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Background: Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. Limited data suggest a wide variation in cetuximab plasma concentrations after standard dosing regimens. We correlated cetuximab plasma concentrations with survival and toxicity., Methods: The CO. 20 study randomized patients with RAS WT advanced colorectal cancer in a 1:1 ratio to cetuximab 400 mg/m 2 intravenously followed by weekly maintenance of 250 mg/m 2 , plus brivanib 800 mg orally daily or placebo. Blood samples obtained at week 5 precetuximab treatment were analyzed by ELISA. Patients were grouped into tertiles based on plasma cetuximab concentrations. Cetuximab concentration tertiles were correlated with survival outcomes and toxicity. Patient demographic and biochemical parameters were evaluated as co-variables., Results: Week 5 plasma cetuximab concentrations were available for 591 patients (78.8%). The median overall survival (OS) was 11.4 months and 7.8 months for patients in the highest (T3) and lowest tertiles (T1) respectively. On multivariable analysis, plasma cetuximab concentration was associated with OS (HR 0.66, 95% confidence interval [CI]: 0.53-0.83, P < .001, T3 vs. T1), and a trend towards progression-free survival (HR 0.82, 95% CI: 0.66-1.02, P = .07, T3 vs. T1). There was no association between cetuximab concentration and skin toxicity or diarrhea., Conclusion: The standard cetuximab dosing regimen may not be optimal for all patients. Further pharmacokinetic studies are needed to optimize cetuximab dosing given the potential improvement in OS., Competing Interests: Disclosure The authors declare no potential conflicts of interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The safety and efficacy of targeted therapy in older patients (≥ 70 years) with metastatic colorectal cancer is not well evaluated., Patients and Methods: Outcomes of older patients (including overall survival [OS], progression-free survival [PFS], toxicity, and quality of life [QoL]) were compared to young patients using data from 2 large previously reported clinical trials, CO.17 (cetuximab vs. best supportive care) and CO.20 (cetuximab plus placebo vs. cetuximab plus brivanib). Only patients with wild-type KRAS tumors were included., Results: A total of 251 (26.3%) of 955 patients were ≥ 70 years old. No significant differences in OS, PFS, or grade 3/4 adverse events were observed between older and younger patients treated with cetuximab (or cetuximab with placebo) in either trial. Younger patients trended toward superior OS in both CO.17 (hazard ratio = 1.80; P = .16) and CO.20 (hazard ratio = 1.34; P = .07). QoL maintenance favored younger patients in CO.17 (3.6 vs. 5.7 months; P = .046) but no difference of QoL maintenance was observed in the larger CO.20 trial (1.7 vs. 1.8 months; P = .64). Combination therapy of cetuximab and brivanib was significantly more toxic in older adults (87% vs. 77%; P = .03)., Conclusion: OS, PFS, and toxicities were similar between older and younger patients with wild-type KRAS metastatic colorectal cancer when treated with cetuximab. Both age groups likely experience similar QoL maintenance with cetuximab. Dual targeted therapy was significantly more toxic in older patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Oncolytic reovirus pelareorep might preferentially infect and destroy rat sarcoma (RAS)-activated cells, and has preclinical and early clinical activity against colorectal cancer (CRC)., Patients and Methods: After a 6-patient safety run-in, 103 patients with metastatic CRC were randomly assigned to standard first-line leucovorin/5-FU/oxaliplatin (FOLFOX6)/bevacizumab (FOLFOX/BEV) every 2 weeks with (n = 51) or without (n = 52) pelareorep 3 × 10 10 tissue culture infective dose 50 on days 1 to 5 (cycles 1, 2, 4, and alternate cycles thereafter). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), quality of life, and correlative analyses., Results: At 13 months' median follow-up, PFS was inferior in the pelareorep arm (median 7 vs. 9 months; hazard ratio [HR], 1.59 [80% confidence interval (CI), 1.18-2.15]; P = .046). There was no statistical difference in OS (median, 19.2 vs. 20.1 months; HR, 1.22; P = .38). An increased ORR was observed with pelareorep (adjusted odds ratio, 2.52 [80% CI, 1.44-4.41]; P = .03), but with a shorter median duration of response (5 vs. 9 months; P = .028). Pelareorep patients experienced more hypertension and proteinuria, and were more likely to omit bevacizumab before progression. A trend to lower dose intensity and shorter oxaliplatin and bevacizumab treatment duration was observed with pelareorep., Conclusion: Combination pelareorep with FOLFOX/BEV was tolerable with an increased ORR, but PFS was inferior. Subgroup analysis of baseline variables including Kirsten rat sarcoma oncogene did not identify subgroups with PFS benefit. Decreased treatment intensity with standard agents likely contributed to the lack of benefit with pelareorep. Future studies might consider alternate pelareorep/chemotherapy strategies or combination therapy with novel agents., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Anal cancer is uncommon. We reviewed the treatment and outcomes of anal cancer patients in a population referred to the Ottawa Hospital Cancer Centre (TOHCC) over a 12-year period., Methods: A chart review was conducted with patient data collected from hospital records, including: demographic, treatment and outcome information. Outcomes of interest included: overall survival (OS), disease free survival (DFS), and colostomy free survival (CFS)., Results: 180 patients were included in the study population. 72% (n = 130) female and 28% (n = 50) male. 6.7% (n = 12 males) of patients were HIV positive - all were on anti-retroviral therapy. 