Oxaliplatin As Adjuvant Therapy for Colon Cancer: Updated Results of NSABP C-07 Trial, Including Survival and Subset Analyses

NSABP Biostatistical Center, One Sterling Plaza, 201 N Craig St, Ste 350, Pittsburgh, PA 15213, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 08/2011; 29(28):3768-74. DOI: 10.1200/JCO.2011.36.4539
Source: PubMed


The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin (FULV) improved disease-free survival (DFS) in patients with stage II or III colon cancer. This analysis is the first publication of overall survival (OS) for the NSABP C-07 study. We updated DFS and examined both end points in clinically relevant patient subsets.
Other studies have identified patients age 70 or older and those with stage II disease as patient subsets in which oxaliplatin may not be effective. We investigated toxicity as a driver of divergent outcomes in these subsets.
In all, 2,409 eligible patients with follow-up were randomly assigned to either FULV (FU 500 mg/m(2) by intravenous [IV] bolus weekly for 6 weeks; leucovorin 500 mg/m(2) IV weekly for 6 weeks of each 8-week cycle for three cycles) or FLOX (FULV plus oxaliplatin 85 mg/m(2) IV on days 1, 15, and 29 of each cycle). With 8 years median follow-up, OS was similar between treatment groups (hazard ratio [HR], 0.88; 95% CI, 0.75 to 1.02; P = .08). FLOX remained superior for DFS (HR, 0.82; 95% CI, 0.72 to 0.93; P = .002). The effect of oxaliplatin on OS did not differ by stage of disease (interaction P = .38 for OS; interaction P = 0.37 for DFS) but did vary by age for OS (younger than age 70 v 70+ interaction P = .039). There was a similar trend for DFS (interaction P = .073). Oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80; 95% CI, 0.68 to 0.95; P = .013), but no positive effect was evident in older patients.
Overall, the addition of oxaliplatin to FULV has not been proven to extend OS in this trial, but the DFS effect remained strong. Unplanned subset analyses suggest a significant OS effect of oxaliplatin in patients younger than age 70.

