Colon Cancer Pts Research Articles

Sentinel lymph node (SLN) mapping (M) in colon cancer (CCa) by da Vinci robotic system (DRS): First pilot study.

589 Background: SLNM in CCa has been established as an aid to the pathologist to identify the nodes most likely to harbor micrometastasis. The technique has been well- established by in vivo and ex vivo technique. No such technique has been described by DRS in CCa. Hence, a pilot study was undertaken to identify if SLNM can be performed by DRS during robotically assisted colectomy as in open cases. Methods: Patients (Pts) with CCa were randomly selected for either robotic or open surgery. During each case, 1% methylene blue dye was injected in vivo subserosally around the tumor. Standard oncologic operations were done in each case. The first 1-4 blue nodes near the tumor were tagged with suture as SLNs. Data was collected for demographics, tumor pathology and peri-operative events. Results: There were a total of 11 consecutive robotic pts and 15 open pts. The data was compared between the robotic vs open groups as follows: Primary sites including Cecum (1 vs 3), Ascending Colon (3 vs 4), Transverse Colon (4 vs 5), Sigmoid Colon (2 vs 3); Average number of LNs (18.5 vs 17.6); Average number of SLNs (3.3 vs 3.0), and nodal positivity (50% vs 50%). The success rate was 100% in each group. Conclusions: There are great similarities for SLNM between robotic and open surgeries for CCa in regards to success rate, nodal harvest, SLNs, and nodal positivity. Hence, SLNM should be pursued when robotic surgeries are performed for CCa pts as in open cases. [Table: see text]

523PD - The 12-Gene Colon Cancer Recurrence Score (RS) Predicts Recurrence in Stage II and III Colon Cancer Patients Treated with 5FU/LV (FU) and 5FU/LV + Oxaliplatin (FU + OX): Validation in NSABP C07

ABSTRACT Background Standardized tools which accurately quantify recurrence risk are needed for optimal adjuvant treatment of colon cancer. The 12-gene RS has been validated in stage II colon cancer pts from QUASAR and CALGB 9581. We conducted a large prospectively-designed clinical validation study of RS, w/ pre-specified endpoints, methods, and analysis plan, in stage II and III colon cancer pts randomized to FU or FU + Ox in C-07. Methods 50% of C-07 pts w/ tissue were randomly selected, stratified on stage and recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually microdissected fixed tumor tissue. Data were analyzed by Cox regression controlling for stage and treatment (TRT). Results RT-PCR was successful in 892/921 pts (97%): 449 FU, 443 FU + Ox; 264 st II, 409 st IIIA/B, 219 st IIIC. The primary endpoint was met: RS predicted recurrence (HR/25 units = 1.96, 95% CI 1.50-2.55 p Conclusions RS predicts recurrence risk in stage II and III colon cancer, capturing underlying biology and providing risk information beyond conventional factors. RS is not predictive of relative Ox benefit but enables better discrimination of absolute Ox benefit as a function of risk. Incorporating RS into the clinical context may better inform adjuvant therapy decisions for pts w/ stage III as well as stage II colon cancer. Disclosure M. Lee: I am an employee and stockholder of Genomic Health, Inc. M. Lopatin: I am an employee and stockholder of Genomic Health, Inc. K.M. Clark-Langone: I am an employee and stockholder of Genomic Health, Inc. C. Millward: I am an employee and stockholder of Genomic Health, Inc. S. Shak: I am Chief Medical Officer and a stockholder of Genomic Health, Inc. All other authors have declared no conflicts of interest.

LBA4 - Adjuvant Folfox4 with or without Cetuximab (CTX) in Patients (PTS) with Resected Stage III Colon Cancer (CC): Dfs and OS Results and Subgroup Analyses of the PETACC8 Intergroup Phase III Trial

ABSTRACT Background The potential benefit of adding CTX to the current standard treatment for stage III CC, was assessed. Subgroup analyses of demographic, oncologic and molecular data may improve our understanding of this patient population. Methods CC pts were randomized 28-56 days following resection. They received 12 biweekly cycles of oxaliplatin 85 mg/m2 day (d) 1, with leucovorin 200 mg/m2, 5-FU 400 mg/m2 bolus IV, followed by 5-FU 600 mg/m2 22-hr IV on d1-2 (FOLFOX4), without (arm A) or with weekly CTX (arm B) 250 mg/m2 (initial dose 400 mg/m2, cycle 1). Primary endpoint was disease free survival time (DFS). Secondary endpoints included overall survival (OS), treatment compliance and safety. Planned accrual of 1,407 KRAS wild-type (wt) pts provided 90% power to detect a hazard ratio (HR) of 0.75 with 2-sided a = 0.05, with interim analyses after 65% of planned events. Preplanned subgroup analyses were performed. Results 1,602 KRAS wt pts (811 arm A, 791 arm B), were randomized. BRAF status was determined in 1134 (71%) KRAS wt pts; median follow-up ∼40 months. This interim analysis showed no difference between arms for DFS (HR 1.047, 95% CI 0.85, 1.29; p = 0.66) or OS (HR 1.09, 95% CI 0.81, 1.46; p = 0.55) in KRAS wt pts or for DFS (HR 0.985, 95% CI 0.75, 1.28; p = 0.91) or OS (HR 0.98, 95% CI 0.67, 1.44; p = 0.92) in KRAS/BRAF wt pts (n = 984). Worse outcomes were seen with CTX in pts >70 years (n = 149, DFS: HR 1.97, 95% CI 0.99, 3.93; p = 0.051), in females (n = 666, HR 1.45, 95% CI 1.03, 2.02; p = 0.03) and pts with right-sided CC (n = 570, HR 1.40, 95% CI 1.01, 1.94; p = 0.04). Conversely, a trend towards a better outcome was seen in pts with poor prognosis tumors (high grade, T4, N2, perforation/obstruction, VELI+) and was significant in pts with pT4N2 at diagnosis (n = 146, HR 0.55, 95% CI 0.35-0.88; p = 0.01). Conclusions In this trial adding CTX to FOLFOX4 offered no benefit to pts with resected stage III KRAS wt and KRAS/BRAF wt CC. Subgroup analyses in this large population suggest that pts with pT4N2 tumors may receive some benefit from CTX in this setting. MSI status determination is ongoing to explore its interaction with poor outcome in female pts and those with right-sided tumors. Supported by Merck-Serono, Sanofi-Aventis. Disclosure J. Tabernero: Participated at a Merck KGaA board G. Folprecht: -Honoraries, for lectures and advisory boards from Merck KGaA and Bristol Mayers Squibb. -Study grant from Merck KGaA -Involved in clinical trials with Imclone and Merck KGaA E.J.D. Van Cutsem: Eric Van Cutsem received research funding from Merckserono. P. Rougier: Consultancy/advisory role and honoraria Merck KGaA. O. Bouche: Membership on an advisory board P. Laurent-Puig: Membership on an advisory board of Merck Serono and Amgen. All other authors have declared no conflicts of interest.

