Citations

10602 Background: Progressive disease (PD) according to RECIST 1.1 (Eisenhauer et al, 2009) is defined as one or more of (1) PD of measurable target lesions, (2) the presence of a new lesion (NL) or (3) the unequivocal PD of non-target disease (NT-PD). We explored the impact of these components, varying over time, on predicting overall survival (OS) in the RECIST database residing at EORTC (Bogaerts et al, 2009). Methods: Data was selected from 12 randomized clinical trials (3530 patients with breast, lung or colorectal cancer). A maximum of 5 target lesions was used to determine the sum of diameters. The following were calculated or assigned at each measurement time t: best response (BR) was best % improvement from baseline up to t (0% if no improvement - 100% if complete response (CR)); tumor growth (TG) was the weekly rate of increase from nadir to t (0 if no increase; irrespective of prior shrinkage), presence of NL (yes/no), and occurrence of NT-PD (yes/no); categories were not mutually exclusive. OS was analyzed by tumor type using a Cox regression model, adjusting for baseline sum, and including BR, TG, presence of NL and NT-PD as time dependent covariates. Results: Thirty-six percent of patients had NL, 26% had NT-PD, 11% achieved CR and 14% did not have shrinkage of target lesions, while 46% experienced TG (median strongest growth per patient of 0.5 mm/week). Regardless of tumor type, the presence of NL (Hazard Ratio (HR) ranging 1.4-2.5), NT-PD (HR 1.2-2.5) and TG (per 1mm/week increase; HR 1.1-1.4) were associated with worse OS, while achieving CR was associated with a longer OS (HR 0.2-0.8). Further analyses exploring the functional shape of the association between BR and TG, and OS are ongoing. This includes putting TG in contrast with the more usual % cutoff defining target PD. Conclusions: All three components of PD according to RECIST are independently strongly associated with OS. Quantification such as this will enable a better understanding of the role of each component (e.g. clinical aspect of NT-PD assessment) in PD evaluation. Work is ongoing to incorporate this information into an updated RECIST with enhanced prediction of subsequent survival.

3564 Background: Lethal-7 (let-7) microRNA has been shown to inhibit colon cancer cell proliferation by inducing KRAS downregulation after binding to specific sites in the 3’- UTR. Recent studies identified a KRAS 3’-UTR polymorphism in the let-7 complimentary site (LCS6) that has been shown to weaken let-7 binding and alter KRAS expression. Carriers of the LCS6 G-allele showed worse survival in metastatic colorectal cancer from prior studies of limited sample size. In the current study, we evaluated the LCS6 variant in 2,834 Stage III colon cancer patients and its association with disease-free survival (DFS), KRAS mutation status, and other clinicopathological features. Methods: In the NCCTG phase III trial (N0147), the LCS6 variant was assayed in germline DNA extracted from whole blood using RT-PCR. Extracted tumor DNA was analyzed for KRAS exon 2 mutations. Chi-squared and two-sample t test were used to compare baseline factors and KRAS mutation status between patients defined by LCS6 variant status. Log-rank tests and multivariate Cox models assessed the unadjusted and adjusted associations between LCS6 status and DFS, respectively. Results: We identified 432 (15.2%) patients heterozygous or homozygous for the LCS6 G-allele and 2402 (84.8%) patients homozygous for the LCS6 T-allele. G-allele carriers were significantly more frequent in Caucasians than other races (Chi-Squared Test, p<0.0001). No associations were found between the LCS6 genotype and T stage, positive lymph node number, tumor differentiation, or primary tumor location (all p>0.2). Moreover, the LCS6 genotype was not associated with DFS (hazard ratio = 0.93, p=0.49) even after combining LCS6 genotype with KRAS mutation status. Conclusions: We report the largest association study investigating the LCS6 polymorphism and colon cancer outcome. There is no significant evidence that the germline LCS6 genotype was associated with DFS in stage III colon cancer patients. Additional studies are needed to determine if LCS6 genotype differs between tumor and germline DNA which may further clarify its prognostic value.

