Efficacy and Safety Analysis of Nelipepimut-S Vaccine to Prevent Breast Cancer Recurrence: A Randomized, Multicenter, Phase III Clinical Trial.

PURPOSE: In phase I/II studies, nelipepimut-S (NP-S) plus GM-CSF vaccine was well tolerated and effectively raised HER2-specific immunity in patients with breast cancer. Results from a prespecified interim analysis of a phase III trial assessing NP-S + GM-CSF are reported. PATIENTS AND METHODS: This multicenter, randomized, double-blind phase III study enrolled females ≥18 years with T1-T3, HER2 low-expressing (IHC 1+/2+), node-positive breast cancer in the adjuvant setting. Patients received 1,000 µg NP-S + 250 µg GM-CSF or placebo + GM-CSF monthly for 6 months, then every 6 months through 36 months. The primary objective was disease-free survival (DFS). Protocol-specified imaging occurred annually. New abnormalities were categorized as recurrence events; biopsy confirmation was not mandated. The interim analysis was conducted as specified in the protocol after 73 DFS events. RESULTS: A total of 758 patients (mean age 51.8 years) were randomized. Adverse events were similar between groups; most common were injection-associated: erythema (84.3%), induration (55.8%), and pruritus (54.9%). There was no significant between-arms difference in DFS events at interim analysis at median follow-up (16.8 months). In the NP-S arm, imaging detected 54.1% of recurrence events in asymptomatic patients versus 29.2% in the placebo arm (P = 0.069). CONCLUSIONS: NP-S was well tolerated. There was no significant difference in DFS events between NP-S and placebo. Use of mandated annual scans and image-detected recurrence events hastened the interim analysis contributing to early trial termination.

Feasibility of using a pragmatic trials model to compare two primary febrile neutropenia prophylaxis regimens (ciprofloxacin versus G-CSF) in patients receiving docetaxel-cyclophosphamide chemotherapy for breast cancer (REaCT-TC).

PURPOSE: Optimal primary febrile neutropenia (FN) prophylaxis (i.e. ciprofloxacin or granulocyte-colony stimulating factors [G-CSF]) for patients receiving docetaxel-cyclophosphamide (TC) chemotherapy is unknown. We assessed the feasibility of using a novel pragmatic comparative effectiveness trial to compare these standard-of-care options. METHODS: Early-stage breast cancer patients receiving TC chemotherapy were randomised to either ciprofloxacin or G-CSF. Trial methodology consists of broad eligibility criteria, simply-defined endpoints, integrated consent model incorporating oral consent, and web-based randomisation in the clinic. Primary feasibility endpoints included patient and physician engagement (if > 50% of patients approached agree to participate and if > 50% of physicians approached patients for the study). Secondary clinical endpoints included the following: first occurrence rates of FN, treatment-related hospitalisation, or chemotherapy dose reduction/delay/discontinuation, as well as patient satisfaction with the oral consent process. RESULTS: Of 204 patients approached, 91.2% (186/204) agreed to randomisation. Sixteen of twenty (80%) participating medical oncologists randomised patients. Median patient age was 57.7 (range 31.8-84.1). The 186 patients received 557 cycles of chemotherapy. Overall incidences of first events by patient (n = 186) were as follows: FN (18/186, 21.43%), treatment-related hospitalisation (11/186, 13.10%), chemotherapy reduction (19/186, 22.62%), chemotherapy discontinuation (16/186, 19.05%), and chemotherapy delays (5/186, 5.95%). A total of 37.77% (69/186) of patients and 12.39% (69/557) of chemotherapy cycles had at least one of these first events. Patients were highly satisfied with the oral consent process. CONCLUSION: This study met its feasibility endpoints. This model offers a means of comparing standard-of-care treatments in a practical and cost-efficient manner. TRIAL REGISTRATION: Trial registration: ClinicalTrials.gov : NCT02173262.

Impact of Postoperative Adjuvant Chemotherapy Following Long-course Chemoradiotherapy in Stage II Rectal Cancer.