Evaluation of relapse-free survival in T3N0 colon cancer: The role of chemotherapy—A multicentric retrospective analysis.

e14082 Background: Use of adjuvant chemotherapy (AC) in Stage II Colon Cancer (CC) is still under debate. Choice should be based on patients (pts) and disease characteristics. According to worldwide guidelines AC should be considered in high-risk (H) T3N0 pts. No data are available for better option in low-risk (L) pts. Aim of the study is to evaluate relapse-free survival (RFS) and disease-free survival (DFS) retrospectively in T3N0 CC pts related to treatment. Methods: RFS and DFS are evaluated with Kaplan Meier method. In order to find the optimal cut off for node number the receiver operating characteristics curve analysis and Maximally Selected Rank Statistics were performed. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15 respectively. Results: 1,000 pts with T3N0 CC were recruited. To date, data of 926 pts are available. Median age was 69 (29-93), M/F 513/413, Grading 1/2/3 46/668/158; 360 L (39%), 411 H (44%), 155 unknown (17%); 137 (15%) pts showed symptoms (S) at diagnosis: 51 pts had perforation (P) or bowel obstruction (BO). Median sampled lymph nodes (LN) were 15 (1-76); 383 (41%) pts were treated with AC. Median follow up (fu) was 5 years (yr) (range 3-24). Survival analysis was performed only for pts with a minimum fu of 3 yr and younger than 80 (80%). 5 yr RFS was 78% and 5 yr DFS was 76% At multivariate analysis S and AC were prognostic factors for RFS. AC is prognostic factor for all endpoints (data are shown in table). In L group 5 yr RFS was 88% in treated pts and 75% in non-treated pts (p 0.03); in H group was respectively 82% and 72% (p 0.006). Conclusions: Preliminary data confirmed the role of known prognostic factors and suggest the relevance of AC also in L stage II T3N0 CC pts. However, the highest risk in L subgroup should be identified to be submitted to AC. Data collection is ongoing, update results will be presented. [Table: see text]

Delivery of adjuvant chemotherapy (AC) to veterans with resected colon cancer.

e16557 Background: Patients (pts) with incomplete administration of AC for colon cancer (CC) likely experience inferior survival while oxaliplatin- and capecitabine-containing AC may not improve survival for older pts. The influence on AC completion of age, other baseline patient characteristics, or regimen characteristics is unknown. We evaluated the association of baseline characteristics and planned AC regimen with AC delivery in resected CC pts. Methods: This retrospective cohort study identified stage II and III resected CC pts from our local VA Medical Center tumor registry who initiated AC between 2004 and 2010. AC delivery was measured as percentage of planned cumulative dose (PCD) of 5-fluorouracil or capecitabine delivered. Baseline characteristics were demographics, CC stage, travel distance to the treatment site (TD), Adult Comorbidity Evaluation-27 score, and labs. We classified AC as fluoropyrimidine (oral or IV)-based and as oxaliplatin-containing. Linear regression tested each association with PCD. We recorded occurrence of toxicity and death. Cox regression models were used for survival analysis. Results: Fifty pts (98% male, median age 63) initiated AC for stage II (n=6) or III (n=44) disease with median interval from resection to AC of 7.4 weeks. The median PCD was 75%; median treatment duration was 5 months. Lower PCD was associated with older age (p=0.05), lower GFR (p=0.05), higher TD (p=0.02), lower baseline hemoglobin (p=0.10), and receipt of capecitabine (p<0.01). Receipt of capecitabine (p=0.008) and TD (p=0.04) remained significantly associated with PCD in a multiple linear regression model. Toxicity was noted for 78%, and PCD tended to be lower for reported cardiac events (p=0.07). Pts older than 63 had inferior survival (HR=4.17, p=0.03). Pts receiving less than 80% PCD tended toward inferior survival (HR=4.31, p=0.07). Conclusions: Capecitabine-based AC and travel distance were associated with lower PCD, which may negatively impact survival. Efficacy of shorter courses of oxaliplatin-based chemotherapy is being evaluated elsewhere. Close attention to quality prescribing and monitoring practices for capecitabine are recommended. These findings should be confirmed in a larger cohort.

Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5FU/LV (FU) and 5FU/LV+oxaliplatin (FU+Ox).