3502 Background: Regorafenib (REG) is an oral multi-kinase inhibitor. The CORRECT trial was conducted to evaluate REG in patients (pts) with mCRC who had progressed after all approved standard therapies. Methods: Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive best supportive care plus either REG (160 mg od po, 3 wks on/1 wk off) or placebo (PL). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate, disease control rate, safety and quality of life (QoL). Efficacy analyses across prespecified subgroups were evaluated using univariate Cox regression. Results: 760 pts were randomized (REG: 505; PL: 255). The OS primary endpoint was met at a preplanned interim analysis. OS and PFS were significantly improved in REG arm compared to PL arm: hazard ratio (HR) for OS 0.77 (95% CI 0.64-0.94, 1-sided p=0.0052), median OS 6.4 vs 5.0 mos; HR for PFS 0.49 (95% CI 0.42-0.58, 1-sided p<0.000001), median PFS 1.9 vs 1.7 mos. Comparable OS and PFS benefits were observed in exploratory subgroup analyses by region, age, time from diagnosis of mCRC to randomization, prior lines of treatment, and KRAS status (shown in table). The most common grade 3+ AEs related to REG were hand-foot skin reaction (16.6%), fatigue (9.6%), hypertension (7.2%), diarrhea (7.2%) and rash/desquamation (5.8%). QoL data will be presented. Conclusions: REG demonstrated statistically significant improvement in OS and PFS over PL, as well as comparable efficacy benefits across pt subgroups analyzed. [Table: see text]

20023 Background: EGFR is a transmembrane receptor tyrosine kinase belonging to the ErbB family of proteins. Anti-EGFR antibodies have shown efficacy as monotherapy and can enhance cytotoxic chemotherapy in patients with advanced colorectal cancers. We studied EGFR expression in primary colon cancers and its association with, microsatellite instability (MSI), clinicopathological variables and patient survival rates. Methods: Archival colon carcinomas were studied from patients with high risk Dukes’ stage B2 (n = 78) and C (n = 230) patients enrolled in a prior adjuvant trial of 5-fluorouracil, leucovorin plus standard dose or high-dose levamisole (NCCTG 91–46–53). EGFR expression (anti-EGFR H11 antibody, DAKO) was analyzed by immunohistochemistry (IHC) and intensity (0–3+), extent and their product (weighted score) were determined. MSI was analyzed using BAT26 and expression of hMLH1, hMSH2 and hMSH6 proteins by IHC. Patients were censored at 5 years after randomization for DFS and censored at 8 years post study randomization for overall survival (OS) data. Results: EGFR protein expression was detected in 216 of 308 (70%) of Dukes’ B2 and C primary colon carcinomas from patients and localized to the plasma membrane. EGFR expression variables (intensity, extent, weighted score) were increased in poor/undifferentiated compared to moderate/well differentiated tumors (p ≤ 0.036). Similar EGFR expression levels were found in MSI-H (n = 27) versus MSS (n = 203) colon cancers and for other clinicopathological variables. EGFR intensity was more likely moderate (2+) or strong (3+) in Dukes’ C versus B2 tumors (p = 0.088). In addition, higher EGFR intensity (2+, 3+) showed a trend toward worse disease-free survival (5 yr DFS %: 62.2 vs. 71.7; p = 0.095), but not overall survival (p = 0.14). Conclusions: EGFR overexpression is associated with increased tumor aggressiveness as indicated by poor tumor cell differentiation and reduced DFS in colon cancer patients receiving adjuvant 5-FU and levamisole. These findings indicate that EGFR may be an important therapeutic target in the adjuvant setting. [Table: see text]

