Aalok Kumar

ARID1A/BAF250a as a prognostic marker for gastric carcinoma: a study of 2 cohorts

ARID1A/BAF250a has been recently implicated as a tumor suppressor in gastric cancer. We sought to clarify the clinical significance of BAF250a/ARID1A in relation to other clinical parameters and relevant biomarkers in gastric carcinoma. Cases from 2 separate cohorts of patients with gastric carcinoma from Vancouver (n = 173) and Toronto (n = 80) were selected for the construction of tissue microarrays, which were used to assess the immunohistochemical status of BAF250a (anti-ARID1A), mismatch repair proteins and p53, as well as in situ hybridization for HER2 amplification and Epstein-Barr virus infection. The Toronto cohort contained a higher proportion of early stage cases (P = .019) and a smaller proportion of cases from the proximal stomach (P < .001). Overall, immunohistochemical loss of BAF250a was observed in 22.5% of gastric adenocarcinomas from the Vancouver group and 20% from Toronto. In both cohorts, loss of BAF250a was positively associated with loss of mismatch repair protein expression (P < .0001 and P = .035, respectively). Loss of BAF250a expression was independently associated with poor overall survival in the Toronto cohort (P = .0015), whereas no significant association with survival was observed in the Vancouver cohort. BAF250a loss was not significantly associated with any additional clinical parameters in either cohort. HER2 amplification was confirmed as a negative prognostic factor in both cohorts. These findings suggest that ARID1A/BAF250a may be of prognostic significance in a subset of patients with early stage gastric cancer and that pathological assessment should increasingly use a multimarker approach.

Clinical outcomes of elderly patients receiving neoadjuvant chemoradiation for locally advanced rectal cancer

BACKGROUND Studies of clinical outcomes of elderly patients treated with neoadjuvant chemoradiation (nCRT) for locally advanced rectal cancer (LARC) are limited. Our aim was to assess the impact of age on clinical outcomes in a large multi-institutional database. PATIENTS AND METHODS Data for patients diagnosed with LARC who received nCRT and curative-intent surgery between 2005 and 2012 were collected from five major Canadian cancer centers. Age was analyzed as a continuous and dichotomous variable (< 70 versus ≥ 70 years) and correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox regression models were used to adjust for important prognostic factors. RESULTS Of 1172 patients included, 295 (25%) were ≥ 70 years, and they were less likely to receive adjuvant chemotherapy (ACT; 60% versus 79%, P < 0.0001), oxaliplatin-based ACT (12% versus 31%, P < 0.0001), less likely to complete nCT (76% versus 86%, P < 0.001), and more likely to be anemic at initiation of nCRT (42% versus 30%, P = 0.0004). In multivariate analyses, age ≥ 70 years was associated with similar DFS [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.68-1.26, P = 0.63], similar CSS (HR 0.81, 95% CI 0.46-1.41, P = 0.45), and similar OS (HR 1.28, 95% CI 0.88-1.86, P = 0.20), compared with the younger age group. As a continuous variable, increasing age was not predictive of DFS (HR 1.00, 95% CI 0.99-1.02, P = 0.49) or CSS (HR 1.002, 95% CI 0.98-1.02, P = 0.88); however, it correlated with an inferior OS (HR 1.02, 95% CI 1.00-1.03, P = 0.04). CONCLUSIONS Elderly patients (≥ 70 years) who receive nCRT followed by surgery appear to have similar outcomes compared with younger patients. Decisions regarding eligibility for nCRT and surgery should not be based on age alone.

Effect of Adjuvant FOLFOX Chemotherapy Duration on Outcomes of Patients With Stage III Colon Cancer

BACKGROUND Studies have demonstrated that patients with stage III colon cancer who receive adjuvant FOLFOX (5-fluorouracil and oxaliplatin) chemotherapy experience an improved disease-free (DFS) and overall survival (OS). However, the magnitude of benefit among patients who discontinue FOLFOX early is not well known. We sought to examine the rate of FOLFOX treatment completion, determine the factors associated with adherence, and explore the relationship between duration of FOLFOX treatment and survival. PATIENTS AND METHODS We analyzed patients diagnosed with stage III colon cancer from 2006 to 2010 and initiated at least 1 cycle of adjuvant FOLFOX at any 1 of 5 regional cancer centers in British Columbia. Logistic regression models were constructed to determine the clinical factors associated with treatment completion, which was defined as receipt of ≥ 10 cycles of FOLFOX. Kaplan-Meier methods and Cox regression that accounted for known prognostic factors were used to evaluate the relationship between early FOLFOX discontinuation and DFS and OS. RESULTS We identified 616 patients: median age of 62 years (range, 26-80), 321 (52%) men, 536 (87%) with T3/4 tumors, and 245 (40%) with N2 disease. Among them, 183 (30%) received < 10 and 433 (70%) received ≥ 10 cycles. Adjusting for covariates, female sex and the absence of obstruction or perforation were each associated with receiving ≥ 10 cycles of FOLFOX (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.12-2.32; P = .01 and OR, 1.82; 95% CI, 1.08-3.05; P = .02, respectively). In multivariate analyses, early discontinuation of FOLFOX did not affect DFS or OS (hazard ratio [HR], 1.16; 95% CI, 0.82-1.63; P = .40 and HR, 1.07; 95% CI, 0.70-1.61; P = .76, respectively). CONCLUSION Early discontinuation of FOLFOX was not associated with differences in survival outcomes, lending support to clinical trials that are under way to evaluate the efficacy of shorter durations of therapy.