3512 Background: Standardized clinical tools which accurately quantify recurrence risk are needed for optimal adjuvant treatment of colon cancer. The 12-gene RS has been validated in stage II colon cancer pts from QUASAR and CALGB 9581. We conducted a large prospectively-designed clinical validation study of RS, w/ pre-specified endpoints, methods, and analysis plan, in stage II and III colon cancer pts randomized to FU or FU+Ox in NSABP C-07. Methods: 50% of C-07 pts w/ tissue were randomly selected, stratified on stage (AJCC 6th) and recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually microdissected fixed colon tumor tissue. Data were analyzed by Cox regression controlling for stage and treatment (TRT). Results: RT-PCR was successful in 892/921 pts (97%): 449 FU, 443 FU + Ox; 264 st II, 409 st IIIA/B, 219 st IIIC. The primary endpoint was met: RS predicted recurrence (HR/25 units=1.96, 95% CI 1.50-2.55 p<.001). RS also predicted disease-free survival (p<.001) and overall survival (p<.001). RS predicted recurrence (p=.001) independent of T and N stage, MMR, nodes examined, grade, and TRT. Predefined high RS group (26% of pts) had higher recurrence risk than low RS group (39% of pts): HR=2.11, p<.001. Cox model 5 yr recurrence risk (95%CI) in FU treated pts by RS group (low, int, high): st II 9% (6-13%), 13% (8-17%), 18% (12-25%); st IIIA/B 21% (16-26%), 29% (24-34%), 38% (30-46%); st IIIC 40% (32-48%), 51% (43-59%), 64% (55-74%). RS did not have significant interaction w/ stage (p=0.90) or age (p=0.76). Relative benefit of Ox was similar across range of RS (interaction p=0.48); accordingly, in Cox model and Kaplan-Meier analyses, absolute benefit of Ox increased w/ higher RS. Conclusions: RS predicts recurrence risk in stage II and III colon cancer, capturing underlying biology and providing risk information beyond conventional factors. RS is not predictive of relative benefit of Ox added to adjuvant FU but enables better discrimination of absolute Ox benefit as a function of risk. Incorporating RS into the clinical context may better inform adjuvant therapy decisions for pts w/ stage III as well as stage II colon cancer.

Relationship between genetic markers and quality of life (QOL) in stage III colon cancer (CC) patients (pts) prior to adjuvant treatment (N0147).

3617 Background: In metastatic colorectal cancer (CRC), previous studies suggested potential relationships between certain drug metabolizing (DM) genes (DPYD, ERCC2, GSTP1 and TYMS) and QOL prior to receipt of chemotherapy (Sloan, Plenary Session ASCO 2004). The current study is the first to examine relationships between similar DM genes and QOL in stage III CC pts. Methods: 1,583 CC pts on a randomized adjuvant stage III, phase III trial received FOLFOX, FOLFIRI, or either +/- Cetuximab. Genomic DNA and baseline QOL data via linear analogue self assessment (LASA) scales with 4 QOL variables were obtained. 53 DM SNPs were selected for known functional effect within potential regulatory sites. Two-sample t-tests assessed differences in QOL between pts with variants and wild-type status. Differences of at least 10 points on a 0-100 point QOL score were considered clinically significant. Results: 14 relationships between DM genes and QOL were detected at the nominal p < 0.05 level; six of these were related to DPYD, ERCC2, GSTP1 and TYMS. Relationships were also observed at the 0.05 level with polymorphisms of genes DPYS, ERCC1, MGMT, MTHFR, OPRT and UGT1A1 based on unadjusted and adjusted association tests. GSTP1 I105V and OPRT 5’UTR 28 A>G markers differed on fatigue scores (p=0.04, 0.005, respectively). Variants on MTHFR R594Q were associated with higher mental acuity scores (p=0.02). These relationships remained after adjusting for age, gender, race, T stage, PS, disease site, lymph nodes involved, and grade. The robustness of the observed associations varied with the multiple comparison adjustment method. Conclusions: Similar to the earlier study of stage IV CRC, we observed a possible relationship in pts with Stage III CC with regard to DM genes and QOL, although these relationships were more modest than observed in Stage IV pts. These DM genes may be in linkage disequilibrium with other genetic variants that more directly affect behavior and QOL. Further genome wide association studies are needed to clarify these relationships.

Guideline-based treatment utilization, treatment time, and cost of chemotherapy for metastatic colon cancer patients treated in U.S. community oncology practices from 2005 to 2009.

e14118 Background: Adherence (Ad) to national treatment guidelines (TG) is important in improving the quality, outcomes, and cost of cancer treatment (TX) in the U.S. We examined regimens (Reg) utilized, TG-Ad, time on metastatic TX, and cost of chemotherapy prescribed by U.S. community oncology practices to treat patients (Pts) with metastatic colon cancer (MCC) in 2005 and 2009. Methods: Adult colon cancer Pts beginning first line metastatic treatment (LOT-1) in each full calendar year for 2005 and 2009 were reviewed from a large U.S. medical oncology clinical database derived from web-based drug dispensing technology. Reg utilized and 2-yr time on metastatic TX were analyzed and compared to TG recommendations. Reg costs based on Medicare reimbursement were compared. Results: The average number of LOT and number of unique drugs Pts were exposed to were similar between 2005 and 2009. About 70% of Pts received only one LOT. In LOT-1 and 2, TG regs were prescribed more often than Non-TG regs for both groups. TG-Ad was significantly higher in 2009 than in 2005 for LOT-1 (p < 0.0001). Pts receiving TG-Ad Reg for LOT-1 had a significantly longer total metastatic treatment time in both 2005 and 2009. In both 2005 and 2009, FOLFOX+Bev was the most frequent LOT-1 Reg given (37% of Pts), while FOLFIRI+Bev was the most frequent LOT-2 Reg given. 69% of Pts received Bev with LOT-1 in both 2005 and 2009; of those, 28-30% continued to receive Bev with LOT-2. Costs for the top 5 LOT-1 Regs were $17,031 to $34,400 and $5,512 to $39,835 for 2005 and 2009, respectively. Conclusions: U.S. community oncology practices significantly improved guideline Ad in the TX of MCC from 2005 to 2009. In LOT-1, TG Regs were prescribed more than non-TG Regs for both groups. TG Ad for LOT-1 significantly improved time on metastatic TX in both groups. FOLFOX+Bev and FOLFIRI+Bev were most frequently prescribed for LOT-1 and LOT-2, respectively. Costs for the five most utilized Regs vary considerably. [Table: see text]