10022 Background: Patients with colon cancers displaying high frequency microsatellite instability (MSI-H) are reported to have a favorable prognosis compared to microsatellite stable (MSS) tumors. However, prognostic factors underlying this observation are poorly understood. We studied apoptotic and proliferative indices and their relationship to MSI status, clinicopathological features, and patient survival rates. Methods: Archival Dukes’ stage B2 (n=83) and C (n=246) primary colon adenocarcinomas from patients enrolled in five 5-fluorouracil-based adjuvant therapy trials were analyzed for MSI using a PCR-based assay (MSI-H: ≥30% of loci with instability), and expression of hMLH1, hMSH2 and p53 proteins by immunostaining. Apoptosis was analyzed by the TUNEL assay and the proliferative index (PI: S phase + G2M) and DNA ploidy by flow cytometry. Correlations between markers and associations with overall survival (OS) censored at 8 yrs were sought. Results: MSI-H (n=58.18%) tumors were more likely proximal, diploid, high grade, p53 negative (vs. MSS/MSI-L; all p<0.0001), and from women (p=0.002). Of 58 MSH-H cases tested, 54 showed loss of hMLH1 (n=50) or hMSH2 (n=4) proteins. Median proliferative index (PI) [12.6 vs. 17.4; p=0.0002] was reduced in MSI-H versus MSS/MSI-L tumors. Lower PI was associated with diploidy (p<0.0001) and negative p53 expression (p=0.003). Apoptotic indices (AIs) were increased in MSI-H cancers (vs. MSS/MSI-L, p=0.082), as was the AI/PI ratio (p=0.0065). Interestingly, AI (p=0.02) and AI/PI (p<0.0001) were significantly increased in diploid versus nondiploid tumors, and after removal of MSI-H cases, relationships held for PI and AI/PI with ploidy. Better OS was related to MSI-H (p=0.032), loss of hMLH1 or hMSH2 (p=0.024), diploidy (p=0.0015), and lower PI (p=0.078), but not AI, AI/PI, nor p53 (adjusting for stage, grade, treatment and stratifying by study). Conclusions: MSI-H tumors are characterized by reduced proliferative indices and a higher ratio of apoptosis to proliferation, reflecting slower tumor growth rates compared to MSS/MSI-L tumors. These features may contribute to their better survival. Lower PI and increased AI/PI are also features of diploid MSS cancers. [Table: see text]

10019 Background: Colon cancers with microsatellite instability (MSI) display resistance to 5-fluorouracil (5-FU), and in vitro resistance can be reversed by restoring DNA mismatch repair proficiency. 5-FU inhibits the thymidylate synthase (TS) enzyme and TS may predict clinical outcome after 5-FU-based chemotherapy. To define molecular predictors of prognosis, we analyzed TS, p53, chromosome 17p allelic imbalance (AI), and patient survival stratified by MSI status. Methods: Primary colon carcinomas from patients enrolled in five 5-FU-based adjuvant therapy trials were analyzed for MSI and 17p AI using 11 microsatellite markers (MSI-H: ≥ 30% of the loci demonstrating instability). For 17p AI, markers included D17S261 and TP53 at or near the p53 locus. Expression of DNA mismatch repair (hMLH1, PharMingen; hMSH2; Oncogene), TS (TS106, Zymed), and p53 (D07, Novacastra) proteins were analyzed by immunohistochemistry. Correlations between markers and associations with overall survival (OS) were determined. Patients were censored at 5 years for DFS and at 8 years post study randomization for overall survival (OS) data. Results: Of 320 Dukes’ stage B2 and C cancers studied, 60 of 320 (19%) were MSI-H. TS expression variables (intensity, extent, weighted score) were similar in MSI-H and MSI stable/low frequency (MSS/MSI-L) cancers; similar results were found using DNA mismatch repair (dMMR) proteins. MSI-H tumors had lower stage (p= 0.0007), fewer metastatic lymph nodes (p= 0.004), and improved OS (vs. MSS/MSI-L tumors; p= 0.01). Loss of dMMR proteins was also associated with better OS (p= 0.006). None of the TS variables were prognostic for OS. Histologic grade (p= 0.0008) and nodal status (p= 0.0002) were associated with OS in contrast to 17p LOH or p53. Only MSI status or dMMR, histologic grade, and tumor stage were independent markers for OS. Conclusions: MSI-H tumors show earlier stage at presentation and better stage-adjusted survival rates. MSI status and TS expression were unrelated and TS was not prognostic, suggesting that TS levels cannot explain therapeutic resistance to 5-FU reported in MSI-H colon cancers. [Table: see text]

