Abstract: Patients with chronic kidney disease are commonly excluded from clinical trials. The impact of chronic kidney disease on outcomes in patients with locally advanced rectal cancer has not been previously studied. OBJECTIVE: This study aimed to investigate the impact of chronic kidney disease on outcomes in patients with locally advanced rectal cancer. DESIGN: This is a multi-institutional, retrospective cohort study. SETTINGS: This study was conducted at academic and community cancer centers participating in the Canadian Health Outcomes Research Database Consortium Rectal Cancer Database. PATIENTS: Consecutive patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation before curative-intent surgery from 2005 to 2013 were selected. MAIN OUTCOME MEASURES: Disease-free survival, overall survival, pathologic complete response, and neoadjuvant chemotherapy/radiotherapy completion rate were the primary outcomes measured. RESULTS: A total of 1254 patients were included. Median age was 62, and 29%/69% had clinical stage II and III disease. Median estimated creatinine clearance was 93 mL/min, with 11% 〈 60 mL/min (n = 136). There was no significant difference in the completion rate of neoadjuvant chemotherapy (82% vs 85%, p = 0.36) or radiotherapy (93% vs 95%, p = 0.45) between patients with and without chronic kidney disease. Patients with chronic kidney disease were less likely to receive adjuvant chemotherapy (63% vs 77%, p 〈 0.01). On multivariate analysis, patients with chronic kidney disease had decreased disease-free survival (HR, 1.37; 95% CI, 1.03–1.82; p = 0.03) but not overall survival (HR, 1.23; 95% CI, 0.88–1.75; p = 0.23) or pathologic complete response (OR, 0.83; 95% CI, 0.50–1.39; p = 0.71). LIMITATIONS: This study was limited by its retrospective design and by limited events for overall survival analysis. CONCLUSIONS: In patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation, baseline chronic kidney disease was associated with less use of adjuvant chemotherapy and decreased disease-free survival. Chronic kidney disease was not independently associated with neoadjuvant chemotherapy/radiotherapy completion rate, pathologic complete response, or overall survival. These data suggest that patients with locally advanced rectal cancer with chronic kidney disease may have distinct outcomes and, accordingly, the results of landmark clinical trials may not be generalizable to this population. See Video Abstract at http://links.lww.com/DCR/B694. LA REPERCUSIÓN DE LA ENFERMEDAD RENAL CRÓNICA EN PACIENTES CON CÁNCER DE RECTO LOCALMENTE AVANZADO TRATADOS CON QUIMIORRADIOTERAPIA NEOADYUVANTE ANTECEDENTES: Los pacientes con enfermedad renal crónica generalmente se excluyen de los ensayos clínicos. La repercusión de la enfermedad renal crónica en el desenlace en pacientes con cáncer de recto localmente avanzado no se ha estudiado previamente. OBJETIVO: Investigar la repercusión de la enfermedad renal crónica en los desenlaces en pacientes con cáncer de recto localmente avanzado. DISEÑO: Estudio de cohorte retrospectivo multiinstitucional. ESCENARIO: Centros oncológicos académicos y comunitarios que participan en la base de datos de cáncer rectal del consorcio CHORD. PACIENTES: Pacientes consecutivos con cáncer de recto localmente avanzado, tratados con quimiorradioterapia neoadyuvante, previa a la cirugía con intención curativa del 2005 al 2013. PRINCIPALES VARIABLES EVALUADAS: Sobrevida libre de enfermedad, sobrevida global, respuesta patológica completa, tasa de conclusión de quimioterapia / radioterapia neoadyuvante. RESULTADOS: Se incluyeron 1254 pacientes. El promedio de edad fue de 62, y el 29% / 69% tenían enfermedad en estadio clínico II y III, respectivamente. El promedio de la depuración de creatinina estimada fue de 93 mililitros / minuto, con un 11% 〈 60 mililitros / minuto (n = 136). No hubo diferencias