Adjuvant FOLFOX Research Articles

O-0024 - Prognostic Value of KRAS Mutations in Stage III Colon Cancer: Post-Hoc Analyses of the Petacc8 Phase III Trial

Introduction: The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined the prognostic impact of KRAS mutations in stage III patients receiving adjuvant FOLFOX +/- cetuximab from the PETACC8 Phase III trial.Methods: KRAS exon2 mutations were examined in BRAF wild type tumors from patients enrolled in the PETACC8 trial. Because no effect from adjuvant cetuximab was reported, tumors from both study arms were pooled for analysis. Association between time to recurrence (TTR) and Disease-free survival (DFS) and KRAS mutation type was evaluated using Cox proportional hazard model.Results: KRAS mutations were found in 638/1657 tumors. KRAS mutations in codon 12 (HR: 1.67; 95% confidence interval [CI] [1.35-2.04]; P < 0.001) but not in codon 13 (HR: 1.23; 95% confidence interval [CI] [0.85-1.79]; P = 0.26) were significantly associated with shorter TTR as compared to patients with KRAS/BRAF wild-type tumors, independently of other covariates. Taking anatomic sites into account, the impact of KRAS mutations on TTR was only found for distal tumors (n = 1043; 692 wild type; 351 mutated) with an increased risk of relapse (HR: 1.96; 95% confidence interval [CI] [1.51-2.56]; P < 0.0001) for KRAS codon 12 mutated tumors and a trend for codon 13 (HR: 1.59; 95% confidence interval [CI] [1.00-2.56]; P = 0.051). Similar results were found for DFS.Conclusion: KRAS exon 2 mutations are independent predictors of TTR for patients with stage III distal CC receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider tumor location and KRAS mutations as important stratification factors. Introduction: The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined the prognostic impact of KRAS mutations in stage III patients receiving adjuvant FOLFOX +/- cetuximab from the PETACC8 Phase III trial. Methods: KRAS exon2 mutations were examined in BRAF wild type tumors from patients enrolled in the PETACC8 trial. Because no effect from adjuvant cetuximab was reported, tumors from both study arms were pooled for analysis. Association between time to recurrence (TTR) and Disease-free survival (DFS) and KRAS mutation type was evaluated using Cox proportional hazard model. Results: KRAS mutations were found in 638/1657 tumors. KRAS mutations in codon 12 (HR: 1.67; 95% confidence interval [CI] [1.35-2.04]; P < 0.001) but not in codon 13 (HR: 1.23; 95% confidence interval [CI] [0.85-1.79]; P = 0.26) were significantly associated with shorter TTR as compared to patients with KRAS/BRAF wild-type tumors, independently of other covariates. Taking anatomic sites into account, the impact of KRAS mutations on TTR was only found for distal tumors (n = 1043; 692 wild type; 351 mutated) with an increased risk of relapse (HR: 1.96; 95% confidence interval [CI] [1.51-2.56]; P < 0.0001) for KRAS codon 12 mutated tumors and a trend for codon 13 (HR: 1.59; 95% confidence interval [CI] [1.00-2.56]; P = 0.051). Similar results were found for DFS. Conclusion: KRAS exon 2 mutations are independent predictors of TTR for patients with stage III distal CC receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider tumor location and KRAS mutations as important stratification factors.

KRAS Codon 12 and 13 Mutations in Relation to Disease-Free Survival in BRAF–Wild-Type Stage III Colon Cancers from an Adjuvant Chemotherapy Trial (N0147 Alliance)

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. 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. KRAS mutations in codon 12 (multivariate HR, 1.52; 95% confidence interval, CI, 1.28-1.80; P < 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 < 0.0001), proximal tumor site (P < 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P < 0.0001). 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.

Detection of activated KRAS from cancer patient peripheral blood using a weighted enzymatic chip array.