Effect of Delay in Adjuvant Oxaliplatin-Based Chemotherapy for Stage III Colon Cancer

BACKGROUND Less than 8 weeks has been recommended as the optimal time to initiate AC based on 2 meta-analyses that suggested worse survival with delayed AC. However, neither study included patients treated with an oxaliplatin-based chemotherapy. We aimed to investigate the effect of delay in initiating oxaliplatin-based chemotherapy on RFS and CSS for stage III colon cancer. PATIENTS AND METHODS Records of patients who initiated oxaliplatin-based AC for stage III colon cancer between 2006 and 2011 at the British Columbia Cancer Agency were retrospectively reviewed. Cox proportional models were used to analyze the effect of time to AC (TTAC) on RFS and CSS. TTAC was categorized into ≤ 8 weeks (G1) and > 8 weeks (G2). RESULTS Six hundred thirty-five patients were included (G1, n = 291; G2, n = 344). Median time from surgery to initiation of AC was 8.3 weeks. At a median follow-up of 57.9 months, 176 patients (27.7%) had disease recurrence and 118 (18.6%) had died. Five-year RFS was 70.9% (95% confidence interval [CI], 65.2-76.5) for G1 and 72.1% (95% CI, 67.2-77) for G2. Five-year CSS was 82% for G1 (95% CI, 87.09-76.91) and 82.8% for G2 (95% CI, 78.30-87.30). On multivariate analysis, delayed TTAC did not have prognostic significance on either RFS (hazard ratio [HR], 1.08; P = .609) or CSS (HR, 1.02; P = .893). CONCLUSION In our population-based study, TTAC after stage III colon cancer resection did not have an effect on RFS or CSS. Contrary to most of the existing data, which are primarily based on 5-fluorouracil-based AC, delay of oxaliplatin-based AC beyond 8 weeks did not appear to be associated with inferior outcomes.

Impact of Duration of Neoadjuvant Radiation on Rectal Cancer Survival: A Real World Multi-center Retrospective Cohort Study

Background: The utility of neoadjuvant radiotherapy (nRT) for the treatment of stage II and III rectal cancer is well‐established. However, the optimal duration of nRT in this setting remains controversial. Using a population‐based cohort of patients with stage II and III rectal cancer (RC) treated with curative intent, our aims were to (1) examine the patterns of nRT use and (2) explore the relationship between different nRT schedules and survival in the real‐world setting. Methods: This is a multi‐center retrospective cohort study based on population‐based data from 5 regional comprehensive cancer centers in British Columbia, Canada. We analyzed patients diagnosed with clinical stage II or III RC from 2006 to 2010 and treated with either short‐course (SC) or long‐course (LC) nRT prior to curative intent surgery. Logistic regression models were constructed to determine the factors associated with the course of nRT delivered to patients. Kaplan‐Meier methods and Cox regression that accounted for known prognostic factors were used to evaluate the relationship between nRT schedule and overall (OS), disease‐free (DFS), local recurrence‐free (LRFS), and distant recurrence‐free survival (DRFS). Results: We identified 427 patients: the median age was 65 years (range, 31 to 94 years), 67% were men, 87% had T3 or T4 tumors, and 74% had N1 or N2 disease. Among them, 241 (56%) received SC and 186 (44%) received LC. Adjusting for confounders, patients with N1 or N2 disease were more likely to undergo LC (odds ratio [OR], 5.08; 95% confidence interval [CI], 2.51–11.22; P < .0001 and OR, 8.35; 95% CI, 3.35–22.39; P < .0001, respectively), whereas older age patients were less likely to receive LC (OR, 0.95; 95% CI, 0.94–0.98; P < .0001). In Kaplan‐Meier analysis, there were no significant differences observed in OS, DFS, LRFS, and DRFS between SC and LC. Likewise, multivariate analyses demonstrated that OS (hazard ratio [HR], 0.91; 95% CI, 0.61–1.37; P = .66), DFS (HR, 1.06; 95% CI, 0.68–1.64; P = .80), LRFS (HR, 0.79; 95% CI, 0.39–1.57; P = .50) and DRFS (HR, 0.99; 95% CI, 0.60–1.61; P = .95) were similar regardless of nRT schedules. Additional baseline clinical and tumor characteristics did not influence outcomes (all P > .05). Conclusion: Appropriate preoperative selection of SC versus LC nRT for locally advanced RC based on patient and tumor characteristics was not associated with differences in survival outcomes in the real‐world setting. Micro‐Abstract: The optimal duration of neoadjuvant radiotherapy in rectal cancer remains controversial. This is a multi‐center retrospective cohort study. Appropriate preoperative selection of radiotherapy duration was not associated with survival differences.

