Saltz, Leonard B.

Abstract Background Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing. Methods The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin). Results Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P < .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P < .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P < .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P < .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P < .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P < .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P < .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P < .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P < .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P < .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P < .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P < .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P < .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P < .001]) were observed, with women being consistently at increased risk. Conclusions Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation.

The NCCN Guidelines for Rectal Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with rectal cancer. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines. These updates include clarifying the definition of rectum and differentiating the rectum from the sigmoid colon; the total neoadjuvant therapy approach for localized rectal cancer; and biomarker-targeted therapy for metastatic colorectal cancer, with a focus on new treatment options for patients with BRAF V600E– or HER2 amplification–positive disease.

Abstract Background: Hyperinsulinemia is considered to be important in the development of colon cancer, but few studies have investigated the associations of hyperinsulinemia with colon cancer survival via dietary scores. Methods: Empirical dietary index for hyperinsulinemia (EDIH) was derived to assess the insulinemic potential of daily diets reflecting the long-term insulin exposure, with higher (more positive) scores indicating higher insulinemic diets. We prospectively estimated the HRs and 95% confidence intervals (CI) to investigate the association of EDIH with disease-free, recurrence-free, and overall survival among patients with stage III colon cancer (1999–2009) enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803). Results: Of 1,024 patients (median follow-up: 7.3 years), 311 died, 350 had recurrences, and 394 had events for disease-free survival. Compared with patients in the lowest quintile of EDIH, the corresponding HRs of patients in the highest quintile for disease-free survival events, cancer recurrence, and overall mortality were 0.80 (95% CI, 0.56–1.15), 0.76 (95% CI, 0.51–1.11), and 0.77 (95% CI, 0.52–1.14). Conclusions: Higher EDIH was not associated with the risk of colon cancer recurrence or mortality in this population of patients with stage III colon cancer. Impact: EDIH, as a measure of dietary insulinemic potential, may be associated with colon cancer risk but not survival in patients with late-stage colon cancer.

7009 Background: Survival outcomes of 2nd line mCRC therapy for OA are poorly understood. We evaluated the rates and survival outcomes of 2nd line therapy among OA age 70+ compared to younger adults (YA) age < 70 following progression on 1st line clinical trials. Methods: Associations between clinical characteristics of pts with available treatment data after progression on 10 of 23 1st line ARCAD trials, time to initial progression (TTiP) and 2nd line therapy were evaluated. Time to progression (TTP) and overall survival (OS) were compared between OA and YA enrolled on 2nd line trials by Cox regression, adjusting for age, sex, ECOG PS, number of metastatic sites, presence of metastasis in lung/liver/peritoneum. Results: Sixteen percent of 1st line ARCAD trial participants were age 70+ (n = 870). Data for 2nd line therapy was available for 60.6% pts (3206/5289). Each additional decade of life was associated with 11% lower odds of receiving 2nd line therapy in multivariate analysis (p = 0.0117). OA participating in 2nd line trials (7.9% age 75+ of 7921) experience similar TTP and OS to YA (mTTP: 5.1 vs. 5.2mos; mOS 11.6 vs 12.4mos, respectively). Conclusions: We did not observe a statistical difference in survival outcomes by age following 2nd line mCRC therapy. Further study is needed to examine unmeasured comorbidity and use of geriatric assessment to select OA likely to benefit from 2nd line therapy. [Table: see text]

4099 Background: Colorectal cancer (CRC) incidence and mortality has decreased since the 1970s but the incidence is increasing in young adults (age 20-49). The incidence of early onset CRC (eoCRC) will keep increasing significantly based on the trends of the SEER CRC registry data. There is limited data suggesting eoCRC may have different behaviors compared to traditional CRC (tCRC, age ≥ 50). Methods: Individual pt data of 47184 stage II/III CRC pts from 25 randomized studies in the ACCENT database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and treatment-related data were summarized by age group. Overall survival (OS), disease-free survival (DFS), recurrence-free rate (RFR), and survival after recurrence (SAR) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for stage, performance status (PS), BMI and grade. Results: Using 5% difference between age groups as clinically meaningful cutoff, eoCRC had similar gender, race, ethnicity, PS, risk group, disease sidedness and T stage as tCRC. eoCRC were less likely overweight (30 vs 36%) and more pts had ≥ 12 lymph nodes resected (63 vs 51%). eoCRC had more frequent dMMR status (18 vs 12%), less BRAF mutations (5 vs 13%), and more dMMR/BRAF wild type (WT) status (17 vs 7%). Overall, eoCRC had better OS, DFS, and SAR, with the most significant differences between the < 30 and > = 70 age groups. Similar results were observed within pMMR pts. eoCRC experienced less hematological side effects, diarrhea, and stomatitis, but had more nausea and/or vomiting. Conclusions: eoCRC have unique characteristics; although statistically significant, the clinical differences in outcomes between eoCRC and tCRC are potentially due to the difference seen in extremely young and old pts. eoCRC have a different adverse events panel compared to tCRC. [Table: see text]