BackgroundThe KRAS oncogene was one of the earliest discoveries of genetic alterations in colorectal and lung cancers. Moreover, KRAS somatic mutations might be used for predicting the efficiency of anti-EGFR therapeutic drugs. The purpose of this research was to improve Activating KRAS Detection Chip by using a weighted enzymatic chip array (WEnCA) platform to detect activated KRAS mutations status in the peripheral blood of non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) patients in Taiwan.MethodsOur laboratory developed an Activating KRAS Detection Chip and a WEnCA technique that can detect activated KRAS mutation status by screening circulating cancer cells in the surrounding bloodstream. We collected 390 peripheral blood samples of NSCLC patients (n = 210) and CRC patients (n = 180) to evaluate clinical KRAS activation using this gene array diagnosis apparatus, an Activating KRAS Detection Chip and a WEnCA technique. Subsequently, we prospectively enrolled 88 stage III CRC patients who received adjuvant FOLFOX-4 chemotherapy with or without cetuximab. We compared the chip results of preoperative blood specimens and their relationship with disease control status in these patients.ResultsAfter statistical analysis, the sensitivity of WEnCA was found to be 93%, and the specificity was found to be 94%. Relapse status and chip results among the stage III CRC patients receiving FOLFOX-4 plus cetuximab (n = 59) and those receiving FOLFOX-4 alone (n = 29) were compared. Among the 51 stage III CRC patients with chip negative results who were treated with FOLFOX-4 plus cetuximab chemotherapy, the relapse rate was 33.3%; otherwise, the relapse rate was 48.5% among the 23 out of 88 patients with chip negative results who received FOLFOX-4 alone. Negative chip results were significantly associated to better treatment outcomes in the FOLFOX-4 plus cetuximab group (P = 0.047).ConclusionsThe results demonstrated that the WEnCA technique is a sensitive and convenient technique that produces easy-to-interpret results for detecting activated KRAS from the peripheral blood of cancer patients. We suggest that the WEnCA technique is also a potential tool for predicting responses in CRC patients following FOLFOX-4 plus cetuximab chemotherapy.

The impact of dose reduction on survival for colon cancer patients treated with adjuvant FOLFOX.

e14576 Background: Dose reduction (DR) is common during oxaliplatin based treatment for stage III colon cancer. In this study we evaluated the impact of DR of adjuvant FOLFOX chemotherapy on diseas...

Complete neoadjuvant therapy in rectal cancer (CONTRE): A Brown University Oncology Research Group phase II study.

3530 Background: After preoperative chemoradiation and surgery, many patients (pts) with clinical stage II-III rectal cancer are unable to tolerate adjuvant FOLFOX chemotherapy, which may compromise disease-free and overall survival (DFS/OS). This study was designed to assess treatment delivery, toxicity and impact on pathologic response of administering chemotherapy prior to chemoradiation and surgery. Methods: Pts with clinical T3-4 and/or N1-2 rectal cancer, staged by endorectal ultrasound (ERUS) and pelvic MRI, received modified (m) FOLFOX6 every two weeks x eight cycles, followed by 50.4 Gy IMRT with concurrent capecitabine 825mg/m2 BID, 5 days per week, followed by surgery 4-8 weeks later. Results: There were 39 pts enrolled between August 2010 and June 2012; median age was 61 (30-79); clinical stage II n=7, stage III n=32. Distance from the anal verge: 5cm n=29. There were four pts presented with lumen obstruction preventing advancement of the endoscope and 31 with rectal blee...

Molecular subtyping of colon cancers and distinct prognostic groups [NCCTG N0147 (Alliance)

3512 Background: Categorization of colon cancers (CCs) into subtypes based upon pathways of tumorigenesis may improve prognostication. CCs were studied from a randomized trial of adjuvant FOLFOX ± ...

