Nair, Suresh

3579 Background: Tumor infiltrating lymphocytes (TIL) indicate a host immune response that may influence survival. Immunoscore was developed using CD3+ and CD8+density and location in primary CC pts with pooled stages, varying treatment and follow-up. We determined if individual immune markers and/or Immunoscore are prognostic in resected stage III CC pts (N=600). Methods: CD3+ and CD8+ T-cell or CD20+ B lymphocyte density in central tumor (CT) and invasive margin (IM) was evaluated by immunostaining and quantified by image analysis. Immunoscore was calculated on a scale of I0 to I4 with high densities of CD3+ and CD8+in both CT and IM scored as I4; low densities scored as I0. Associations with disease-free survival (DFS) were evaluated by multivariable Cox regression adjusting for covariates. Results: Data for CD3+, CD8+ and CD20+ were generated (N=595). Higher density of CD3+ CT, CD3+ IM and CD8+ IM were associated with longer DFS adjusting for covariates (Table). CD3+ IM had the strongest association with DFS, and was stronger in left-sided (HRadj.=0.81, 95% CI, 0.70-0.94, padj.= 0.0049) vs right-sided (HRadj.=0.93, 95% CI, 0.85-1.0 padj.=0.52) tumors (pinteraction=0.039). Higher density of CD3+ IM was associated with older age (p=0.034), T1/2 (p<.0001), N1 (p=0.017), right-sided (p=0.013), high TILs (p=0.0008), and deficient MMR (p=0.0003). Using a prior Immunoscore risk stratification, higher scores were associated with better DFS (HR.=0.62, CI, 0.44-0.87, p=0.006) (Table). Conclusions: Densities of CD3+ and CD8+, especially at IM, are individually prognostic in FOLFOX-treated pts. Association of CD3+IM with prognosis differed by primary CC site. Immunoscore was strongly prognostic, and this result provides validation in a clinical trial cohort. [Table: see text]

3516 Background: Epidemiological data suggest a protective effect of vitamin D on CC risk. However, association of serum vitamin D level with clinical outcome in pts with surgically resected CC remains unknown. We analyzed total circulating 25-hydroxyvitamin D [25(OH)D)] with clinical outcome in pts with resected stage III CC treated with FOLFOX +/- cetuximab in a phase III trial. Methods: Association of pre-treatment level of plasma 25(OH)D with disease-free survival (DFS) and time-to-recurrence (TTR) was analyzed with 25(OH)D as a continuous variable by a relative risk model with splines and as a binary variable (vitamin D deficient [<30 ng/mL]) using multivariable Cox regression. Results: Overall, 49% (291/600) of pts were vitamin D deficient. Prevalence of vitamin D deficiency was significantly higher in women vs men (52% vs. 48%, p=0.030) and in blacks vs whites (74% vs. 45%, p=0.0003). The continuous 25(OH)D level and pt sex were associated by the interaction test (pinteraction=0.044). There were no statistically significant associations with DFS/TTR for either continuous 25(OH)D level (DFS, p=0.22; TTR, p=0.26) nor for vitamin D deficiency (DFS, adjusted hazard ratio [HRadj]=1.01, 95% CI, 0.74-1.38; padj=0.94; TTR, HRadj=1.00; CI, 0.72-1.38; padj=0.99. A comparison of the highest vs lowest tertile showed a significant association between the highest 25(OH)D level and better outcomes in men (DFS, HRadj.=0.18, CI, 0.04-0.76, padj=0.020; TTR, HRadj.=0.12, CI, 0.02-0.64, padj=0.014), but not in women (DFS, pinteraction=0.039; TTR, pinteraction=0.033). Conclusions: Nearly one-half of pts in the clinical trial cohort were vitamin D deficient with lowest 25(OH)D levels found in women and blacks. While vitamin D deficiency was not associated with adverse outcome, high levels of vitamin D in men, but not women, were associated with longer survival. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180863, U10CA180888, U10CA077202, CCSRI 021039. ClinicalTrials.gov Identifier: NCT00079274.