Senescence, a new concept in pathologic response evaluation of rectal carcinomas (RC) after neoadjuvant treatment.

e21021 Background: Available protocols of response evaluation after therapy are based on the presence of viable cells, fibrosis and necrosis. Senescence is an irreversible cell cycle arrest that can be activated by different kinds of stress like DNA damage and cytotoxic drugs. Senescent cells are histologically very similar to viable neoplasic cells and usually evaluated alike. Our hypothesis is that neoadjuvant treatment can induce senescence as part of the therapeutic response and its presence may impact the prognosis. Methods: Tumor samples of 45 consecutive patients (pts) with RC treated between sept/02 and feb/2007 with fluorouracil-based chemotherapy and neoadjuvant radiotherapy, and of 33 non-treated colon cancer pts (controls), were selected. p53 and P16-ki67 double immunostaining were retrospectively evaluated in endoscopic-pretreatment biopsies, post-therapy specimens, and controls. P16+/ki67- malignant glands were considered as senescent-like glands. SPSS v20.0 (Kruskal-Wallis, Cox regression and log-rank test) was employed for analysis. Results: After a median follow up of 60 months 13 pts had relapsed. Significant differences in the percentage of senescent-like glands were observed between treated carcinomas and their pre-treatment samples (p=0.0001) and also with the colonic-non-treated carcinomas (p=0.0001). A tendency toward a better disease free survival (DFS) (p=0.236) in those patients with more than 30% of senescent glands after treatment was observed. No differences in p53 were found between the 3 groups. However, low levels of p53 expression in pretreatment-rectal biopsies correlate with a better pathologic response (GR) (p=0.029), and better DFS (p=0.0958). Conclusions: The number of senescent-like glands increases after neoadjuvant therapy. There was a tendency for a better DFS in the pts with treatment-induced senescence. Moreover, an inverse correlation between p53 expression in pretreated endoscopic-samples and pathologic response and DFS was observed. Further and larger studies should be performed to confirm the prognostic implications of evaluating senescence markers in treated rectal carcinomas.

Adjuvant chemotherapy (AC) use and outcomes in stage II colon cancer (CC) with and without poor prognostic features.

3527 Background: AC is frequently considered inpatients (pts) with "high risk" stage II CC, defined by the presence of >/=1 poor prognostic features, such as obstruction or perforation, T4 stage, <12 lymph nodes retrieved, positive margins, and lymphovascular or perineural invasion. However, survival benefits associated with AC use in high risk pts remain largely unproven. Our aims were to 1) examine patterns of AC use in stage II CC and 2) explore the relationship between AC use and survival in high vs low risk pts. Methods: All pts diagnosed with stage II CC in British Columbia from 1999 to 2008 and evaluated at any 1 of 5 regional centers were reviewed. Kaplan-Meier and Cox regression methods were used to correlate a) high vs low risk status and b) receipt of AC with relapse-free (RFS), disease specific (DSS) and overall survival (OS). Results: We identified 1,697 stage II CC pts: 1,236 (73%) high risk and 461 (27%) low risk among whom 363 (29%) and 61 (13%) received AC, respectively. Individuals with high risk features who received AC were younger (median 62 vs 72 years, p<0.001) and had better performance status (ECOG 0/1 47% vs 34%%, p=0.02). In the high risk group, AC was associated with improved 5-year OS, but not with RFS or DSS (Table). After adjusting for confounders, an OS advantage from AC persisted for high risk pts (HR 0.67, 95CI 0.52-0.86, p=0.002), but no significant RFS or DSS benefits were seen (HR 0.76, 95CI 0.58-0.99, p=0.05 and HR 0.75, 95CI 0.55-1.02, p=0.11, respectively). Subgroup analyses showed that individuals with T4 lesions had improved RFS (HR 0.63, 95CI 0.42-0.95, p=0.03), DSS (HR 0.59, 95CI 0.37-0.93, p=0.02), and OS (HR 0.50, 95CI 0.33-0.77, p=0.002). Conclusions: In this population-based cohort of stage II CC, AC was associated with an OS advantage in high risk pts, likely due to pt selection. RFS and DSS benefits were mainly seen in T4 lesions, suggesting a limited role for AC in pts deemed high risk based on clinical and pathological factors. Risk stratification based on molecular testing should be further explored. [Table: see text]

Abstract 4833: Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutics antibody cetuximab