significativas en la tasa de conclusión de la quimioterapia neoadyuvante (82% vs 85%, p = 0,36) o radioterapia (93% vs 95%, p = 0,45) entre pacientes con y sin enfermedad renal crónica. Los pacientes con enfermedad renal crónica tenían menos probabilidades de recibir quimioterapia adyuvante (63% contra el 77%, p 〈 0,01). En el análisis multivariado, los pacientes con enfermedad renal crónica tenían una sobrevida libre de enfermedad menor (HR 1,37, IC 95% 1,03-1,82, p = 0,03) pero no en la sobrevida global (HR 1,23, IC 95% 0,88-1,75, p = 0,23) o respuesta patológica completa (OR 0,83, IC 95% 0,50-1,39, p = 0,71). LIMITACIONES: Diseño retrospectivo y acontecimientos limitados para el análisis de sobrevida global. CONCLUSIONES: En pacientes con cáncer de recto localmente avanzado tratados con quimiorradioterapia neoadyuvante, la enfermedad renal crónica de base se asoció con un menor uso de quimioterapia adyuvante y una menor sobrevida libre de enfermedad. La enfermedad renal crónica no se asoció de forma independiente con la tasa de conclusión de la quimioterapia / radioterapia neoadyuvante, la respuesta patológica completa o la sobrevida global. Estos datos sugieren que los pacientes con cáncer de recto localmente avanzado con enfermedad renal crónica pueden tener resultados distintos y, en consecuencia, los resultados de los ensayos clínicos de referencia pueden no ser generalizables a esta población. Consulte Video Resumen en http://links.lww.com/DCR/B694.

Abstract: e13049 Background: Inconsistencies in RCAT EEPs definitions and reporting complicate the evaluation of EEPs as adequate surrogates for overall survival (OS) and the comparison of the EEPs between trials. We aimed to identify issues in reporting and defining of EEPs used in melanoma RCATs. Methods: To identify phase 3 melanoma RCATs published in English language journals from 1994- 2011, a Pubmed database search and systematic review of published meta-analyses were performed. RCAT characteristics and endpoint definitions were obtained. Original protocols were requested. Results: A total of 34 RCATs met the criteria for review. Interferon alone or in combination with another agent was the most commonly tested treatment. Node positive disease was included in 24 studies with 1 including resected metastatic disease. The eligibility criteria in regards to age, previous treatment, and performance status were not reported in 26%, 32%, and 53% of studies respectively. The baseline and follow-up radiological tests were not specified in 35% and 26% of studies respectively. Eight time-to-event (TTE) EEPs were identified, with most studies using more than one (See Table). The primary EEP was not specified 23% of the time. Clear definitions of TTE EEPs start and end time criteria were absent in 58% and 44% of studies, respectively. Conclusions: The inconsistencies in the reporting of EEPs in melanoma RCATs is due to a lack of standardization in their definition and measurement. Standardizing EEPs will reduce resource consumption and enhance the comparison of agents across studies in melanoma RCATs. [Table: see text]

Abstract: e22013 Background: Adjuvant immunotherapies and adjuvant targeted therapy for melanoma became available in clinical practice in 2018 in Alberta, Canada. We describe the delivery of adjuvant systemic therapy, local-regional treatment, recurrence patterns, and treatment toxicity, in tertiary academic centers. Methods: We conducted a retrospective chart review of patients who received adjuvant systemic therapy for melanoma in Alberta. Adjuvant systemic treatment options included Nivolumab, Pembrolizumab, and Dabrafenib/Trametinib. Results: From September 2017 to January 2020, 71 patients were identified. Forty-one (61%) were male with a median age of 60 years (15-88). Seven (9.8%), 26 (36.6%), 27 (38%), 4 (5.6%), and 3 (4.2%) patients were stage IIIA, IIIB, IIIC, III-unspecified, and