P0056 Treatment of non-metastatic colon adenocarcinomas in Morocco

Background Adenocarcinoma of the colon is a common cancer and the annual incidence is increasing. Treatment is essentially surgical, combined with adjuvant chemotherapy in advanced cases. Methods This is a retrospective study of 100 patients with non-metastatic colon adenocarcinoma, treated at the gastroenterology and oncology centre in Ibn Rushd Hospital, Casablanca, over a period of 5 years from January, 2006, to January, 2010. Diagnosis was made after a histological study of biopsies taken during colonoscopy. Findings One hundred patients were diagnosed with non-metastatic colon adenocarcinoma. The sex ratio was 3:2 (M:F), the average age was 52 years, and approximately 50% of patients were diagnosed after a period of 7 months from the appearance of their first symptoms of rectal bleeding events, melena, and dysentery syndrome. Histologically, non-metastatic colon adenocarcinoma is well-differentiated in 80% of cases. All patients were operated on. The distribution of patients by stage was: 61% classified as stage II, 30% stage III, and 9% stage I. Adjuvant chemotherapy FUFOL, FOLFOX IV, or capecitabine was given in 85% of patients and monitoring without adjuvant therapy in 15%. The immediate follow-up after completion of chemotherapy showed complete remission in 95% of patients and 5% were in disease progression. After a mean follow-up of 30 months, 71% were in remission. 18% had a local or metastatic recurrence treated by second line chemotherapy (FOLFIRI or XELIRI), with remission seen in three patients, stable disease in seven patients, and treatment failure in eight patients. Interpretation The multidisciplinary approach to all stages of the process requires the involvement of various disciplines to give the patient the best quality of care. Adenocarcinoma of the colon is a common cancer and the annual incidence is increasing. Treatment is essentially surgical, combined with adjuvant chemotherapy in advanced cases. This is a retrospective study of 100 patients with non-metastatic colon adenocarcinoma, treated at the gastroenterology and oncology centre in Ibn Rushd Hospital, Casablanca, over a period of 5 years from January, 2006, to January, 2010. Diagnosis was made after a histological study of biopsies taken during colonoscopy. One hundred patients were diagnosed with non-metastatic colon adenocarcinoma. The sex ratio was 3:2 (M:F), the average age was 52 years, and approximately 50% of patients were diagnosed after a period of 7 months from the appearance of their first symptoms of rectal bleeding events, melena, and dysentery syndrome. Histologically, non-metastatic colon adenocarcinoma is well-differentiated in 80% of cases. All patients were operated on. The distribution of patients by stage was: 61% classified as stage II, 30% stage III, and 9% stage I. Adjuvant chemotherapy FUFOL, FOLFOX IV, or capecitabine was given in 85% of patients and monitoring without adjuvant therapy in 15%. The immediate follow-up after completion of chemotherapy showed complete remission in 95% of patients and 5% were in disease progression. After a mean follow-up of 30 months, 71% were in remission. 18% had a local or metastatic recurrence treated by second line chemotherapy (FOLFIRI or XELIRI), with remission seen in three patients, stable disease in seven patients, and treatment failure in eight patients. The multidisciplinary approach to all stages of the process requires the involvement of various disciplines to give the patient the best quality of care.

Positive effects of oral β-glucan on mucositis and leukopenia in colorectal cancer patients receiving adjuvant FOLFOX-4 combination chemotherapy.

The present study aimed to determine the effect of oral β-glucan on mucositis and leukopenia in 62 consecutive patients with colorectal cancer treated with an adjuvant FOLFOX-4 regimen. The patients were retrospectively evaluated in 2 groups: one group received β-glucan and the other did not (control group). Leucocytes, neutrophils, and platelets were evaluated before and 1 week after chemotherapy and oral mucositis and diarrhea were noted. Leucocyte and neutrophil counts after chemotherapy in the β-glucan group were 7,300/mm3 and 3,800/mm3, respectively, and the reductions, as compared to baseline, were not significant (p=0.673 and 0.784). The median platelet count was 264,000/mm3 after chemotherapy in the β-glucan group and the reduction, as compared to baseline, was borderline significant (p=0.048). In the control group, reduction in leucocyte, neutrophil, and platelet counts was statistically significant. Oral mucositis and diarrhea were less common in the β-glucan group. We conclude that β-glucan can be used to reduce the adverse effects of chemotherapy.

Longitudinal study of cognitive dysfunctions induced by adjuvant chemotherapy in colon cancer patients

Chemotherapy can induce cognitive impairment in cancer patients. The main goal of this longitudinal study was to determine the incidence, characteristics, and duration of cognitive dysfunction in patients treated with adjuvant chemotherapy for colon cancer. We assessed cognitive function, quality of life, anxiety and depression, fatigue, and hemoglobin levels in colon cancer patients at three assessment points: pre-chemotherapy (n=81), post-chemotherapy (n=73), and after 6-month follow-up (n=54). All patients were treated with oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) for 6 months. Thirty patients (37%) had cognitive impairment in the pre-chemotherapy evaluation, mainly in processing speed and psychomotor executive function (Trail Making Test A and B). At the end of treatment, the main domain affected was the verbal memory, with an acute decline detected in 56% of patients. Fifty-four percent of the patients improved their dysfunction after 6 months of follow-up, whereas 18 (33%) of them showed worsening in at least one test. Cognitive impairment was most common in older patients and in those with less years of education. Quality of life, anxiety, depression, fatigue, and hemoglobin did not influence the results of the cognitive tests. Adjuvant FOLFOX4 in patients with colon cancer can have a negative effect on verbal memory. This deterioration is usually mild and transient.

Predicting toxicities from adjuvant treatment in a population-based cohort of early colon cancer (CC) patients (pts): A strategy to improve use of curative chemotherapy.