Abstract <Background> The epidermal growth factor receptor directed antibody, cetuximab (Cmab), is an effective therapy for patients (pts) with colorectal cancer (CRC) particularly with KRAS and BRAF wild type. Treatment in all pts is limited eventually by the development of acquired resistance but little is known about the underlying mechanism. <Methods> We established 3 Cmab resistant cell lines HCC827CR, GEOCR and A431CR through the exposure to increasing concentration of Cmab. In order to determine why these cell lines were resistant to Cmab we performed genome wide copy number analyses and analysis of ERBB family ligands. We analyzed the growth of Cmab sensitive and resistant cells in vitro and in vivo. Furthermore, we obtained clinical specimens from colon cancer pts treated with Cmab based therapy. Specimens obtained prior to therapy and at the time of Cmab resistance were evaluated. <Result> Genome-wide copy number analysis detected the localized genomic amplification in HCC 827CR, which was identified as ERBB2 and confirmed using FISH. Amplification of ERBB2 was also detected in the GEO CR cells. ERBB2 inhibition, with either trastuzumab or lapatinib, restored the Cmab sensitivity in those cell lines. In drug sensitive cell lines, Cmab effectively inhibited growth and ERK1/2 signaling both of which were inhibited in presence of ERBB2 amplification. In contrast, despite detecting ERBB2 activation in the A431 CR cells we did not identify ERBB2 amplification. Instead we detected increased levels of the ERBB3 ligand heregulin. The disruption of ERBB2/ERBB3 herterodimerization using pertuzumab restored Cmab sensitivity in A431CR in vitro and in vivo. CRC patients with ERBB2 amplification (n=13) treated with Cmab based therapy survived significantly shorter than pts without ERBB2 amplification (n=220) (The median OS 89 vs 149 days, p=0.0013; log-rank test). We also identified evidence of ERBB2 amplification at the time of acquired drug resistance using either tumor biopsies or by analyzing serum HER2 extracellular domain (ECD). We further analyzed plasma heregulin from CRC patients and the concentrations ranged widely (Median, 1622 pg/ml; range 0-18,045 pg/ml). Pts who achieved response to Cmab therapy (n=16) had significantly lower heregulin concentration than pts without response (n=49) (Mean, 1,050 vs 3,601 pg/ml, p<0.001; unpaired t test). In addition we identified a significant increase in plasma heregulin levels obtained at the time of clinic cetuximab resistance compared to pre-treatment specimens (p=0.0313). <Conclusion> We identify activation of ERBB2 signaling, either through ERBB2 amplification or through heregulin upregulation, as a mechanism of both de novo and acquired cetuximab resistance. These results suggest that ERBB2 inhibitors, in combination with Cmab, may represent a rational therapeutic strategy in Cmab-resistant cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4833. doi:1538-7445.AM2012-4833

Evaluation of relapse-free survival in T3N0 colon cancer: The role of chemotherapy—A multicentric retrospective analysis.

578 Background: Use of adjuvant chemotherapy (AC) in stage II colon cancer (CC) is still under debate. Choice should be based on patients (pts) and disease characteristics. According to worldwide guidelines AC should be considered in high-risk (H) T3N0 pts. No data are available for better option in low-risk (L) pts. Aim of the study is to evaluate relapse-free survival (RFS) and disease-free survival (DFS) retrospectively in T3N0 CC pts related to treatment. Methods: RFS and DFS are evaluated with Kaplan Meier method. In order to find the optimal cut off for node number the receiver operating characteristics curve analysis and maximally selected rank statistics were performed. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15 respectively. Results: 1,000 pts with T3N0 CC were recruited. To date, data of 764 pts are available. Median age was 68 (29-93), M/F 42/344, grading 1/2/3 40/561/132; 303 L (40%), 356 H (46%), 105 unknown (14%); 121 (16%) pts showed symptoms (S) at diagnosis: 43 pts had perforation (P) or bowel obstruction (BO). Median sampled lymph nodes (LN) were 15 (1-76); 339 (44%) pts were treated with AC. Median follow up (fu) was 5 years (yr) (range 3-24). Survival analysis analysis was performed only for pts with a minimum fu of 3 yr and younger than 80 (79%). 5 yr RFS was 79% and 5 yr DFS was 77%. At multivariate analysis S, LN and AC were prognostic factors for RFS. AC is prognostic factor for all endpoints (Table). In L group 5 yr RFS was 88% in treated pts and 71% in non-treated pts (p 0.004); in H group was respectively 84% and 70% (p 0.002). Conclusions: Preliminary data confirmed the role of known prognostic factors and suggest the relevance of AC also in L stage II T3N0 CC pts. However, the highest risk in L subgroup should be identified to be submitted to AC. Data collection is ongoing. [Table: see text]

Validation of a 12-gene colon cancer recurrence score (RS) in patients (pts) with stage II colon cancer (CC) from CALGB 9581.

3518 Background: The 12-gene RS (Genomic Health, Inc.) has been shown to predict risk of recurrence in stage II colon cancer (CC) pts in QUASAR. We conducted a validation study in tumor specimens from pts enrolled in CALGB 9581, which found no difference for edrecolomab (MoAb 17-1A) v. observation in 1672 pts with, on average, low risk stage II CC (14% 5-yr recurrence.) Methods: Cohort sampling included all pts with available tissue and recurrence and random pts w/o recurrence (3:1 ratio). Gene expression was analyzed by RT-PCR using FFPE from primary tumor. Mismatch repair (MMR) protein status (D= Deficient; I= Intact) was assessed by IHC for MLH1 and MSH2. Primary aim: prognostic value of continuous RS alone and in presence of MMR and traditional clinical/pathologic prognostic variables. A weighted Cox proportional hazards model was used to test the association between RS and recurrence-free interval (RFI) based on a Wald-type test statistic constructed using a weighted partial likelihood estimate and robust variance estimate. Results: Tumor was available for 1361/1672 (81%) pts. RT-PCR was successful in 690 (162 recurrences) of 736 pts (21% MMR-D, 35% > 70 yrs old, 47% < 12 nodes.) The continuous RS was significantly associated with RFI in univariate analysis (hazard ratio (HR)/ 25 units, 1.52; 95% CI, 1.09-2.12; p=0.01). MMR-D was also associated with RFI (HR, 0.62; 95%CI, 0.39-0.99; p=0.04); # nodes examined and lymphovascular invasion (LVI) were borderline significant (both p=0.06). In a pre-specified multivariate analysis w/ MMR, T-stage, nodes examined, grade, and LVI, RS was the only significant predictor of recurrence (HR/25 units=1.68, 95%CI 1.18-2.38; p=0.004). Recurrence risk at 5 yrs increased as RS increased and among subgroups defined by T-stage and MMR. In pts with T3, MMR-I tumors (n=488) pre-specified low (44% of pts RS < 29), intermediate (33%), and high (22% w/ RS > 39) RS groups had average 5-yr recurrence risks of 13%, 16%, and 21%, respectively. Conclusions: In 9581, RS improves the ability to discriminate higher from lower recurrence risk stage II CC pts beyond known prognostic factors, particularly in T3, MMR-I pts where traditional factors like grade and LVI were not prognostic.