IV, respectively. BRAF mutations were detected in 31 (50.8%) patients. The median time from last surgical procedure to start of treatment was 10.8 weeks (4-28), with a median follow up time of 12 months. Sixty-one patients (85.9%) received Nivolumab, four (5.6%) patients received Pembrolizumab, and four (5.6%) Dabrafenib/Tremetinib. Twenty-eight (87.5%) of 32 patients with a positive sentinel lymph node biopsy did not complete elective regional lymph node dissection. Only two patients received adjuvant radiation. Local-regional surveillance with regular nodal ultrasound was not consistently performed. Seven (9.8%) patients had clinical or radiographic finding of enlarged regional lymph node while on treatment. At time of analysis, thirteen (18.3%) patients have completed adjuvant therapy, 18 (25.3%) discontinued therapy, and 39 (54.9%) patients were still on treatment. Eleven (15.4%) patients discontinued treatment due to toxicity, 8 (13.1%) from Nivolumab, 3 (75%) from Dabrafenib/Trametinib. Nine (12.6%) patients relapsed on treatment, of those, five (55.5%) had incidental findings on baseline imaging. Hypothyroidism affected 11 (15.4%) patients, hypophysitis and other immune-related side effects were described in 14 (19.7%) cases. Conclusions: Our cohort reflects excellent patient selection and delivery of adjuvant therapy consistent with clinical trial data. Surgical and radiation oncology care has adapted, and differs from trial procedure. Adjuvant immunotherapy was used in most patients. There appears to be a higher rate of discontinuation due to toxicity with Dabrafenib/Trametinib. Toxicity and recurrence findings are preliminary and will be updated.

Abstract: 794 Background: Chronic kidney disease (CKD) and cancer are common with advancing age. CKD may influence drug tolerance/efficacy and is an independent prognostic factor in some cancers. The impact of CKD on outcomes in patients (pts) with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiation (nCRT) has not been previously studied. Methods: We reviewed pts with LARC undergoing nCRT prior to surgery with curative intent from 2005-2013 across 4 Canadian provinces. Data regarding demographics, staging, baseline renal function, treatments and outcome were collected. CKD was defined as having an estimated glomerular filtration rate (eGFR) (Cockroft-Gault) 〈 60 ml/min. Primary endpoints were neoadjuvant treatment completion rate, disease-free survival (DFS), and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for an association between renal function and outcomes. Results: 1122 (71%) of 1580 pts were included for analysis. Median age was 61 (IQR 54-69), 70% male, 84% performance status 0-1. 28% and 68% had clinical stage II and III disease, respectively. Median eGFR was 93 ml/min (IQR 74-114), with 11% 〈 60 ml/min (n = 120). 97% of all pts received ≥ 44 Gy (median 50 Gy [range 20-80]). 53% received 5-fluorouracil and 44% received capecitabine as neoadjuvant chemotherapy (nCT). 84% completed nCT, 95% completed neoadjuvant radiotherapy (nRT), and 76% received adjuvant chemotherapy (aCT). Pts with CKD were less likely to receive aCT (62% vs 78%; p 〈 0.01). There was no significant difference in completion rate of nCT (80% vs 85%; p = 0.15) or nRT (93% vs 95%; p = 0.20) based on renal function. After a median follow up time of 62 months, 8% developed local recurrence, 21% developed distant recurrence and 21% have died. 5-year OS and DFS were 78% and 73%, respectively. Pts with CKD had decreased OS on univariate analysis (HR 1.59, 95% CI 1.11-2.28; p = 0.01), but not on multivariate analysis. DFS was not significantly different based on renal function (HR 1.27, 95% CI 0.89-1.81; p = 0.18). Conclusions: In LARC pts undergoing nCRT, CKD was associated with less use of aCT but did not have any independent association with nCT and nRT completion rate, DFS or OS.