412 Background: CC pts treated with chemotherapy are at risk of experiencing a number of toxicities. The identification of pts who may be at a higher risk of developing toxicities allows clinicians to be more vigilant in preventing and managing side effects early, thus enabling more optimal delivery of chemotherapy. Our aim was to determine clinical factors associated with toxicities from adjuvant FOLFOX in early CC. Methods: Pts diagnosed with stage III CC from 2005 to 2008, seen at any 1 of 5 regional cancer centers of the British Columbia Cancer Agency, and treated with adjuvant FOLFOX chemotherapy were reviewed. We evaluated various toxicities, including gastrointestinal, hematologic, cardiovascular, and neurological side effects. Baseline and clinical factors were assessed in univariate and multivariate models to determine potential predictors for each of the different chemotherapy toxicities. Results: In total, 475 pts were included: median age was 62 years (range 26-89), 16.2% were aged &gt;70 years, and 54.5% were men. In terms of function, the majority (90.1%) was ECOG 0/1. Time to adjuvant chemotherapy (TTAC) &gt;8 weeks (OR 1.91, 95% CI 1.8-3.1, p=0.006) and renal dysfunction with a GFR &lt;50 (OR 1.69, 95% CI 1.1-2.6, p=0.0038) were significantly associated with higher odds of any GI toxicity. Likewise, TTAC &gt;8weeks (OR 2.8, 95% CI 1.5-5.2, p=0.002), ECOG PS &gt;1 (OR 2.86, 95% CI 1.2-6.7, p=0.016), and low white blood cell count &lt;6.4 (OR 2.32, 95% CI 1.3-4.0, p=0.0043) were correlated with a greater risk of significant neutropenia. Multiple toxicities were more prevalent among those who waited &gt;8 weeks to initiate adjuvant FOLFOX (OR 1.69, 95%CI 1.1-2.7, p=0.03). Further, advanced age &gt;70 years was an indepenent risk factor for worse nausea and diarrhea. Conclusions: Consideration of important baseline characteristics such as TTAC, advanced age, renal function, and specific laboratory parameters when recommending adjuvant FOLFOX can be useful in identifying patients with increased likelihood of toxicities. This group of patients may benefit from increased monitoring in order to enable optimal doses of curative chemotherapy to be delivered.

Tolerability study of adjuvant modified FOLFOX6 treatment in curatively resected stage II/III colon cancer (JFMC41-1001-C2: JOIN trial).

530 Background: Adjuvant FOLFOX is a widely accepted standard regimen for resected colon cancer. The incidence of grade ≥ 3 peripheral sensory neuropathy (PSN) was 12.4% and 5.7% in Western MOSAIC and Eastern MASCOT (outside Japan) trials, while that of grade ≥ 3 allergic reactions (AR) was 2.9% and 3.1%, respectively. JOIN Trial investigated the tolerability of modified FOLFOX6 (mFOLFOX6) in Japanese patients (UMIN ID: 000004443). Methods: Twelve cycles of mFOLFOX6 were given to patients fitting the following criteria, which were the same as those of MOSAIC: stage II/III resected colon cancer, PS of 0-1, 20 years or older, starting FOLFOX within 7 weeks of surgery, and adequate organ function. The primary endpoint was the incidence of PSN persisting for at least 8 days that interfered with daily activities and that of grade ≥ 3 AR. Target sample size was 800, assuming the expected incidence of grade ≥ 3 PSN and grade ≥ 3 AR would be 12.0% and 3.0%, and the two-sided 95% confidence interval (CI) would not include the corresponding threshold levels (16.5% for PSN and 6.5% for AR) with a 95% probability. Results: From Nov 2010 to Mar 2012, 882 patients were enrolled at 198 institutions. The safety data was analyzed in 828 patients whose data were finalized out of 848 patients received mFOLFOX6, and patient characteristics included: median age of 64 years (21-83); Male/ Female: 444/384; PS 0/1: 776/52; colon/rectosigmoid: 633/195; and stage IIA/IIB/IIC/IIIA/IIIB/IIIC: 96/33/23/61/437/178. The incidence of persistent PSN was 3.3% (95% CI: 2.2%-4.7%), while that of grade ≥ 3 AR was 1.7% (95% CI: 1.0%-2.8%), and the primary endpoint was met. Only grade ≥ 3 neutropenia showed a ≥ 10% incidence (28.7%). The incidence of grade ≥ 3 PSN was 5.8% and interstitial pneumonitis was observed in one case. There was no treatment-related death. The median number of cycles of chemotherapy was 12, and the completion treatment rate was 67.0%. The median total dosage of oxaliplatin (L-OHP) was 811.1 mg/m2. The median relative dose intensity of L-OHP, fluorouracil (FU) bolus and FU infusion were 90.0%, 76.9% and 81.7%, respectively. Conclusions: Adjuvant mFOLFOX6 is tolerable in Japanese patients with colon cancer. Clinical trial information: UMIN000004443.

