6%) of which included LMD-specific enrollment criteria. 67/245 (27.3%) trials explicitly excluded all patients with LMD, while 8 trials (3.3%) allowed conditional enrollment of patients with LMD; these stipulated that LMD must be asymptomatic/stable, and in some cases, treated. All 8 trials which conditionally allowed LMD patients to enroll were lung cancer trials. No temporal trend towards LMD inclusion was noted. CNS-specific outcomes, which did not include specific mention of LMD, were noted in 13/245 (5.4%) trials, 2 (15.4%) of which used standardized response criteria. No trials included LMD-specific outcomes. Conclusion: In this review, high rates of LMD exclusion and a complete lack of LMD-specific outcomes were noted in phase III trials for advanced breast cancer, lung cancer, and melanoma, despite these cancers carrying the highest risks of LMD. Lung cancer trials were most likely to include patients with LMD; this may be due to differences in tumor biology, drug penetration in the CNS and drug efficacy. Standardized and validated measures should be integrated into clinical trial design to facilitate inclusion of these patients when feasible and allow for meaningful assessment of LMD response to therapy. Table 1: Trial factors associated with exclusion of patients with leptomeningeal metastases a.based on study start date listed on clinicaltrials.gov, defined as “the actual date on which the first participant was enrolled in a clinical study.” b.based on studies with known location. Statistical test was between intercontinental versus single continent studies. Citation Format: Alisha Sharma, Kathryn Corbett, Maleeha Qazi, Hany Soliman, Arjun Sahgal, Sunit Das, Mary Jane Lim-Fat, Gregory R. Pond, Katarzyna Jerzak. Inclusion of Patients with Leptomeningeal Disease in Phase III Randomized Clinical Trials of Patients with Advanced Breast Cancer, Lung Cancer, and Melanoma: A Systematic Review [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-04.

141 Background: Health behaviors including tobacco use, alcohol consumption, and physical activity (PA) can impact outcomes in cancer survivors. While the peri-diagnostic period can be a "teachable moment" for behavior change, patients may face barriers including mental health comorbidities. We have previously identified that patient perceptions of behaviors can influence behavior change. Here, we evaluated the impact of anxiety and depression on patient perceptions of these behaviors. Methods: Cancer patients from all disease sites were surveyed (2016-17) on their smoking, alcohol habits, and PA, and perceptions of the impact of these behaviors on fatigue, survival, and quality of life (QofL). Survey data were linked with same day Edmonton Symptom Assessment Symptom (ESAS) anxiety and depression scores. Logistic regression models evaluated the impact of anxiety and depression on patient perceptions. Results: Of 496, 53% were male; median age, 60 years. At diagnosis, 20% were current smokers, 47% were current drinkers, and 67% were not meeting PA guidelines. 30% screened positive for anxiety (ESAS anxiety > 3) and 34% screened positive for depression (ESAS depression > 2); mean [standard deviation] scores were 1.9 [2.3] for anxiety and 1.5 [2.2] for depression. Most current smokers (> 80%) perceived smoking to negatively impact fatigue, survival and QofL. Smokers screening positive for anxiety were more likely to perceive smoking as harmful on survival (OR=9.09, 95% CI (1.15-100), P=0.04); greater ESAS anxiety scores were associated with perceiving smoking to worsen survival (OR=1.51 per point, 95% CI (1.04-2.17), P=0.03). While those less physically active at diagnosis (> 65%) felt that PA improves fatigue, survival and QofL and half of current drinkers (45%-50%) felt that alcohol worsens outcomes, anxiety and depression were not found associated with perceptions (P > 0.10). Conclusions: Among current smokers, greater anxiety scores and those screening positive for anxiety were more likely to perceive continued smoking as harmful to survival. Mental health comorbidities were not found to have an impact on patient perceptions of the effect of alcohol consumption and PA on fatigue, survival, and QofL.

96 Background: Palliative chemotherapy, the mainstay for incurable eMPM, is offered to patients with good standing performance status (ECOG 0-1). We determined the proportion of eMPM patients experiencing moderate (Mod) to severe (Sev) symptoms while on palliative chemotherapy using ESAS symptom scores at diagnosis and during first and subsequent lines of systemic therapy. Methods: ESAS scores (0=no symptom; 10=worst symptom) were routinely captured in eMPM patients at Princess Margaret (Toronto, Canada). Retrospective chart review collected ESAS, clinical, treatment and outcome data. ESAS scores and proportions were summarized within baseline, firstline, and subsequent lines of therapy. Mod symptom was defined as ESAS scores of 4-6, and Sev as 7-10. ESAS scores between treatment lines were analyzed by Mann-Whitney U tests. Locally weighted smoothing (LOESS) plots assessed ESAS scores over treatment duration. Results: Of 37 palliative eMPM patients, the most frequent baseline symptoms were fatigue (33% Mod, 25% Sev), dyspnea (27% Mod; 17% Sev), anxiety (21% Mod; 21% Sev) and depression (34% Mod; 4% Sev). Overall well-being was poor in 45% of patients (31% Mod; 14% Sev). Compared to baseline, patients on firstline therapy reported increased pain ( p = 0.002), poor appetite ( p = 0.005) and nausea ( p = 0.02); decreased depression ( p = 0.03) and anxiety ( p = 0.006); and stable well-being ( p = 0.27). In patients well enough for subsequent therapy, patients reported reduced drowsiness ( p = 0.01) and improved overall well-being ( p = 0.04) compared to firstline therapy. LOESS plot patterns were similar between firstline and subsequent lines of treatment. Conclusions: eMPM patients had high symptom scores at the time of diagnosis. However, patients’ depression and anxiety decreased when starting initial treatment, and general well-being was stable. Of patients fit enough for subsequent lines of therapy, there were improvements in drowsiness and overall well-being. When selectively used, palliative systemic therapy of all lines are associated with some improved symptoms, but pain, poor appetite, and nausea need to be monitored and managed more effectively.