P-307 Immunomodulatory switch maintenance therapy to improve overall survival in metastatic colorectal carcinoma: The phase 3 IMPALA study

13011 Background: Previous work suggests that DNA repair enzyme polymorphism and microsatellite instability (MSI) may bear prognostic value in metastatic colorectal carcinoma (MCRC), but this is either retrospective or do not involve irinotecan-based regimens. Methods: We prospectively treated 43 MCRC patients with irinotecan-based regimens (XELIRI or IFL). MSI was measured by PCR at 5 different chromosomal loci: BAT-25, BAT-26, D5S346, D2S123, and D17S250. XPD (Lys751Gln) and XRCC1 (Arg399Gln) polymorphisms were also analysed by PCR-RFLP method. Clinical outcome variables; overall survival (OAS), progression free survival (PFS) and the occurrence of grade 3 or 4 hematological and gastrointestinal (GIS) toxicities were evaluated. Results: MSI subtypes MSS, MSI-L and MSI-H were seen in 23.3%, 43.3% and 33.3% of cases. In the univariate analysis for OAS (n=43) only XPD and XRCC1 polymorphisms were significant (P=0.05 and P=0.04, respectively). After adjustment for performance status (ECOG=0, 1 vs. 2) and disease extent (single vs. multiple metastatic site), XRCC1 genotype and performance status retained significance (P=0.04, HR=2.85, and P=0.02, HR=3.19, respectively). Arg/Gln versus Arg/Arg and Gln/Gln versus Arg/Gln genotypes indicated approximately 3 times increased risk of death for each comparison. Type of presentation (metastatic versus local disease at first presentation) was the only significant predictor of PFS in the univariate analysis (n=40, P=0.003). After adjustment for performance status and disease extent, type of presentation retained its significance (P=0.003, HR=4.35). MSI was not associated with survival. Although absence of “liver only” disease was associated with the occurrence of grade 3–4 GIS toxicity, it lost significance in the multivariate analysis. None of the factors tested correlated with the likelihood of grade 3–4 hematological toxicity. Conclusions: XRCC1 genotype independently predicted overall survival in metastatic colorectal carcinoma patients treated with irinotecan-based chemotherapy. However, MSI status did not emerge as a prognostic factor in our cohort. No significant financial relationships to disclose.

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Phase II study of capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15125 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15125-e15125

Author(s):

R. Xu none ◽

Y. Li ◽

H. Luo ◽

F. Wang

Keyword(s):

Colorectal Carcinoma ◽

Maintenance Therapy ◽

Healthcare Providers ◽

Progression Free Survival ◽

Chinese Patients ◽

Line Treatment ◽

Metastatic Colorectal Carcinoma ◽

First Line ◽

Oral Capecitabine ◽

First Line Treatment

e15125 Background: The purpose of this study was to evaluate the safety and efficacy of the capecitabine-oxaliplatine combination (XELOX) in Chinese patients with metastatic colorectal carcinoma (mCRC). Furthermore, we aimed to explore whether a maintenance therapy with oral capecitabine in patients responding to XELOX is able to maintain the response and improve the duration of disease control (DDC). Methods: Patients with mCRC were treated with a 3-weekly regimen of oxaliplatin at a dose of 130 mg/m2 intravenously on Day 1 plus capecitabine 1000 mg/m2 orally twice daily from Days 2 to 15. Patients who did not progress after finished the XELOX therapy were choice to stop or receive oral capecitabine until disease progression or unacceptable toxicity. Results: 124 patients received a total of 637 cycles (median, 6) of treatment. Responses rate was 49.1%. Median overall and median progression-free survival was 20.0 months and 8.0 months, respectively. Main grade 3–4 drug-related toxicities included neutrapenia (5.6%), nausea/vomiting (4%), thrombocytopenia (2.4%), and hand-foot syndrome (2.4%). 23 of 101 patients responding to XELOX received oral capecitabine as maintenance therapy.The median DDC was 8 months for patients in the group of not using maintenance therapy, versus 12 months in the group of using capecitabine as maintenance therapy. Conclusions: XELOX is a highly effective first-line treatment for mCRC and provides a more convenient regimen, likely to be preferred by both patients and healthcare providers. Furthermore, these results support the feasibility of maintaining good response and improving DDC with oral Capecitabine after combination chemotherapy in mCRC. No significant financial relationships to disclose.

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Analysis of plasma biomarkers potentially associated with antiangiogenic resistance in NCIC CTG/AGITG CO.20: A phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refractory, k-RAS wild-type (WT), metastatic colorectal carcinoma (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3572 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3572-3572

Author(s):

Jeremy David Shapiro ◽

Lillian L. Siu ◽

Christopher J O'Callaghan ◽

John Raymond Zalcberg ◽

Malcolm J. Moore ◽

...

Keyword(s):

Overall Survival ◽

Colorectal Carcinoma ◽

Randomized Trial ◽

Phase Iii ◽

Plasma Samples ◽

Wild Type ◽

Metastatic Colorectal Carcinoma ◽

Plasma Biomarkers ◽

Anti Vegf ◽

Brivanib Alaninate

3572 Notice of Retraction: "Analysis of plasma biomarkers potentially associated with antiangiogenic resistance in NCIC CTG/AGITG CO.20: A phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refractory, k-RAS wild-type (WT), metastatic colorectal carcinoma (mCRC)." Abstract 3572, published in the 2012 Annual Meeting Proceedings Part I, a supplement to the Journal of Clinical Oncology, has been retracted by Jeremy Shapiro, MBBS, and Lillian Siu, MD, on behalf of the NCIC, AGITG, and all authors of the abstract. The authors have been unable to finalize their data presentation due to the complexity of the analysis, and difficulties with the statistical interpretation of the significance of several possible predictive biomarkers. Background: In the CO.20 trial, the addition of BRIV, a tyrosine kinase inhibitor targeting vascular endothelial and fibroblast growth factor receptors (VEGFR2,3 and FGFR 1,2,3), to CET, increased objective response rate and progression free survival, but did not significantly increase overall survival. Previous clinical studies demonstrated modulation of circulating angiogenic factors (CAF) in CRC which occur on therapy or upon progression (Kopetz JCO 2010). Methods: CO.20 pts were randomized 1:1 to CET plus either BRIV (Arm A) or placebo (ARM B) in a double-blind design. Pts may have had 1 prior anti-VEGF based therapy, but no prior anti-EGFR therapy. Primary endpoint was overall survival (OS). Baseline pre-treatment plasma samples were analyzed using commercial Multi-Analyte ELISAs to measure CAF, immunologic, and growth factors, with an initial discovery and subsequent validation data set. Results: 750 pts were randomized (376 in Arm A and 374 in Arm B). Median OS in the intent-to-treat population was 8.8 months in Arm A and 8.1 months in Arm B, hazard ratio (HR)=0.88; 95%CI=0.74-1.03; p=0.12. In an exploratory subgroup analysis, there is a statistically non-significant trend favoring the effect of brivanib on OS among the 41% pts who received prior anti-VEGF therapy versus those who did not.Baseline plasma samples were collected from 96% of pts, and analysis is ongoing. Results of the largest circulating biomarker analysis will be presented. CAF results will be compared with response and survival data to look for potential patient subgroups that may benefit more from the combination treatment. Conclusions: This large scale analysis will provide insights on the potential use of CAF or CAF profiles as predictive markers in CRC.

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