Dose intensity and survival outcomes with adjuvant FOLFOX for colon cancer.

423 Background: Adjuvant FOLFOX chemotherapy for resected high-risk colon cancer is associated with a low risk of febrile neutropenia (FN). Nonetheless, neutropenia is a common cause of dose modification or delay with unknown consequences on outcomes. We examined the effect of neutropenia-related and other dose limiting toxicities (DLT), relative dose intensity (RDI) of oxaliplatin and 5-FU, on relapse-free (RFS) and overall survival (OS) in patients treated with FOLFOX chemotherapy for resected high-risk colon cancer. Methods: A chart review was conducted on patients treated at the British Columbia Cancer Agency with ≥ 1 cycle of FOLFOX chemotherapy for resected stage II or III colon cancer between January 1, 2006 and December 31, 2007. RFS and OS were analyzed by the Kaplan-Meier method and multivariate Cox proportional-hazards models. Results: 114 patients (median age 59.2 years, 43.8% male, 98% stage III, median follow-up 5.2 years) were included. 90% of patients experienced any DLT, while 58% of patients had a neutropenia related DLT. There were no documented episodes of FN. G-CSF was used in 9.6% of patients. Median RDI was 81% and 85% for oxaliplatin and 5-FU, respectively. Oxaliplatin and 5-FU RDI were not associated with RFS or OS when analyzed as continuous variable or categorically (Table). Conclusions: DLTs affect the majority of patients on adjuvant FOLFOX for high-risk colon cancer, but RFS and OS do not appear to be affected by the associated lower RDI of oxaliplatin and 5-FU. [Table: see text]

Predicting the risk of gastrointestinal (GI) toxicity in early colon cancer (CC) patients (pts) treated with adjuvant chemotherapy: Developing a GI toxicity scoring system.

420 Background: Baseline demographics and clinical factors may contribute to a pt’s overall risk for developing chemotherapy-related GI toxicity, such as nausea, vomiting, and diarrhea. We aimed to develop a GI toxicity scoring system to better stratify early CC pts who may be at higher risk of developing GI toxicity from adjuvant FOLFOX chemotherapy. Methods: Pts diagnosed with early CC from 2005 to 2008 and treated with FOLFOX at the British Columbia Cancer Agency were reviewed. GI toxicities of interest included (1) nausea/vomiting, (2) diarrhea, and (3) any GI side effects. Baseline variables that were analyzed consisted of age, sex, ECOG, time to adjuvant chemotherapy (TTAC), and laboratory parameters. Stepwise regression was used to develop a multivariate model for each toxicity and a weighted risk scoring system was subsequently devised based on the magnitude of the parameter estimates in the multivariate model. Results: In total, 475 pts were included: median age was 62 years (range 26-89), 16.2% were aged &gt;70 years, and 54.5% were men. The majority (90.1%) was ECOG 0/1. Independent predictors for nausea/vomiting included age &gt;70 years (OR 2.46, 95%CI 1.3-4.8, p=0.011), GFR &lt;50 (OR 1.68, 95% CI 1.1-2.7, p=0.025), and TTAC &gt;8 weeks (OR 1.33, 95% CI 0.9-2.1, p=0.14) whereas independent predictors for diarrhea included age &gt;70 years (OR 1.44, 95% CI 0.79-2.62, p=0.12) and GFR &lt;50 (OR 1.67, 95% CI 1.1-2.6, p=0.018). The multivariate model for the risk of any GI toxicity included age &gt;70 years (OR: 2.61, 95% CI 1.1-6.1, p=0.049), GFR &lt;50 (OR 1.69, 95% CI 1.1-2.6, p=0.0038), and TTAC &gt;8 weeks (OR 1.79, 95% CI 1.2-2.7, p=0.0059). Points were assigned: 2 points for long TTAC and poor GFR and 1 point for advanced age. The study cohort was classified into their risk groups based on their score (Table). Conclusions: We developed a simple 5-point scoring system to stratify early CC pts receiving adjuvant FOLFOX into low and high risk groups for GI toxicity based on baseline clinical factors. Further validation of this scoring system is required. [Table: see text]

Local recurrence rates after radiofrequency ablation or resection of colorectal liver metastases. Analysis of the European Organisation for Research and Treatment of Cancer #40004 and #40983