PURPOSE: A meta-analysis of six North Central Cancer Treatment Group (NCCTG) trials involving patients receiving their first ever fluorouracil (5-FU)–based chemotherapy was undertaken to explore the association of sex with reports of the incidence and severity of stomatitis. PATIENTS AND METHODS: Data were obtained on a total of 731 patients (402 men and 329 women). Comparisons of incidence and severity rates and average stomatitis across sex were performed using standard binomial testing and t tests, respectively. Logistic regression analysis and a weighted analysis using data summarized to study level served as evidence of cross-validation. RESULTS: Women reported stomatitis both more often and with greater severity than did men. The incidence of any stomatitis for women was 63% versus 52% for men (P = .002). The incidence of severe or very severe stomatitis for men and women was 22% and 12%, respectively (P = .0006). On average, women reported stomatitis of roughly 0.4 points higher than men on a 0 to 4 ordinal scale (P < .00001). Comparison of results across treatment and placebo arms was carried out to validate the initial findings. Logistic regression modelling further confirmed the results conditional on the presence of a number of potentially confounding covariates. Women were also 11% more likely than men to experience leukopenia of common toxicity criteria grade ≥ 1, (70% v 59%, respectively; P < .00001) and grade 3+ (18% v 11%, respectively; P = .004). CONCLUSION: More women than men reported 5-FU–induced stomatitis. The precise mechanism resulting in different degrees of stomatitis across sex is not evident.

PURPOSE: The toxicity profile of fluorouracil (5-FU)–based chemotherapy given on 5 consecutive days at doses of 370 to 450 mg/m2 has been well documented. A meta-analysis of six North Central Cancer Treatment Group (NCCTG) cancer control trials involving 786 patients indicated that women treated with this type of regimen experienced more severe stomatitis and leukopenia than men. After these findings, an additional meta-analysis of the toxicity profiles on five NCCTG colorectal cancer treatment trials was undertaken. METHODS: Data for 1,093 women and 1,355 men from 12 different treatment arms were included. The primary end points were the incidence of stomatitis, leukopenia, alopecia, diarrhea, nausea, and vomiting, recorded with standard National Cancer Institute common toxicity criteria. Fisher’s exact test was used to compare incidence and severity across sexes, supplemented by Forrest meta-analysis plots and logistic regression. RESULTS: The incidence of four out of six toxicities studied was significantly greater for women than men; the exceptions were severe nausea and vomiting. Overall, almost half of the women compared with a third of the men experienced severe toxicity (P < .0001). Logistic regression confirmed the univariate findings while adjusting for the effects of study, dose, body mass index, and age. The differences were consistent across treatment cycles. Response rates and survival distributions were the same for both sexes. CONCLUSION: This study confirms an earlier finding that women receiving 5-FU–based chemotherapy in a 5-day bolus schedule experience toxicity more frequently and with more severity than men. These data raise the question of whether the recommended initial dose of 5-FU–based chemotherapy for women should be lower than that for men.

AbstractBackground.Preclinical and epidemiological data suggest that metformin might have antineoplastic properties against colon cancer (CC). However, the effect of metformin use on patient survival in stage III CC after curative resection is unknown. The survival outcomes were comparable regardless of the duration of metformin use.Patients and Methods.Before randomization to FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) with or without cetuximab, 1,958 patients with stage III CC enrolled in the N0147 study completed a questionnaire with information on diabetes mellitus (DM) and metformin use. Cox models were used to assess the association between metformin use and disease-free survival (DFS), overall survival (OS), and the time to recurrence (TTR), adjusting for clinical and/or pathological factors.Results.Of the 1,958 patients, 1,691 (86%) reported no history of DM, 115 reported DM with metformin use (6%), and 152 reported DM without metformin use (8%). The adjuvant treatment arms were pooled, because metformin use showed homogeneous effects on outcomes across the two arms. Among the patients with DM (n = 267), DFS (adjusted hazard ratio [aHR], 0.90; 95% confidence interval [CI], 0.59–1.35; p = .60), OS (aHR, 0.99; 95% CI, 0.65–1.49; p = .95), and TTR (aHR, 0.87; 95% CI, 0.56–1.35; p = .53) were not different for the metformin users compared with the nonusers after adjusting for tumor and patient factors. The survival outcomes were comparable regardless of the duration of metformin use (&lt;1, 1–5, 6–10, ≥11 years) before randomization (ptrend = .64 for DFS, ptrend = .84 for OS, and ptrend = .87 for TTR). No interaction effects were observed between metformin use and KRAS, BRAF mutation status, tumor site, T/N stage, gender, or age.Conclusions.Patients with stage III CC undergoing adjuvant chemotherapy who used metformin before the diagnosis of CC experienced DFS, OS, and TTR similar to those for non-DM patients and DM patients without metformin use.