4029 Background: The clearance of 5-FU differs significantly between men (M) and women (W). Adjuvant chemotherapy (CT) for CRC has a higher toxicity in W. The impact of sex on efficacy and toxicity in first-line trials of metastatic CRC (mCRC) is unknown. Methods: We analyzed patient (pt) and tumor characteristics, toxicities (nausea (AE1), vomiting (AE2), diarrhea, neutropenia (AE3)) and efficacy (overall survival (OS), progression-free survival (PFS)) according to sex in the following treatment groups: A: CT alone, B: CT + bevacizumab, C: CT + EGFR-antibodies, with subgroup analyses in the CT alone group for single-agent, doublets and triplets, as well as irinotecan- and oxaliplatin-based regimens. Pts from trials with treatments still used today and all relevant data available were eligible. OS and PFS were assessed using Kaplan-Meier and Cox models adjusted for primary tumor location and performance status (PS). Results: We included 28 trials with 18.399 pts (11.352 M and 7.047 W). W were younger (61 vs. 63 years), had more often a PS of 1 (49 vs 45%), BRAF mutations (10 vs. 7%), right-sided tumors (42 vs. 35%) and less often rectal tumors (26 vs. 32%). Significant differences in toxicity are reported in table. Rates of diarrhea were similar. There was no sex disparity in OS in the predefined subgroups except for pts receiving triplets where OS was better in M (HRadj=1.39 (1.05 - 1.85)). Median (interquartile range) OS in months for M and W was 16.7 (9.2-27.4) and 16.2 (8.9-27.2) in group 1, 21.9 (12.7-37.5) and 22.3 (12.9 – 39.0) in group 2, and 26.8 (14.6-45.3) and 24.8 (12.3-49.2) in group 3. HRsadj (W vs M) (95% CI), p values for OS were 1.02 (0.96-1.09), .557, 0.92 (0.83-1.03), .142, 0.99 (0.85-1.14), .866. Conclusions: M and W with mCRC differ significantly regarding patient and tumor characteristics. The significant higher toxicity in W does not translate in a higher treatment efficacy. Apart from known sex differences in pharmacokinetics of 5-FU, differences in pharmacodynamics must be postulated. [Table: see text]

3618 Background: Current prognostic tools and staging systems in CC use relatively few patient (pt) characteristics; including additional covariates may improve prediction. Using the large ACCENT database, we constructed clinically based NGs for OS and TTR in stage III CC that better separate pts into risk groups compared to AJCC v7 staging. Methods: 15,936 stage III pts accrued to phase III clinical trials since 1989 were used to construct Cox models for TTR and OS. Variables included age, sex, race, BMI, performance status, tumor grade, tumor stage, ratio of positive lymph nodes to nodes examined, number/location of primary tumors (any multiple versus single left, right, or transverse), and treatment (5FU variations vs. 5FU with oxaliplatin or irinotecan). Missing data (<18%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions included if p < 0.001. Final models were internally validated via bootstrapping for corrected calibration and C-indices for survival data. NG-defined risk tertiles were compared to AJCC v7 stage III for observed 3-year (yr) TTR and 5-yr OS for a subset of 7400 pts with complete data. Results: All variables were statistically and clinically significant for OS; age and race did not predict TTR. No meaningful interactions existed. NGs for OS and TTR were well calibrated and associated with C-indices of 0.66 and 0.65, respectively, vs. 0.58 and 0.59 for AJCC. NG risk tertiles were better separated than AJCC groups, (3-yr TTR, 5-yr OS below), with fewer mid-risk NG pts. Removing treatment from NGs did not affect performance (C=0.66 for OS and 0.65 for TTR). Conclusions: The proposed ACCENT NGs are internally valid and have the potential to aid prognostication, decision-making, and patient/physician communication in pts with stage III CC. [Table: see text]