AimThe aim of this study is to describe local tumour control after radiofrequency ablation (RFA) and surgical resection (RES) of colorectal liver metastases (CLM) in two independent European Organisations for Research and Treatment of Cancer (EORTC) studies. BackgroundOnly 10–20% of patients with newly diagnosed CLM are eligible for curative RES. RFA has found a place in daily practice for unresectable CLM. There are no prospective trials comparing RFA to RES for resectable CLM. MethodsThe CLOCC trial randomised 119 patients with unresectable CLM between RFA (±RES)+adjuvant FOLFOX (±bevacizumab) versus FOLFOX (±bevacizumab) alone. The EPOC trial randomised 364 patients with resectable CLM between RES±perioperative FOLFOX. We describe the local control of resected patients with lesions ⩽4cm in the perioperative chemotherapy arm of the EPOC trial (N=81) and the RFA arm of the CLOCC trial (N=55). ResultsLocal recurrence (LR) rate for RES was 7.4% per patient and 5.5% per lesion. LR rate for RFA was 14.5% per patient and 6.0% per lesion. When lesion size was limited to 30mm, LR rate for RFA lesions was 2.9% per lesion. Non-local hepatic recurrences were more often observed in RFA patients than in RES patients, 30.9% and 22.3% respectively. Patients receiving RFA had a more advanced disease. ConclusionsLR rate after RFA for lesions with a limited size is low. The local control per lesion does not appear to differ greatly between RFA and surgical resection. This study supports the local control of RFA in patients with limited liver metastases. Future studies should evaluate in which patients RFA could be an equal alternative to liver resection.

Phase 2 Timing of Rectal Cancer Response to Chemoradiation: Analysis of Radiation Therapy (RT)

Purpose/Objective(s): Concurrent preoperative chemoradiation therapy (CRT) with 5FU is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents have increased morbidity with little benefit. We report 2 year outcomes of a prospective trial intended to (1) include the benefits of preoperative radiation therapy (RT) on local control (LC), (2) provide preoperative FOLFOX chemotherapy (CT), and (3) avoid the morbidity of concurrent RT and multi-drug CT. Materials/Methods: Eighty patients with cT3-4, any N, any M rectal cancer planned for resection of the primary tumor were enrolled prospectively on an institutional phase II trial from November 2009 through April 2012. Preoperative treatment included short course RT (25 Gy to involved mesorectum, 20 Gy to elective nodes in 5 fractions), followed by 4 cycles of mFOLFOX6. Postoperatively, 6-8 cycles of adjuvant FOLFOX was suggested at the discretion of the medical oncologist. The primary endpoint was T-stage downstaging (ypT < cT) and acute grade 3+ GI morbidity equal or better than historic controls. Pathologic response was additionally evaluated post-hoc for the low-risk patient subgroup eligible for enrollment to the ongoing PROSPECT trial. Patient reported quality of life data was obtained prospectively using the FACT-C questionnaire (Version 4) prior to RT, immediately prior to surgery, and 1 year following surgery. LC and PFS were estimated at 1and 2years using the Kaplan Meier method. Results: The primary endpoint was evaluable for 76 of 80 patients. The median follow-up was 21 months. The 76 evaluable cases included 7 cT4 and 69 cT3; 59 cN+, 7 cM1. Sphincter preserving surgery was performed on 59 cases. Grade 3 preoperative GI morbidity occurred in 7 cases (9%), and no patient had Grade 4 or 5 morbidity. At surgery 53 (70%) had ypT02 disease including 21 (28%) ypT0. Among low risk, PROSPECT eligible patients (n Z 38), 16 (42%) achieved ypT0 and 33 (87%) ypT0-2 disease. LC at years 1 and 2 for the entire cohort was 100% and 95%; PFS among cM0 patients at years 1 and 2 was 96% and 89%. Analysis of patient reported quality of life data revealed no decrement in patient reported outcomes at any time point. Conclusions: Sequential short course radiation and FOLFOX as preoperative therapy for locally advanced rectal cancer provides excellent tumor downstaging, with high 2-year LC and PFS. Therapy was well tolerated; supporting the ongoing RAPIDO trial that compares a similar regimen to conventionally fractionated 5FU based CRT for high risk locally advanced rectal cancer. Author Disclosure: J.R. Olsen: None. P.J. Parikh: None. S. Hunt: None. B. Tan: None. R.J. Myerson: None.