6006 Background: In March 1998, the Common Toxicity Criteria version 2.0 was implemented and introduced the collection and reporting of attribution of adverse events to study treatment. Collection and reporting of attribution adds time and cost to the clinical trial process, and its use while reporting adverse events (AE) in the literature has varied. We investigate whether attribution adds value to the interpretation of AE data. Methods: Patients on the placebo arm of trial 97–24–51 (CAI vs. Placebo) were chosen since the true relationship of the event to the study treatment is known (“unrelated”). Attribution was collected per CTCv2.0 and categorized as “not related” (not related or unlikely) and “related” (possible, probable, or definite). All reported AEs and the maximum severity for a given AE were evaluated. Patterns were evaluated using generalized estimating equations adjusting for multiple events per patient. Changes in attribution over time for the same event were computed. Results: 84 patients on the placebo arm experienced a total of 1013 AEs. 47% of AEs were reported as “related” with 36% reported as possibly related. Known CAI AEs were more likely to be reported as “related” (p = 0.005). Pulmonary AEs were more likely to be reported as “not related” (p = 0.0006). No patterns were observed by gender, age, PS, severity or treatment cycle of AE. When the same event was reported on the same patient in multiple cycles, the attribution category changed at least once 36% of the time with 25% changing from “related” to “unrelated” or vice versa. Conclusion: Almost 50% of events on a placebo arm of a phase III trial were reported as being attributed to study treatment and 25% of the time the same event was not consistently attributed. These data suggest that attribution is difficult to determine, unreliable, and thus its value in large phase III trials is questionable. [Table: see text] No significant financial relationships to disclose.

3525 Background: The prognosis for patients with hepatic metastases from M-CRC can be poor. However, surgery followed by HAI FUDR plus systemic (SYS) 5-FU improves 5-yr survival rates. Oxaliplatin (OXAL) combined with capecitabine (CAPE) has demonstrated activity in advanced CRC. We report early results of an analysis of SYS OXAL plus CAPE, alternating with HAI FUDR. The primary endpoint is 2-yr survival (2YS). Methods: Patients with M-CRC liver lesions amenable to resection ± ablation were eligible. HAI + SYS therapy was initiated following metastasectomy. Alternating courses of HAI consisted of 0.2 mg/m2/d FUDR and dexamethasone, d1–14 weeks 1 & 2. SYS therapy included 130 mg/m2 OXAL d1, with CAPE at 1000 mg/m2 p.o. BID, d1–14, weeks 4 & 5. Two additional 3-wk courses of SYS therapy were given. CAPE was reduced to 850 mg/m2/BID after interim review of toxicity (GI Cancer Symposium 2004). Patient Characteristics: 54 of 70 patients were able to initiate HAI FUDR + SYS. 52% had a solitary met and 24% presented with bilobar mets. Results: Patients completed median of 6 cycles (range 1 - 6). Reasons for discontinuation included: refusal/toxicity (10), completed per protocol (32), recurrence (4), and medical/other (3). No post-operative or treatment related deaths were reported. 69% (31/45) of evaluable patients are alive with a minimum 18 mos of follow-up. 6 deaths occurred in less than 2 yrs. 44% (20/45) have recurred, with 40% (8/20) having liver involvement. Median time-to-progression is 32 mos with an estimated 2YS rate of 86% (95% CI 76–97%). Conclusions: The combination of HAI FUDR and SYS therapy appears to improve outcome following resection of hepatic CRC-M. Updated follow-up is necessary to solidify the primary endpoint of 2YS. Supported by NIH Grant CA25224–18, Sanofi-Synthelabo, and Roche Laboratories, Inc. Maximum Severity, Grade 3+ (N=54) [Table: see text] [Table: see text]