OBJECTIVES: Use of adjuvant chemotherapy (AC) following neoadjuvant chemoradiation (nCRT) is controversial in rectal cancer (RC). We assessed a multi-institutional database to determine if there was benefit from AC for pathologic stage II RC patients and whether the addition of oxaliplatin to fluoropyrimidine (OXAC) therapy impacted outcomes. MATERIALS AND METHODS: We included patients who underwent nCRT and had pathologic stage II (ypT3/4 ypN0) tumors. Disease-free survival and overall survival were assessed. Multivariate Cox models adjusting for age, sex, Eastern Cooperative Oncology Group, high-risk features (pT4, poor differentiation, <12 nodes removed, lymphovascular/perineural invasion, or obstruction/perforation), and clinical stage were constructed. RESULTS: Of 485 patients, 73.6% received AC, of which 25.5% received OXAC. Patients receiving AC were younger (median age 61 vs. 64; P=0.003) and had higher rates of total mesorectal excision (81.5% vs. 78.9%; P=0.049), but had similar high-risk features, performance status, clinical stage, margin status, preoperative carcinoembryonic antigen, and nCRT regimen. In univariate analysis, overall survival was improved with fluoropyrimidine AC compared with no AC or OXAC (P=0.049), but not disease-free survival (P=0.33). In multivariate analysis, any AC, fluoropyrimidine AC, or OXAC did not improve outcomes. After stratifying patients by the presence of high-risk features, elevated carcinoembryonic antigen, margin status, or preoperative clinical stage, we did not identify a group with improved outcomes following AC. CONCLUSIONS: In this multi-institutional cohort of yp stage II RC patients, we failed to identify a group that derives benefit from AC following nCRT. The addition of oxaliplatin did not appear to improve outcomes when compared with fluoropyrimidine alone.

PROSPECT Eligibility and Clinical Outcomes: Results From the Pan-Canadian Rectal Cancer Consortium.

BACKGROUND: The PROSPECT trial (N1048) is evaluating the selective use of chemoradiation in patients with cT2N1 and cT3N0-1 rectal cancer undergoing sphincter-sparing low anterior resection. We evaluated outcomes of PROSPECT-eligible and -ineligible patients from a multi-institutional database. PATIENTS AND METHODS: Data from patients with locally advanced rectal cancer who received chemoradiation and low anterior resection from 2005 to 2014 were retrospectively collected from 5 Canadian centers. Overall survival, disease-free survival (DFS), recurrence-free survival (RFS), and time to local recurrence (LR) were estimated using the Kaplan-Meier method, and a multivariate analysis was performed adjusting for prognostic factors. RESULTS: A total of 566 (37%) of 1531 patients met the PROSPECT eligibility criteria. Eligible patients were more likely to have better PS (P = .0003) and negative circumferential resection margin (P < .0001). PROSPECT eligibility was associated with improved DFS (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.61-0.91), overall survival (HR, 0.73; 95% CI, 0.57-0.95), and RFS (HR, 0.68; 95% CI, 0.54-0.86) in univariate analyses. In multivariate analysis, only RFS remained significantly improved for PROSPECT-eligible patients (HR, 0.75; 95% CI, 0.57-1.00, P = .0499). The 3-year DFS and freedom from LR for PROSPECT-eligible patients were 79.1% and 97.4%, respectively, compared to 71.1% and 96.8% for PROSPECT-ineligible patients. CONCLUSION: Real-world data corroborate the eligibility criteria used in the PROSPECT study; the criteria identify a subgroup of patients in whom risk of recurrence is lower and in whom selective use of chemoradiation should be actively examined.

Predictors of Pathologic Complete Response After Neoadjuvant Treatment for Rectal Cancer: A Multicenter Study.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) for rectal cancer is associated with better long-term outcomes, and is used as an early indicator of response to novel agents. To assess the rate and predictors of pCR, we performed a retrospective multicenter study involving 5 Canadian cancer centers. PATIENTS AND METHODS: Cancer registries identified consecutive patients with locally advanced rectal adenocarcinoma from the Tom Baker Cancer Centre, Cross Cancer Institute, British Columbia Cancer Agency, Ottawa Hospital Cancer Centre, and the Dr H. Bliss Murphy Cancer Centre who received fluoropyrimidine-based CRT and had curative intent surgery from 2005 to 2012. Patient, tumor, and therapy characteristics were correlated with response. RESULTS: Of the 891 patients included, 885 patients had pCR data available. Of the included patients, 161 (18.2%) had a pCR to CRT, and 724 (81.8%) did not. Patients with a pCR had a lower pretreatment carcinoembryonic antigen (CEA) level, and higher hemoglobin level in univariate analysis. In multivariable analysis, statin use at baseline (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.02-2.92; P = .04), lower pretreatment CEA level (OR, 1.03; 95% CI, 1.01-1.06; P = .03), and distance closer to anal verge (OR, 1.07; 95% CI, 1.01-1.15; P = .04) were significant predictors of pCR. The 3-year disease-free survival was 86% in those with a pCR versus 62.5% in those without a pCR (P < .0001) and pCR was associated with improved overall survival (hazard ratio, 0.29; 95% CI, 0.17-0.51; P < .0001). CONCLUSION: Lower pretreatment CEA level, proximity to anal verge, and statin use are predictors of pCR in our large retrospective cohort. Clinical trials to investigate statins combined with neoadjuvant CRT might be warranted.