Prognostic Value of Mucinous Histology Depends on Microsatellite Instability Status in Patients with Stage III Colon Cancer Treated with Adjuvant FOLFOX Chemotherapy: A Retrospective Cohort Study

The close association between mucinous histology and microsatellite instability (MSI) may have hindered the evaluation of prognostic significance of mucinous histology. The aim of this retrospective study was to investigate whether mucinous histology was associated with a worse prognosis, independent of MSI status, compared to nonmucinous histology in patients with stage III colon cancer. This study enrolled 394 consecutive patients with stage III colorectal cancer treated with adjuvant FOLFOX after curative resection (R0). Clinicopathological information was retrospectively reviewed. Tumors were analyzed for MSI by polymerase chain reaction to determine MSI status. Kaplan-Meier method, log-rank test, and Cox proportional hazard regression models were used. The estimated rate of 3-year disease-free survival (DFS) in patients with nonmucinous adenocarcinoma (NMA 79.2%) was significantly greater than that in patients with mucinous adenocarcinoma (MA) and adenocarcinoma with mucinous component (MC) (56.9%; log-rank, P=0.002). In univariate analysis, histology (NMA vs. MA/MC), American Joint Committee on Cancer stage (IIIA, IIIB, and IIIC), and lymphovascular invasion (present vs. absent) were significantly associated with DFS. In multivariate analysis, mucinous histology (MA/MC) was associated with decreased DFS in all patients (hazard ratio 1.82, 95% confidence interval 1.03-3.23, P=0.0403). In patients with MA/MC, no difference in DFS was observed between MSI and microsatellite stability (log-rank, P=0.732). Mucinous histology is an independent poor prognostic factor for DFS in patients with stage III colon cancer after adjuvant FOLFOX chemotherapy.

Incidence of Chemotherapy-Induced Amenorrhea in Premenopausal Women Treated With Adjuvant FOLFOX for Colorectal Cancer

BackgroundStudies indicate that the incidence of young women diagnosed with colorectal cancer is rising, thus there is an increasing number of female colorectal cancer survivors of premenopausal and child-bearing age. Adjuvant FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy is the most widely used standard treatment for stage III and high-risk stage II colon cancer. We evaluated the incidence of FOLFOX-induced amenorrhea in women age 50 and younger treated with adjuvant therapy for colorectal cancer. Patients and MethodsA search of pharmacy records identified 119 women age 50 or younger who received adjuvant FOLFOX chemotherapy at Memorial Sloan-Kettering for stage II or III colorectal cancer from January 2002 and January 2011. Eligible patients were mailed an anonymous questionnaire. The returned surveys were reviewed and the results tallied. ResultsSeventy-three patients returned the questionnaire. Twenty-four patients were excluded from analysis: 19 were treated with pelvic radiotherapy, 2 patients had undergone bilateral oophorectomy, 2 had a hysterectomy, and 1 stopped menstruating before diagnosis. Forty-nine patient responses were analyzed. In total, 41% (n = 20) experienced amenorrhea during chemotherapy. Sixteen percent had persistent amenorrhea 1 year after completion of chemotherapy. The incidence of amenorrhea during chemotherapy trended higher in patients aged older than 40 compared with patients aged 40 and younger (59% vs. 31% [P = .075]). There was no statistically significant difference in persistent amenorrhea between the 2 age groups (24% vs. 13%; P = .42). ConclusionIn this retrospective series, there appears to be a trend toward FOLFOX induced amenorrhea during chemotherapy increasing with age. Twenty-four percent of women older than the age of 40 were found to have persistent amenorrhea after FOLFOX therapy. Because of the small sample size, the study is underpowered to detect a statistically significant difference between older and younger patients. Prospective studies are planned to further characterize the effect of FOLFOX on early menopause and fertility.

Oncologic Outcomes after Adjuvant Chemotherapy Using FOLFOX in MSI‐H Sporadic Stage III Colon Cancer

Little is known of the oncological outcomes after adjuvant FOLFOX chemotherapy in patients with stage III colon cancer showing microsatellite instability high (MSI-H). In the present study we investigated the prognostic impact of MSI-H in patients with stage III colon cancer receiving FOLFOX chemotherapy. We analyzed the MSI status in 127 patients with stage III colon cancer who underwent curative surgical resection followed by FOLFOX chemotherapy between January 2003 and December 2010. We assessed disease-free and overall survival (OS) in patients with MSI-H colon cancer compared with those showing microsatellite instability low or microsatellite stable (MSI-L/MSS) disease. Sixteen of the patients (12.6 %) were MSI-H, and 111 patients (87.4 %) were MSI-L/MSS. There was no significant difference between patients showing MSI-H and MSI-L/MSS except for age (P = 0.030), tumor location (P < 0.001), and differentiation (P = 0.031). Compared with MSI-L/MSS colon cancer, patients with MSI-H colon cancer had no significant difference in 5-year disease-free and OS (72.2 vs 68.5 %, P = 0.874; 68.1 vs 71.1 %, P = 0.437). Our study indicates that FOLFOX chemotherapy can be considered to treat stage III colon cancer patients with MSI-H after surgery, although the study was not randomized and included only a limited number of patients.