Alcohol consumption is associated with a modest increased risk of colon cancer, but its relationship with colon cancer survival has not been elucidated. Using data from a phase III randomized adjuvant trial, we assessed the association of alcohol consumption with colon cancer outcomes. Patients completed a risk factor questionnaire before randomization to FOLFOX or FOLFOX + cetuximab (N = 1984). Information was collected on lifestyle factors, including smoking, physical activity and consumption of different types of alcohol. Cox models assessed the association between alcohol consumption and outcomes of disease‐free survival (DFS), time‐to‐recurrence (TTR) and overall survival (OS), adjusting for age, sex, study arm, body mass, smoking, physical activity and performance status. No statistically significant difference in outcomes between ever and never drinkers were noted [hazard ratio (HR)DFS = 0.86, HRTTR = 0.87, HROS = 0.86, p‐values = 0.11–0.17]. However, when considering alcohol type, ever consumers of red wine (n = 628) had significantly better outcomes than never consumers (HRDFS = 0.80, HRTTR = 0.81, HROS = 0.78, p‐values = 0.01–0.02). Favorable outcomes were confirmed in patients who consumed 1‐30 glasses/month of red wine (n = 601, HR = 0.80–0.83, p‐values = 0.03–0.049); there was a suggestion of more favorable outcomes in patients who consumed >30 glasses/month of red wine (n = 27, HR = 0.33–0.38, p‐values = 0.05–0.06). Beer and liquor consumption were not associated with outcomes. Although alcohol consumption was not associated with colon cancer outcomes overall, mild to moderate red wine consumption was suggestively associated with longer OS, DFS and TTR in stage III colon cancer patients.

Abstract Purpose: We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF–wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. Experimental Design: The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF–wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models. Results: KRAS mutations in codon 12 (multivariate HR, 1.52; 95% confidence interval, CI, 1.28–1.80; P &lt; 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04–1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P &lt; 0.0001), proximal tumor site (P &lt; 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P &lt; 0.0001). Conclusion: KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting. Clin Cancer Res; 20(11); 3033–43. ©2014 AACR.

Purpose To answer the question, “should elderly non–small-cell lung cancer patients be offered elderly-specific trials?” Patients and Methods The North Central Cancer Treatment Group (NCCTG) performed a pooled analysis of elderly patients who participated in elderly-specific trials (required age ≥ 65 years) and age-unspecified trials (required age ≥ 18 years). Between 1998 and 2000, all NCCTG non–small-cell lung cancer (NSCLC) patients with incurable cancer, age ≥ 65 years, and receiving first-line chemotherapy were included. A total of 118 elderly patients participated in elderly-specific trials, and 108, in age-unspecified trials. Demographics and outcomes were compared based on trial type. Results The median age of elderly patients in elderly-specific trials was greater: median (range): 73 years (65 to 87) and 70 years (65 to 85), respectively (P < .001), as was the percentage older than 80 years: 17% and 3%, respectively (P = .0008). Median survival times were 232 and 302 days, respectively (P = .08). After adjustment for baseline age, Eastern Cooperative Oncology Group performance score, cancer stage, and body mass index, this survival difference was not statistically significant (hazard ratio = 1.25; P = .16). Grade 3 or worse nonhematologic adverse event rates were greater in age-unspecified trials (81% v 57%, respectively; P < .001), as were grade 3 or worse hematologic events (68% v 10%, respectively; P < .001). Conclusion Elderly patients in NSCLC elderly-specific trials suffered lower rates of severe adverse events with no statistically significant differences in survival. It seems that elderly-specific trials are providing quality care and helping to define optimal cancer therapy in the elderly, particularly among the “oldest of the old.”

Purpose Surgical resection of liver-only metastases from colorectal cancer has undergone extensive evaluation and review. The use of neoadjuvant chemotherapy to improve the likelihood of resection in disease that is not optimally resectable has not been as well studied. Patients and Methods Patients with liver-only metastases from colorectal cancer deemed not optimally resectable by a surgeon with expertise in liver surgery received fluorouracil, leucovorin, and oxaliplatin (FOLFOX4). Patients were periodically reassessed for resectability. Surgical response was classified as completely resectable (S-CR), partially resectable (S-PR), or unresectable (S-UR). Study design specified the accrual of 39 patients, with two or more S-CRs considered evidence of promising activity with respect to increasing the S-CR rate. Results Forty-two of 44 patients were assessable for this analysis. Twenty-five patients (60%) had tumor reduction by serial imaging. Seventeen patients (40%) underwent surgery (S-CR, n = 14; S-PR, n = 1; and S-UR, n = 2) after a median of 6 months of chemotherapy. With a median postsurgical follow-up of 22 months (range, 13 to 32 months), 11 recurrences have occurred in the 15 S-CR and S-PR patients. Median survival time was 26 months. Conclusion Our data suggest that FOLFOX4 has a high response rate (complete response, partial response, or reduction) in patients with liver-only metastases from colorectal cancer, allowing for successful resection of disease in a portion of patients initially not judged to be optimally resectable. However, a high recurrence rate after surgery was observed, which, in 73% of patients, involved the liver. Further trials are indicated based on the promising results observed in this trial.