Compliance with adjuvant capecitabine in patients with stage II and III colon cancer: comparison of administrative versus medical record data

We aimed to examine the frequency of treatment delays as well as the reasons and appropriateness of such delays in early stage colon cancer patients receiving adjuvant capecitabine by comparing data from pharmacy dispensing versus medical records. Patients diagnosed with stage II or III colon cancer from 2008 to 2012 and who received at least two cycle of adjuvant capecitabine were reviewed for treatment delays. Data from pharmacy dispensing and patient medical records were compared. Multivariate regression models were constructed to identify predictors of treatment delays. A total of 697 patients were analyzed: median age was 70 years (IQR 30–89), 394 (57%) were men, 598 (86%) reported Eastern Cooperative Oncology Group 0/1, and 191 (27%) had stage II disease. In this study cohort, 396 (57%) patients experienced at least 1 treatment delay during their adjuvant treatment. Upon medical record review, half of treatment delays identified using pharmacy administrative data were actually attributable to side effects, of which over 90% were considered clinically appropriate for patients to withhold rather than to continue the drug. The most prevalent side effects were hand‐foot syndrome and diarrhea which occurred in 176 (44%) and 67 (17%) patients, respectively. Multivariate analysis revealed a statistically significant association between stage and inappropriate treatment delays whereby patients with stage II disease were more likely to experience drug noncompliance (OR 1.79, 95% CI: 1.27–2.53, P < 0.001) than those with stage III disease. Compliance with adjuvant capecitabine was reasonable. Adherence ascertained from pharmacy administrative data differs significantly from that obtained from medical records.

Survival Benefit of Adjuvant Radiotherapy: An Analysis of Low-Stage Invasive Ovarian Mucinous Carcinomas

Objective Our aim was to evaluate the population-based outcomes of stages I and II invasive ovarian mucinous carcinomas (MCs) treated with adjuvant platinum-based chemotherapy and abdominopelvic radiotherapy (XRT). Methods International Federation of Gynecology and Obstetrics stage I/II MC cases referred to the British Columbia Cancer Agency between 1984 and 2014 were reviewed. Chemotherapy (minimum of 3 cycles) and XRT were the institutional policy for stages IA/B (grade 2/3) and IC/II (any grade). Physician patterns of practice determined XRT use in eligible patients, allowing for the comparison of outcomes based on receipt of XRT treatment on disease-free survival (DFS) and overall survival (OS). Results We identified 129 patients. Univariate analyses on substages IA, IC no rupture, IC with intraoperative rupture, and IC with preoperative rupture demonstrated 10-year DFS rates of 67%, 67%, 67%, and 27% (P = 0.004), respectively, and OS rates of 72%, 72%, 67%, and 38% (P = 0.01), respectively. For all patients, adjuvant XRT demonstrated improved 10-year DFS (78% vs 36%, P = 0.05) and OS (83% vs 36%, P = 0.02). Subgroup analysis did not detect a benefit of adjuvant therapy for stage IA grade 1/2. Multivariate analysis confirmed the benefit of XRT on DFS (hazard ratio, 0.14; 95% confidence interval, 0.02–0.98; P = 0.047) and a trend to improved OS (hazard ratio, 0.12; 95% confidence interval, 0.009–1.64; P = 0.11), whereas decision tree analysis demonstrated a reduced rate of relapse (33% vs 77%) and death (20% vs 46%) with the use of XRT, exclusive of patients with preoperative rupture. Conclusions This population-based retrospective study is the first to demonstrate that the use of adjuvant abdominopelvic XRT after chemotherapy can improve survival in patients diagnosed as having stage I/II MC. Patients with stage IA grade 1 and grade 2 MC can have adjuvant therapy omitted.