Molecular characteristics and prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX.

3550 Background: There have been controversies in prognostic impact of mucinous histology in colorectal cancer (CRC) and its implication in pts treated with adjuvant FOLFOX is unclear. This study aimed at elucidating the molecular characteristics and prognostic implication of mucinous histology in pts treated with adjuvant FOLFOX. Methods: Stage II and III CRC pts who received adjuvant FOLFOX were analyzed. Pts were grouped according to the mucinous content: &gt; 50%, mucinous adenocarcinoma (MAC); &lt; 50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, nonmucinous adenocarcinoma (NMA). Clinicopathologic features, MSI status (N = 518), CpG island methylator phenotype (CIMP) (N = 322) BRAF mutation (N = 269) and disease-free survival (DFS) were compared. Results: Among a total of 521 pts, 27 (5.2%) had MAC, 41 (7.9%) AIM, and 453 (86.9%) NMA. MAC and AIM had higher frequency of proximal location and lower angiolymphatic invasion. MAC had higher proportion of T4 tumors. AIM had higher frequency of age ≥65 years and female. In terms of molecular characteristics, MAC and AIM showed similarly higher proportion of MSI-high and CIMP-high compared to NMA. BRAF mutation also showed similar trend. In contrast to the similarities between MAC and AIM, DFS was significantly different. MAC showed significantly worse DFS compared with AIM and NMA, whereas AIM and NMA showed similar DFS. Multivariate analysis revealed MAC as an independent negative prognostic factor of DFS (adjusted HR 7.96, 95% CI 3.76-16.8). Conclusions: AIM and MAC has distinct clinico-pathologic features and molecular characteristics compared with NMA. Only MAC but not AIM has an adverse prognostic impact on stage II or III CRC treated with adjuvant FOLFOX compared with NMA. [Table: see text]

Double KRAS and BRAF mutations in colorectal cancer in a single oncologic department series.

e14657 Background: KRAS and BRAF mutations have prognostic and predictive value in colorectal cancer and are predominantly mutually exclusive. Only a few cases of double mutations (DM) have been reported so far but the actual incidence and presumed role in worsening prognosis is still unknown. Here we report on a series of KRAS and BRAF mutations, focusing on three cases of KRAS and BRAF DM. Methods: since May 2010, 316 consecutive colorectal cancer samples were collected by our Oncology Department; ten patients (3%) had high risk localized disease and 306 (97%) metastatic disease. Genome DNA from formalin-fixed paraffin embedded samples with tumor cells &gt; 50% was analyzed by reverse dot blot with KRAS-BRAF StripAssay kit (Nuclear Laser Medicine). Results: KRAS point mutations were found in 141 patients (44.6%): 32% G12V, 30.5% G12D, 14.9% G13D, 6.4% G12S, 5.7% G12C, 4.9% G12A, 4.9% G12R, 0.7% G13C; V600E BRAF point mutation was found in 21 patients (6.6%). Three patients (1%) displayed DM: 2 KRAS G13D + BRAF V600E (A and B) and 1 KRAS G12V + BRAF V600E (C). Patients A and C, both aged 59, presented with metastatic disease. Patient A had a rectal primary, a single lung lesion and mediastinal nodes. He failed first line FOLFOX4 plus bevacizumab and underwent salvage surgery both on primary and metastatic disease. He relapsed in 3 months with liver and brain metastasis and died after one year from diagnosis. Patient B had huge liver lesions at presentation. She progressed after 3 courses of FOLFIRI and died after 6 months from diagnosis. Patient C was operated on for a right colon cancer, G3, pT2N2, stage IIIB with lymph vascular invasion and had adjuvant FOLFOX 4. The 6-month assessment did not show relapse. Conclusions: in our series KRAS mutation incidence was in line with literature, but G12V was far more frequent. KRAS-BRAF DM accounted for 1% of all cases and the 2 patients with metastatic disease had an aggressive course with a much lower than expected survival. To our knowledge no series of DM have been described, hindering the understanding of their biological meaning. According to our experience, metastatic double mutated patients do not respond to standard therapy and should be treated with new drugs combinations in clinical trials.