Atypical reversible posterior leukoencephalopathy syndrome (RPLS) induced by cediranib in a patient with metastatic rectal cancer.

BACKGROUND: Reversible posterior leukoenecphalopathy syndrome (RPLS) is a rare clinicoradiologic syndrome characterized by neurologic symptoms such as seizures, headaches, visual abnormalities, confusion and encephalopathy, accompanied by vasogenic edema of posterior white matter seen on neuroimaging. It has been reported in association with many anti-angiogenic therapies, including bevacizumab, sunitinib, sorafenib, pazopanib and regorafenib. Cediranib is a potent, orally available small molecule tyrosine kinase inhibitor with anti-angiogenic activity, which has been shown to have activity against various solid tumors. CASE REPORT: We present a case of a 65 year old male with metastatic adenocarcinoma of the rectum who received cediranib as part of a phase I clinical trial. He developed confusion and fluctuations in his level of consciousness. MRI of the brain revealed diffuse low level T2 signal abnormality in the cerebral peduncles, pons, and medulla and patchy T2 signal in both thalami, consistent with RPLS. With conservative management, including tight blood pressure control, his symptoms improved and MRI findings resolved. CONCLUSION: RPLS is a rare, but serious, clinicoradiologic syndrome which has been described as an adverse effect of many anti-angiogenic agents and should also be considered in patients on cediranib who present with neurologic symptoms along with vasogenic edema seen on MRI. If RPLS is suspected, cediranib should be discontinued and blood pressure should be aggressively controlled.

Impact of a dedicated cancer center surveillance program on guideline adherence for patients with stage II and III colorectal cancer.

UNLABELLED: Surveillance after curative treatment for stage II/III colorectal cancer identifies surgically resectable disease and improves survival. We evaluated adherence to guidelines and outcomes for 408 patients enrolled in an innovative follow-up program at our cancer center. We found that a dedicated intensive surveillance program can impact adherence to guidelines for patients with colorectal cancer. BACKGROUND: Our aims were to evaluate adherence to guidelines on colorectal cancer surveillance and outcomes for patients enrolled in an innovative follow-up program at our cancer center. PATIENTS AND METHODS: A retrospective chart review was conducted at the Cross Cancer Institute in Edmonton, Canada. Patients with stage II/III colorectal cancer who completed treatment and who entered into the program from December 1, 2007, to December 31, 2009, were identified. The minimum standard of care follow-up was defined as (1) carcinoembryonic antigen (CEA) testing every 120 days for 3 years; (2) computed tomography of chest, abdomen, and pelvis at 10 to 14 months and 22 to 26 months after surgery; and (3) colonoscopy within 14 months of surgery. RESULTS: A total of 408 patients met inclusion criteria. Two hundred (49.0%) patients were adherent to all 3 components of surveillance. Among all patients, 57 (14.0%) were nonadherent to computed tomography imaging, 135 (33.1%) were nonadherent to colonoscopy, and 96 (23.5%) were nonadherent to CEA testing. Determinants of nonadherence are described. In total, 192 (47.2%) patients had an abnormal surveillance investigation that led to 307 follow-up events. After a median of 1.6 years, 69 (16.9%) patients had documented tumor recurrence. Sixty-one (88.4%) of these 69 patients had recurrence diagnosed via surveillance, and 31 (44.9%) patients were considered potentially resectable. CONCLUSIONS: Our study demonstrated an improvement in CEA testing since the program began; however, adherence rates for all components are not yet optimal. Alterations to surveillance program management are outlined. Further investigation will determine whether intense follow-up improves patient survival locally.