Palliative oxaliplatin-based chemotherapy after exposure to oxaliplatin in the adjuvant setting for colon cancer

BACKGROUND Little is known regarding the efficacy of oxaliplatin-based chemotherapy for metastatic colon cancer patients who have already received adjuvant oxaliplatin-based chemotherapy. METHODS We retrospectively reviewed 22 consecutive patients who developed recurrence after adjuvant oxaliplatin-based chemotherapy for stage III colon cancer and received another course of oxaliplatin-based chemotherapy for their metastatic disease. The main endpoint was progression-free survival (PFS). RESULTS A total of 635 patients received oxaliplatin-based chemotherapy for stage III colon cancer at the British Columbia Cancer Agency from 2006 to 2011. A total of 176 patients recurred, 22 (12.5%) of whom were re-exposed to oxaliplatin in the metastatic scenario. Oxaliplatin in combination with fluoropyrimidine was given as first, second and third line in in 3 (13.6%), 14 (63.6%), and 5 (22.7%) patients respectively. Median time from the last cycle of adjuvant oxaliplatin-based chemotherapy to the first cycle of palliative oxaliplatin-based chemotherapy was 44.3 months. Median PFS and overall survival (OS) were 3.3 (95% CI, 1.4-5.1) and 10.0 months (95% CI, 5.3-14.6), respectively. There was no difference in PFS for patients re-exposed to oxaliplatin less than 36 months compared to longer (3.6 versus 3.1 months, P=0.793, HR =0.88). CONCLUSIONS In this population-based study, only a small proportion of pts who recurred after oxaliplatin-based adjuvant therapy received oxaliplatin in the metastatic setting. Re-exposure of oxaliplatin in combination with fluoropyrimidine is associated with only modest PFS benefit. Larger studies evaluating the role of oxaliplatin re-exposure are needed.

Measuring compliance to capecitabine in colon cancer: A comparison of administrative data and medical records.

531 Background: Studies of administrative data indicate that compliance with oral anti-neoplastic agents, including capecitabine, is suboptimal. Using a population-based cohort of colon cancer, our aim was to evaluate the proportion of patients deemed non-compliant that actually had a reasonable indication for not adhering to their prescribed oral systemic therapy. Methods: Consecutive patients diagnosed with stage III colon cancer from 2008 to 2010, referred to any 1 of 5 regional cancer centers in British Columbia, Canada, and who initiated at least 1 cycle of oral adjuvant capecitabine within 12 weeks of curative resection were reviewed. Administrative data from the provincial oncology pharmacy database were analyzed to assess for non-compliance, which was defined as any prescription refill delays of >/=1 week from the end date of the preceding cycle. Electronic medical records were abstracted to examine the factors, if any, which contributed to non-compliance. We compared administrative vs. medical re...

911PETOPOSIDE BENEFIT IN 2ND LINE AND BEYOND RELAPSED EPITHELIAL OVARIAN CANCER (EOC): A POPULATION BASED ANALYSIS

ABSTRACT Aim: Etoposide is an option for treatment in women with EOC who relapse. Our aims were to characterize patterns of etoposide use in relapsed EOC and assess its benefit based on when etoposide was used. Methods: Women with high grade serous ovarian cancer (HGSC) and treated at 1 of the British Columbia Cancer Agency (BCCA) centres with oral etoposide at recurrence/progression from years 2000-2010 were identified. Kaplan-Meier and Cox regression methods were used to correlate line of therapy of etoposide with overall survival (OS), progression free survival (PFS) and interval between etoposide start and next progression/death (EPFS). Results: We identified 219 women who received etoposide at relapse, median age of 61 years. Majority had stage 3 disease at initial presentation (80%). Patients received etoposide in 2nd (17%), 3rd (30%), 4th (26%), 5th (17%) and 6-8th (11%) line of therapy. The median number of cycles received was 2-4 depending on line of therapy. Most patients discontinued etoposide due to progression (81%). Patients receiving etoposide in 4th-8th line of treatment had a significantly longer median OS and initial PFS vs. 2nd-3rd line (47.8 vs. 25.8 mo, p Conclusions: In this population based cohort study, the benefit of etoposide was similar regardless of the line of therapy it was instituted in. Etoposide remains an important option in the treatment of relapsed HGSC. The outcomes reported are likely the best possible as selection bias must have been operational to exclude from treatment of the ill or those deemed unlikely to benefit. Variable EPFS HR 95% CI p-value Age at Diagnosis 0.99 0.98–1.01 0.89 Etoposide Line of Tx 2nd 3rd 4th 5th 6th-8th 1.00 0.82 0.77 0.34 1.03 0.53–1.29 0.49–1.23 0.19–0.63 0.59–1.82 0.39 0.27 0.0006 0.91 Disclosure: All authors have declared no conflicts of interest.