Abstract: 612 Background: Patients with rectal cancer may experience disparities in outcomes due to various socioeconomic (SES) factors. We assessed the impact of SES factors on outcomes in patients with LARC who received neoadjuvant chemoradiation (nCRT) and surgery (Sx) in three Canadian provinces. Methods: Associations between clinical variables, demographics, community characteristics (2015 Canadian Census data), distance and time to the nearest cancer center (mapping software), and outcomes were evaluated. Results: 1,098 patients were included (Table 1). Median follow-up time was 67.8 months. The 5-year survival rate was 0.80 (95% CI 0.77-0.82). Factors predictive of disease-free survival in univariate analysis (UVA) included age, worse performance status (PS), driving time 〉 1 hour, median community income, and driving distance 〉 100 km. Factors that remained significant in multivariate analysis (MVA) included age (HR 1.01; 95% CI 1.00-1.02; p = 0.01), worse PS (HR 1.30; 95% CI 1.01-1.68; p = 0.04) and driving time 〉 1 hour (HR 1.31; 95% CI 1.01-1.71; p = 0.04). Factors predictive of overall survival in UVA included age, worse PS, driving time to the cancer centre 〉 1 hour, median community income, and community proportion with post-secondary education. Factors that remained significant in MVA included age (HR 1.03; 95% CI 1.02-1.04; p 〈 0.001), worse PS (HR 1.41; 95% CI 1.03-1.94; p = 0.03), and median community income (HR 1.00; 95% CI 1.00-1.00; p = 0.05). Conclusions: Outcomes of patients with LARC undergoing nCRT are significantly associated with driving time to the nearest cancer centre and community household income. Further efforts to understand and reduce these socioeconomic disparities are warranted. [Table: see text]

Abstract: 9542 Background: Immune checkpoint blockade (ICB) has revolutionized the treatment of metastatic melanoma (MM). Immune-related Adverse Events (irAEs) associated with ICB have been shown to correlate positively with survival outcomes across solid tumours. In MM, conclusions on the impact of irAE severity have been conflicting, and combination ICB therapy experience is limited to smaller cohorts. We sought to clarify these relationships using the Alberta Immunotherapy Database (AID). Methods: The AID provides a multi-centre, province-wide observational cohort comprising consecutive patients treated with ICB. We included adult patients with MM, treated with ICB (single agent nivolumab or pembrolizumab, or combination ipilimumab and nivolumab) at any line of therapy, agnostic to site of origin, from August 2013 to May 2020, with analysis in December 2021. The primary endpoint of interest was the identification of a relationship between development of irAEs and subsequent overall survival (OS, defined from time of ICB initiation). To minimize immortal time bias from poor prognosis patients who may have died prior to the development of irAEs, patients who died before 12 weeks were excluded from OS and time-to-next-treatment (TTNT) analysis. Adjusted Cox regression analyses were performed to determine the association of variables with OS. Results: Of 492 MM patients receiving ICB, 124 received combination ICB, 198 developed an irAE and 67 required hospitalization for an irAE. irAEs were more common in patients 〈 50 years old (p = 0.02), with ECOG 0 (p 〈 0.001) and normal albumin (p = 0.002). Median time to irAE development (2.6 months) and frequency of individual irAEs were consistent with the published literature. In the overall population, patients who experienced an irAE had longer median OS (56.3 vs 18.5mo, p 〈 0.0001), and TTNT (49.6 vs 12.9mo, p 〈 0.0001). This remained consistent in combination ICB-treated patients (median OS 56.3 vs 19mo, p 〈 0.0001). Patients hospitalized for an irAE had improved OS and TTNT over patients requiring only outpatient treatment (median OS NR vs 27.9mo, p = 0.0039), while ICB re-challenge after an irAE also improved OS (56.3 vs 31.5mo, p = 0.0093). Development of an irAE retained independent association with OS after adjusted multivariable regression (HR 0.376, p 〈 0.001). Conclusions: These data support the association of irAEs and improved survival outcomes in MM, including those patients treated with combination ICB. Among patients with irAE, hospitalization for irAE, and ICB re-challenge post-irAE, were further associated with improved outcomes.