3533 Background: PFS has previously been established as a surrogate for OS based on IPD from first-line mCRC trials conducted before 1999. As mCRC treatment (trt) has advanced in the last decade and OS has increased from 1 to 2 years, this surrogacy required re-examination. Methods: IPD from 16,762 pts, median age 62, 62% male, 53% ECOG PS 0 were available from 22 1st line mCRC studies conducted from 1997-2006; 12 tested targeted (anti-angiogenic and/or anti-EGFR) regimens. The relationship between PFS (first event of progression or death) and OS was evaluated at patient-, trt-arm-, and trial-levels using correlation (corr.) coefficients and R2 (closer to 1 the better) from weighted least square (WLS) regression of arm-specific survival rates and trial-specific hazard ratios (HRs), estimated using Cox and Copula bivariate models. The concordance of significance (CoS) of the treatment effects (TEs) on both endpoints was calculated. Results: 44% pts received a targeted regimen. Median PFS was 8 and OS was18 months. The corr. between PFS and OS was modest at all three levels with low CoS in TE comparisons (see Table). Analyses limited to trials testing targeted trts, non-strategy trials, or superiority trials did not improve surrogacy. Conclusions: In modern mCRC trials, where survival post-first progression exceeds time to first progression, PFS TEs do not reliably predict TEs on OS. Nonetheless, until alternative endpoints of clinical benefit can be validated, PFS remains a relevant primary endpoint for 1st line mCRC trials, as our data demonstrate that the ability for any agent to produce an OS benefit from a single line of therapy is challenging. [Table: see text]

4020 Background: Adjuvant chemotherapy (AC) presents a substantial patient education challenge to medical oncologists (MOs). Findings from our 2005 pilot survey suggest that a significant fraction of colorectal cancer (CRC) survivors are willing to undergo AC for modest treatment benefits, but their understanding of risks and benefits may be suboptimal. This project attempted to validate these findings by surveying patients with CRC (Pts) who previously received AC. Methods: 150 Pts who received AC for CRC in the last 5 years were recruited to listen to an audio program on AC featuring interviews with clinical investigators (CIs) and Pts who received AC. Based on this input, Pts were asked whether they would undergo the same AC again for varying absolute treatment benefits. A corresponding survey asked 24 CRC CIs and 150 MOs to predict how patients would respond. The survey also queried Pts about their expectations of and experiences with AC side effects. Results: About 1/3 of Pts would be treated again with AC for a 1% absolute reduction in recurrence risk (ARRR), and about 2/3 believed a 5% ARRR would justify treatment. There were no statistically significant differences between responses of males and females or between Pts receiving oxaliplatin (OX) and those receiving other regimens. ( Table 1 ) The corresponding estimates of CIs and MOs were lower. Additionally, AC side effects were different than expected: 57% and 66% of Pts experienced less GI toxicity and alopecia, respectively, while 38% and 46% of Pts receiving OX experienced greater cold intolerance and numbness. Conclusions: Many potential obstacles exist in communicating with Pts about AC including heterogeneity in Pts’ attitudes towards risk/benefit trade-offs and preconceptions about treatment side effects. The next step in this initiative will be to examine these issues prospectively by evaluating the impact of an audio/web education supplement on the decision-making process. [Table: see text] No significant financial relationships to disclose.

89 Background: Monitoring of adverse events (AE) is crucial in clinical trials. Maximum grade per patient (pt) is commonly used but better metrics are needed to aid describing and comparing AE profiles. Methods: We developed and evaluated 2 longitudinal AE summary metrics. 1) Onset time of max grade refers to whether a pt has max grade within pre-specified timeframes for an AE, e.g. onset can be defined as “early” (max grade before the 6th cy) or “late” (≥ 6th cy). 2) Adverse effect load (AEL) is a longitudinal score of worst grade possible excluding death over the entire treatment for an AE. Higher AEL means worst overall experience of AE. We applied these metrics to real trial data. Pts were from 6 mCRC trials included in ARCAD database and received Irinotecan-based (n = 1,119) or Oxaliplatin-based (n = 1,230) treatments that did not include biologicals. AEs were diarrhea, nausea/vomiting, neutropenia/leukopenia, and neuropathy. We used linear model to AEL and logistic model to the other metrics, adjusting for age, sex, and number of metastases. Results: For nausea/vomiting, pts in Oxali-based chemo showed a higher AEL compared to patients in Iri-based (mean (M) [standard deviation (SD)] = 0.04 [0.06] vs. 0.02 [0.04]; p < 0.001) even though less pts had gr ≥ 3 (10.4% vs. 16.2%, resp.; p < 0.001), suggesting a lower-grade but persistent nausea/vomiting for Oxali-based. Among pts with diarrhea max gr 2, pts in Iri-based had higher AEL than with Oxali-based (M [SD] = 0.11 [0.11] vs. 0.08 [0.09]; p = 0.008), indicating more persistent diarrhea for Iri-based trts even among pts with same max grade. For neutropenia/leukopenia, pts in Oxali-based trts experienced higher AEL (M [SD] = 0.09 [0.13] vs. 0.05 [0.11], p < 0.001), and more pts in Oxali-based trts had gr ≥ 3 (70.1% vs. 64.4%; p = 0.002), suggesting that pts in Oxali-based trts experienced worst overall and max grade neutropenia/leukopenia compared to pts in Iri-based. Conclusions: To improve toxicity assessment in clinical trials, AEL and onset time of max grade are new measures that describe the evolution of adverse events over time. Further validation is warranted.