Body mass index (BMI) as a prognostic and predictive factor in stage II/III colon cancer: An analysis of the ACCENT database.

e21126 Background: Obesity is an established risk factor for developing colon cancer. We determined the impact of body mass index (BMI) upon prognosis and treatment benefit using the Adjuvant Colon Cancer Endpoints (ACCENT) database. Methods: BMI (kg/m2) was categorized at baseline in patients (pts) with TNM stage II and III colon carcinomas (n= 23,315) enrolled in 20 randomized trials of 5-fluorouracil-based adjuvant therapy. Cox models were used to determine the association of BMI with time-to-recurrence (TTR), disease-free (DFS) and overall survival (OS). Results: Among colon cancer pts, 4194 (18%) were obese (BMI ≥30 kg/m2), 8347 (35.8%) overweight (BMI 25-29.9 kg/m2), 9062 (38.9%) normal weight (BMI 20-24.9 kg/m2), and 1712 (7.3%) underweight (BMI < 20 kg/m2). Obese vs normal weight pts were more likely to be younger (median age 60 vs 61 yr; p=0.0006), have distal tumors (57% vs 55%; p=0.0066), and be stage III vs II (68% vs 64%; p<0.0001). In univariate analyses, obese [HR 1.13 (1.06, 1.20), p=0.0003] and underweight [HR 1.12 (1.02, 1.23), p=0.0145] pts had poorer OS compared to normal weight pts. Analysis by gender demonstrated that underweight men [HR 1.26 (1.09, 1.47), p=0.0022], but not women (HR=1.09, p=0.13), had a worse OS vs normal weight pts. Similar results were found for DFS and OS; TTR was weaker among underweight pts. BMI category was not predictive of treatment benefit. Conclusions: Obese and underweight colon cancer survivors have a statistically significant, but clinically modest, worse prognosis. Obesity does not predict chemotherapy benefit. Studies to determine if weight loss can attenuate the adverse prognostic impact of obesity are warranted. BMI Category TTR HR (95% CI) 5-yr TTR Rate (95% CI) P-value OS HR (95% CI) 5-yr OS Rate (95% CI) P-value Obese 1.07 (1.01, 1.14) 67.5% (66.0-68.9) 0.0357 1.11 (1.04, 1.18) 72.6% (71.3-74.0) 0.0024 Overweight 1.01 (0.96, 1.06) 69.5% (68.5-70.5) 0.7856 0.99 (0.94, 1.05) 74.5% (73.6-75.5) 0.7141 Normal* 1.0 69.9% (69.0-70.9) NA 1.0 74.9% (74.0-75.8) NA Underweight 1.13 (1.03, 1.24) 67.0% (64.8-69.4) 0.0080 1.22 (1.11, 1.33) 72.6% (70.5-74.8) <0.0001 Adjusted for age, stage, treatment, and gender.*Reference group.

Predictive and prognostic value of gender in early-stage colon cancer: A pooled analysis of 33,345 patients from the ACCENT database.

3619 Background: While gender has been shown to be a predictive and prognostic factor in certain cancers, data for colon cancer (CC) are conflicting, with prior studies mainly focusing on 5-fluorouracil (5-FU) alone. To clarify the influence of gender on CC outcomes, our aims were to 1) compare outcomes between men and women in a large cohort of patients (pts) with early stage disease and 2) describe whether the effect of gender varies based on age, stage, time period and type of adjuvant therapy received. Methods: A pooled, retrospective analysis of individual data from 33,345 CC pts enrolled in 24 trials of various adjuvant systemic therapies was conducted. Chemotherapy consisted of 1) 5-FU, 2) 5-FU variations, 3) oxaliplatin, 4) irinotecan, or 5) oral-based regimens. The primary endpoint was disease-free survival (DFS); secondary endpoints included overall survival (OS) and time to recurrence (TTR). Cox proportional hazard models and interaction analyses were used to explore the effect of gender on outcomes. Results: We included 18,245 men and 15,100 women. Baseline characteristics were comparable between genders: median age was 61 years; 91% were White; 31% and 69% had stage II and III disease, respectively, in the entire cohort. Overall, men had inferior prognoses when compared to women for all endpoints, even after adjusting for age, stage and treatment (Table). Gender was not a predictive factor of treatment efficacy (interaction p for gender and treatment = 0.39, 0.61 and 0.78 for DFS, OS and TTR, respectively). In exploratory analyses, worse outcomes in men were more prominent in the older subset (HR 1.08 in age≤65 vs. 1.19 in age>65, interaction p=0.006 for DFS and HR 1.11 in age≤65 vs. 1.19 in age>65, interaction p=0.02 for OS). Stage of disease, study time period and type of adjuvant regimen did not modify the prognostic value of gender. Conclusions: Gender is a modest independent prognostic marker in early stage CC, particularly in older pts. Prognostic value of gender. Outcome Gender Hazard ratio (95% CI) 5-year outcome rate P value DFS Women 1.0 64.7% <0.001 Men 1.12 (1.08-1.16) 62.2% OS Women 1.0 72.7% <0.001 Men 1.13 (1.09-1.18) 70.3% TTR Women 1.0 67.4% <0.001 Men 1.06 (1.02-1.09) 66.2%

GCC expression in lymph nodes (LNs) as a significant determinant of recurrence in stage II colon cancer (CC) patients (pts).