60% (n = 108) of patients were ever-smokers, mean patient age was 62 [range 35-90] years. The most frequent presenting symptoms were blood per rectum and anal pain. Treatment intent was curative in 87%. Treatment included radiotherapy (94%), brachytherapy (26%), chemotherapy (73%). Among patients treated with curative-intent, 72% had a complete response, 31% had local/regional recurrence, 16% required salvage surgery and 21% had distant recurrence. The colostomy rate was 23%. 5 year overall survival (OS) was not significantly different for patients by HIV status. Survival was superior if MMC-FU was used first vs. CIS-FU; OS HR 0.47 (0.24-0.94), p < 0.033., Conclusions: The outcomes of patients in this large retrospective cohort study are similar to the outcomes of patients in highly selective clinical trials. Five year overall survival and colostomy free survival are encouraging. MMC-FU was found to be superior to CIS-FU., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Cetuximab-induced hypomagnesemia has been associated with improved clinical outcomes in advanced colorectal cancer (CRC). We explored this relationship from a randomized clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pretreated advanced CRC., Patients and Methods: Day 28 hypomagnesemia grade (0 versus ≥1) and percent reduction (<20% versus ≥20%) of Mg from baseline was correlated with outcome., Results: The median percentage Mg reduction at day 28 was 10% (-42.4% to 63.0%) for cetuximab (N = 260) versus 0% (-21.1% to 25%) for BSC (N = 251) [P < 0.0001]. Grade ≥1 hypomagnesemia and ≥20% reduction from baseline at day 28 were associated with worse overall survival (OS) [hazard ratio, HR 1.61 (95% CI 1.12-2.33), P = 0.01 and 2.08 (95% CI 1.32-3.29), P = 0.002, respectively] in multivariate analysis including grade of rash (0-1 versus 2+). Dyspnea (grade ≥3) was more common in patients with ≥20% versus < 20% Mg reduction (68% versus 45%; P = 0.02) and grade 3/4 anorexia were higher in patients with grade ≥1 hypomagnesemia (81% versus 63%; P = 0.02)., Conclusions: In contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor OS, even after adjustment for grade of rash.

Background: Neoadjuvant chemoradiation followed by surgery (NeoCRT) has been advocated as standard therapy for resectable esophageal cancer. Our objective was to compare oncologic outcomes between NeoCRT and upfront surgical resection (SURG)., Methods: We conducted a single-institution, retrospective review of all potentially resectable esophageal cancer patients treated with NeoCRT or SURG., Results: From 2003 to 2010, 151 patients had NeoCRT (n = 48; 31.8%) or SURG (n = 103; 68.1%). Histology was mostly adenocarcinoma (77.5%) or squamous carcinoma (19.2%). Mean radiation dose was 44 ± 0.1 Gy, and 80.8% received platinum-based doublet chemotherapy. There were more women in the SURG group (23.3% vs 4.2%; p < 0.01) and more cardiovascular comorbidity in the NeoCRT group (39.6% vs 21.4%; p = 0.027). There was no difference in age, histology, R0 resection rate, and treatment-related mortality (NeoCRT = 4.2%; SURG = 3.9%; p = 0.15). Failure to undergo resection after NeoCRT (n = 11; 22.9%) was mainly due to disease progression (n = 6) or treatment-related mortality (n = 4). Resection could not be performed in 4 SURG patients (3.9%; p < 0.001; unresectable = 2; occult metastases = 2). NeoCRT did not improve median survival (NeoCRT = 29 ± 6; SURG = 26 ± 3 months; p = 0.376) or recurrence-free interval (NeoCRT = 25.8 ± 5; SURG = 19.4 ± 2 months; p = 0.19). Complete pathologic response (n = 8; 21.6%) was not associated with improved survival. If we exclude from analysis NeoCRT patients who did not undergo surgery, survival was significantly improved after NeoCRT (NeoCRT = 41 ± 15; SURG = 24 ± 8 months; p = 0.0082)., Conclusions: Patient selection and early assessment of treatment response may be key factors in identifying the best candidates for trimodality therapy., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors., Patients and Methods: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD., Results: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts., Conclusion: In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.

Background: the interplay between comorbidity, age and performance status (PS) as predictors of outcome in advanced colorectal cancer (ACRC) is poorly understood. We examined these factors as predictors of treatment toxicity and outcome in cetuximab-treated patients with ACRC., Patients and Methods: comorbidity was independently evaluated using the Charlson Comorbidity Index (CCI), a validated measure of comorbidity based on the presence of medical conditions weighted according to their effect on mortality. CCI score was correlated with clinical and outcome data., Results: five hundred and seventy-two patients were included; 41% were ≥ 65 years and 25% had comorbidities at randomization. In multivariate analysis (MVA) of all covariates, only older age was associated with greater comorbidity (P = 0.008). Overall survival (OS) was significantly better for patients with greater comorbidity in univariate analysis (P = 0.047). Conversely, better PS was associated with better OS in MVA (hazard ratio 1.92 for PS = 2 versus PS = 0, P < 0.0001). Age was not associated with OS (P = 0.13). Elderly patients had significantly less grade ≥ 3 vomiting (P = 0.034) but more dyspnea (P = 0.005). Patients with greater comorbidity had significantly less grade ≥ 3 vomiting (P =  0.002) but more non-neutropenic fever (P = 0.005)., Conclusion: better PS was associated with improved OS. For patients with good PS, restricting cetuximab use in the setting of significant comorbidity does not appear justified.