3520 Background: This report examines UGT1A1*28, toxicity, and outcome in trial NCCTG N9741 patients (pts) receiving combination chemotherapy for advanced colorectal cancer. Methods: Blood samples were collected from 520 pts randomized between 2/18/00 and 7/18/02. Pts were treated with irinotecan/5-fluorouracil (5FU)/leucovorin (LV) (IFL, n=114), oxaliplatin/5FU/LV (FOLFOX, n=299), irinotecan/oxaliplatin (IROX, n=107). 19% of IFL pts received full-dose (125 mg/m2) irinotecan; the rest received a reduced dose (100 mg/m2). Toxicity was evaluated every cycle. Correlation of dichotomous outcomes and genotype status used Fisher’s exact tests. Univariate logistic regression was used to test the association between continuous variables and binary outcomes, including a test of trend, and multivariate logistic regression to adjust for known risk factors: performance status, age, gender. Time to progression (TTP) and overall survival (OS) were tested for association with UGT1A1 using the log-rank test. Statistical significance was prospectively set at .01 to control for multiple comparisons. Results: Frequency of UGT1A1 genotype was 44% 6/6, 42% 6/7, and 9% 7/7. In all arms, the rate of grade (G) 4 neutropenia (neut) ( Table ) and G3+ febrile neut (FN) was higher in pts with the 7/7 than in pts with 6/7 and 6/6. No association was seen between UGT1A1 and diarrhea, tumor response, TTP, or OS overall or for any treatment arm. The odds ratios for pts with 7/7 developing G4 neut and G3+ FN compared with pts with 6/6 are shown ( Table ). Statistically significant associations between the 7/7 polymorphism and G4 neut were seen in pts treated with IROX (P=.004) and in all pts (P=.007). The association between 7/7 and G3+ FN was also significant for IROX (P=.006). Conclusions: There is a higher risk of neut in 7/7 pts. Due to low frequency of the 7/7, exclusion of all pts with 7/7 reduces the overall G4 neut rate from 18% to 17%. UGT1A1 was not a predictor of response, TTP, or OS for any arm. [Table: see text] [Table: see text]

3517 Background: The combination of oxaliplatin, fluorouracil, and leucovorin is effective in many patients with colon cancer treated in either the advanced or adjuvant disease setting. To better identify the risks & benefits of this regimen for elderly patients we compared safety & efficacy data for the FOLFOX4 regimen (oxaliplatin plus fluorouracil/leucovorin administered bimonthly) in patients over & under 70 years of age. Methods: We conducted a retrospective analysis of 3742 patients (614 aged ≥ 70) with colorectal cancer enrolled in four clinical trials using the same FOLFOX4 regimen as adjuvant therapy, or as first- or second-line therapy in advanced disease. Endpoints included grade ≥ 3 adverse events, response rate (RR) (in studies of advanced disease), progression (metastatic)/relapse free (adjuvant) survival (P/RFS), overall survival (OS), and dose intensity. Results: Age ≥ 70 was associated with slightly higher rates of neutropenia and thrombocytopenia but no other grade ≥ 3 adverse events (see table). There was no difference in 60-day mortality (1.1% vs 2.3%, p=0.20). We observed no significant difference in any measure of therapeutic impact of FOLFOX based on age, including P/RFS, OS, response rate, or dose intensity (see table). Conclusions: The FOLFOX4 regimen maintains its efficacy/safety ratio in elderly patients with colorectal cancer, and was administered per protocol at similar drug doses compared to the younger patients enrolled on these trials. Age alone should not be a factor limiting the use of FOLFOX4 provided patients are carefully evaluated and monitored. This analysis was supported by Sanofi-Aventis [Table: see text] [Table: see text]