369 Background: A multi-center prospectively specified retrospective study Validating Indicators to Associate Recurrence (VITAR) is assessing the relationship between guanylyl cyclase C (GCC) gene expression in formalin fixed LNs and recurrence risk in stage II CC pts not treated with adjuvant chemotherapy. Here we report the preplanned initial analysis performed with 241 pts. Methods: GCC mRNA was quantified by RT-qPCR using FFPE LNs tissues from untreated stage II CC pts diagnosed from 1999-2006 with at least 10 LN examined blinded to clinical outcomes. Cox regression models examined the relationship between GCC nodal status and the prespecified primary endpoint of recurrence risk. Results: Twenty-ninepts (12%) had a disease recurrence or cancer death, median follow-up was 60 months and median LNs examined was 15. The ratio of the number of GCC+ LNs over the total number of informative LNs (LNR) significantly predicted higher recurrence risk for 84 pts classified as high risk (HR, 2.38; p=0.02). The estimated 5-yr recurrence rates were 10% and 27% for the low and high risk group, respectively. After adjusting for age, T stage, number of LNs assessed, and MMR status, the significant association remained (HR, 2.61; 95% CI, 1.17-5.83; p=0.02). In a subset of 181 pts with negative margin, T3 tumor only and ≥12 LN examined, the GCC LNR had a HR for recurrence of 5.06 (95% CI 1.61-15.91, p=0.003), translating into 5-yr recurrence rates of 4% among low risk pts and 27% for the high-risk group. Conclusions: Our results suggest that GCC expression in LNs is a significant determinant of recurrence in appropriately staged CC pts not treated with adjuvant chemotherapy. The validation component of the study is ongoing. [Table: see text] [Table: see text]

Expression of dUTP nucleotidohydrolase (dUTPase) and thymidylate synthase (TS) in stage III colon cancer patients treated with either bolus 5-FU or infusional 5-FU in the adjuvant setting: Results of a translational study of the PETACC-2 trial.

417 Background: Pts with stage III colon cancer have been treated with either infusional 5-FU or bolus 5- FU in the adjuvant setting (PETACC-2 trial). DUTPase and TS demonstrated potential as predictive markers for 5-FU efficacy in pts with advanced colorectal cancer. Here we aimed to explore whether TS or dUTPase protein levels may predict recurrence of disease for stage III colon pts treated with 5-FU. Methods: Tumor (T) blocks of 324 pts were analyzed for protein expression of dUTPase and TS. For analysis monoclonal antibodies DUT415 and TS106 were used. T were evaluated by two investigators as follows. Only nuclear staining for both, TS and dUTPase, was analyzed. If tumor cells (TC) showed a nuclear dUTPase expression in &gt;10% of cells, the sample was scored positive. Positive nuclear staining for &gt;20% of TC, when using the TS antibody, determined a positive sample. Results: Analysis for dUTPase was successful in 308 samples (95.1%, 308/324). 263 out of those 308 pts showed a positive dUTPase expression (85.3%). 297/324 samples (91.7%) could be evaluated for TS. In the TS group 62.3% (185/297) showed a positive expression for TS protein. In 281 cases analyses were successful for both TS and dUTPase. We observed a significant association between dUTPase and TS expression with a majotity of 71.4% (172/241) dUTPase positive T also being positive for TS as compared to 32.5% (13/40) of dUTPase negative T that showed positivity for TS protein expression (p&lt; 0.0001). Of pts with dUTPase positive T 64.7% showed no recurrence of disease as compared to 44.7% of those with dUTPase negative T 5 years after completion of therapy (HR 0.61 [95% CI 0.36, 1.03], p=0.06). No associations between TS and DFS were observed. Both TS and dUTPase expression did not correlate with OS in this patient cohort. Conclusions: High TS protein levels appeared to be significantly correlated with high protein levels of dUTPase in stage III colon cancer pts. Neither dUTPase nor TS protein levels appeared to be significantly associated with DFS or OS of stage III colon cancer pts that received adjuvant chemotherapy with 5-FU. No significant financial relationships to disclose.

Six months compared with 12 months of capecitabine as adjuvant chemotherapy for stage III (Dukes' C) colon cancer: Rationale for the open-label randomized phase III study, JFMC37-0801.

517 Background: The standard duration of adjuvant chemotherapy (CT) in patient with stage III colorectal cancer is 6 months. On the other hand, no clinical trial which investigate an optimal duration of oral chemotherapeutic agents has yet been implemented for adjuvant treatments. According to the ACCENT database (Sargent, et al. J Clin Oncol 27: 872- 877, 2009), 83% of recurrences in stage II and III pts have occurred within the first 3 years after surgery and peak was observed around one year after surgery. Also, single-agent FU-based adjuvant CT reduced the hazard rate of OS, DFS, and TTR, although the peak of events around one year was still remained especially for stage III pts. We analyzed the data of recurrent risk of curatively resected colon cancer pts provided by JFMC7-1-7-2-15, X-ACT. Surgery alone group and 6 months CT (5FU/LV or capecitabine [Cape]) showed highest peak between 12 months to 18 months after surgery, but 12 months oral 5-FUs group did not show recurrence peak between 12 months to 18 months after surgery. Therefore, to clarify the benefit of 12 month administration of Cape, we planned a phase III randomized trial for a comparison of 6 months treatment and 12 months treatment. Methods: JFMC37 is a multicenter, randomized phase III trial. Patients with fully resected stage III colon or recto sigmoid cancer were eligible. Patients were randomized 1:1 to receive Cape of 6 months (arm A) or Cape of 12 months (arm B). Primary endpoint is disease-free survival. The statistical design is based on superiority hypothesis; 5-yrs DFS is 60% in arm A, 67% in arm B; unilateral α=0.05, 1-β=0.8; and planed accrual is 1200 pts. Results: Between September 2008 to December 2009, 1,304 pts were randomized. Patients characteristics are (armA/armB); number 653/651, gender M352-F301/M343-F308, median age 65 years/65 years, ECOG PS=0-1 620-33/632-19, involvement of lymph nodes=N0-N1-N2 503-130-20/499-128-24. There were no differences in baseline characteristics between arm A and arm B. Conclusions: This trial is expected to show if 1 year adjutant chemotherapy with capecitabine can reduce the peak of recurrence in 1 year and provide long-term OS benefit. [Table: see text]

Adjuvant therapy in colorectal cancer – studies of the FOGT group

The FOGT (Study Group for GI-Oncology) was formed among clinicians and scientists with the aim of testing innovative scientific concepts in gastrointestinal tumors, especially colorectal cancers, within controlled clinical studies. In the FOGT-1 trial (n=813stage III or II(T4N0) colon cancer patients) the effect on recurrence-free and overall survivalwas tested by an adjuvant chemotherapy protocol with double-modulation of 5-fluorouracil (5-FU) and levamisole (LEV) with either folinic acid (FA) or interferon-alpha (IFNa) in a three arm randomized trial within 60 German cancer centers. In parallel, in the FOGT-2 trial stage II or III rectal cancer patients (n = 796 pts.) were treated with additional postoperative radiochemotherapy (50,4 Gy). The most effective arm of these trials was tested as control arm versus a 5-FU/FA/irinotecan (FOLFIRI) protocol in the two-arm FOGT-4 trial (n = 281stage III or II(T4N0) colon cancer pts.) for adjuvant therapy in colon cancer. In the FOGT-1 trial, we found a 11% overall survival (OAS) benefit in patients who were treated for one year adjuvantly with 5-FU plus FA (77% OAS), compared to treatment with either 5-FU or 5-FU plus interferon-alpha (each 66% OAS). This effect was statistically significant for colon cancer patients (FOGT-1), but not for rectal cancer patients (FOGT-2). In rectal cancer, the 5-FU plus FA arm showed this effect with a 12% survival benefit only in the stage II subgroup. The FA modulation of 5-FU was safe and cost-effective. The modulation with IFNa was less effective and caused more toxicity, mainly diarrhea in rectal cancer patients. When the 5FU/FA protocol was slightly modulated (treatment for 6 months, no LEV) and compared to the FOLFIRI protocol (FOGT-4), survival and toxicity in the 5FU/FA arm was similar to the toxicity observed in the earlier studies, and the FOLFIRI arm was significantly more toxic (40% vs. 14% grade III/IV toxicity) without any benefit in recurrence rates (25% vs. 23% local/systemic recurrence) or survival. The FOGT-4 study confirms three other studies that – in contrast to palliative treatment protocols – did not find any benefit for the role of irinotecan in the adjuvant treatment of colon cancer. In conclusion, by conducting the three FOGT-studies with more than 1800 patients, we identified a safe and effective treatment protocol for adjuvant therapy in colon cancer, consisting of infusional 5-fluorouracil and folinic acid, given for at least six months, and well combinable with additional postoperative radiotherapy. This protocol was not improved by addition of irinotecan in colon cancer patients.

FOLFOX4 as adjuvant therapy in elderly patients (pts) with colon cancer (CC): Subgroup analysis of the MOSAIC trial.

3522 Background: In elderly CC pts, adjuvant 5FU-based chemotherapy increases overall survival (OS) and disease-free survival (DFS) (Sargent, NEJM 2001). FOLFOX4 improved DFS and OS in stage III (André, JCO 2009). In a pooled analysis of NSABP-C07 and MOSAIC trials, oxaliplatin/5FU-based chemotherapy was not superior to 5FU/LV in pts ≥ 70 years (Jackson Mc Cleary, ASCO 2009). Methods: We performed a subgroup analysis of pts aged ≥ 70 yrs in the MOSAIC trial, reviewing clinical characteristics, comorbidities according to Adult Comorbidity Evaluation-27, SAEs, 2nd cancer and cause of death. Results: 315 pts ≥ 70 yrs were randomized between FOLFOX4 (155 pts) and LV5FU2 (160 pts). Median follow-up was 6 yrs. DFS hazard ratio (HR) was 0.91; 95% confidence interval (CI) 0.62 to 1.34 and OS HR was 1.10; 95% CI 0.73 to 1.65. No imbalance was observed for initial characteristics. In the FOLFOX4 arm and the LV5FU2 arm, 59 and 66 pts were stage II, 38 and 42 high risk stage II (pT4 and/or < 12 lymph nodes), 96 and 94 pts were stage III, 24 and 29 N2, 85 and 93 pts had grade 1-2 comorbidities, including 74 and 75 pre-existing cardiovascular disease, respectively. 30 pts had a SAE (treatment related 9, cardiovascular 4 and other 19) with FOLFOX4 compared to 15 pts (treatment 3, cardiovascular 2, other 10) with LV5FU2 (p = 0.02). Less patients had surgery of metastases (9 vs. 22; p = 0.01) and irinotecan- or oxaliplatin-based therapy (16 vs. 30; p = 0.01) at relapse in the FOLFOX4 than in the LVFU2 arm. More deaths not CC-related occurred with FOLFOX4 than with LV5FU2 (22 vs. 11; p = 0.043), including second cancer deaths, 9 vs. 1 pts, respectively (p = 0.02). Conclusions: The DFS benefit of FOLFOX4 in elderly pts could be of less magnitude than in the younger population. Lack of OS benefit is not related to initial tumor characteristics or comorbidities, but to different management or outcome of relapses or second cancers. More pts died of second malignancy in FOLFOX4 arm. Higher occurrence of SAEs and difficulties in treatment of relapses argue to reduce the FOLFOX4 duration (IDEA study). An ongoing update and a 10-year follow up will allow the further evaluation of these findings. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Baxter International, Roche, sanofi-aventis Baxter International, Pfizer, Roche, sanofi-aventis sanofi-aventis Roche, sanofi-aventis