1 Follower
43 Reads
    • "Alternatively, the use of capecitabine, an oral pro-drug of 5-FU, as monotherapy has demonstrated a comparable efficacy when compared to 5-FU with a lower percentage of toxic events (Twelves et al., 2005, 2012). To improve 5-year diseasefree-survival (DFS) and 6-year OS in completely resected patients, the addition of the platinum derivate oxalipatin to both 5-FU (FOL- FOX) and capecitabine (CAPOX or XELOX) has been successfully investigated by many clinical trials in the adjuvant settings; these combination regimens represent now the treatment of choice for stage III CRC patients with an exception for those cases where oxaliplatin is contraindicated (Van Loon and Venook, 2011; Haller et al., 2011; Yothers et al., 2011). In contrast, the addition of irinotecan, a semisynthetic analog of camptothecin that acts through the inhibition of topoisomerase I resulting in blockade of DNA repair and DNA replication, to fluoropyrimidines-or to oxaliplatin-based regimens of the novel targeted biological agents (i.e. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal cancer (CRC) represents one of the most common malignancies and is major cause of cancer-related deaths worldwide. A great improvement in response rate and patient's survival was recently achieved through the introduction of new targeted agents including the anti-EGFR monoclonal antibodies cetuximab and panitumumab, the anti-angiogenic drugs bevacizumab and aflibercept, as well as the multi-kinase inhibitor regorafenib, in combination with standard fluoropyrimidines-based chemotherapeutic regimens. Intrinsic and acquired chemoresistance continue to be a major hindrance toward curative therapy. To overcome the obstacle of the currently unpredictable inter-individual variability in the therapy outcome, concentrated research efforts have been focused on elucidating the contribution of genetic variants predictive of pharmacoresistance in CRC. The occurrence of tumor somatic mutations in the RAS/RAF/MAPK and PI3K/PTEN/AKT pathways remains the main challenge for CRC treatment with the new biological agents. It has been recently proposed to consider a quadruple negative profile for CRC, based on the status of KRAS exon 2, BRAF-p.V600E, PI3KCA-exon 9 and PTEN, as tumor markers of sensitivity to anti-EGFR treatment. However, in the last years, great efforts have been devoted to address germline genetic profiles of pharmacoresistance. Heritable genetic variants in the ABC and SLC transport pathways; in the CYP450, GST, and UGT-mediated phase I and II metabolism; in the folate metabolic pathway; as well as in the EGF and VEGF signaling pathways, have been associated with a distinct tumor sensitivity phenotype in CRC patients treated with fluoropyrimidines combined with either irinotecan, oxaliplatin or targeted biological agents. More recently, computation of clinical-pharmacogenetic algorithms, combining multiple host polymorphisms with clinico-demographic features, appeared to be a more reliable strategy to test a complex phenomenon as tumor response to therapy. The final goal of the pharmacogenomics research in the domain of pharmacoresistance in CRC should be the definition of integrated somatic and germline genetic profiles of both intrinsic and acquired resistance. The aim of the present review is to provide a comprehensive update on the most important findings regarding the research of pharmacogenomics markers in the field of CRC treatment that could be integrated in clinical practice in order to accomplish an efficacious personalized treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 05/2015; 20. DOI:10.1016/j.drup.2015.05.003 · 9.12 Impact Factor
  • Source
    • "Many colorectal cancer patients treated with chemotherapy suffer from mucositis and gastrointestinal complaints, such as severe diarrhoea, nausea and vomiting [28,29]. Knowledge on the role of the gut microbiota - a major compartment of the gastrointestinal tract- in human health has emerged in the past years [30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background There is clear evidence that nutrition and lifestyle can modify colorectal cancer risk. However, it is not clear if those factors can affect colorectal cancer treatment, recurrence, survival and quality of life. This paper describes the background and design of the “COlorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that may influence colorectal tumour recurrence, survival and quality of life” – COLON – study. The main aim of this study is to assess associations of diet and other lifestyle factors, with colorectal cancer recurrence, survival and quality of life. We extensively investigate diet and lifestyle of colorectal cancer patients at diagnosis and during the following years; this design paper focusses on the initial exposures of interest: diet and dietary supplement use, body composition, nutrient status (e.g. vitamin D), and composition of the gut microbiota. Methods/Design The COLON study is a multi-centre prospective cohort study among at least 1,000 incident colorectal cancer patients recruited from 11 hospitals in the Netherlands. Patients with colorectal cancer are invited upon diagnosis. Upon recruitment, after 6 months, 2 years and 5 years, patients fill out food-frequency questionnaires; questionnaires about dietary supplement use, physical activity, weight, height, and quality of life; and donate blood samples. Diagnostic CT-scans are collected to assess cross-sectional areas of skeletal muscle, subcutaneous fat, visceral fat and intermuscular fat, and to assess muscle attenuation. Blood samples are biobanked to facilitate future analyse of biomarkers, nutrients, DNA etc. Analysis of serum 25-hydroxy vitamin D levels, and analysis of metabolomic profiles are scheduled. A subgroup of patients with colon cancer is asked to provide faecal samples before and at several time points after colon resection to study changes in gut microbiota during treatment. For all patients, information on vital status is retrieved by linkage with national registries. Information on clinical characteristics is gathered from linkage with the Netherlands Cancer Registry and with hospital databases. Hazards ratios will be calculated for dietary and lifestyle factors at diagnosis in relation to recurrence and survival. Repeated measures analyses will be performed to assess changes over time in dietary and other factors in relation to recurrence and survival.
    BMC Cancer 05/2014; 14(1):374. DOI:10.1186/1471-2407-14-374 · 3.36 Impact Factor
  • Source
    • "In our center, most patients receiving neoadjuvant CRT were clinical T4 or N+, and might have more opportunities to benefit from a high intensity treatment, whether chemotherapy or radiotherapy [11-13]. To decrease the additional toxicities from a high-dose treatment, especially diarrhea, intensity modulated radiotherapy (IMRT) was used to lessen radiation-associated toxicities by decreasing the volume of high irradiation dose of surrounding normal tissues [14-16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aim: This study was designed to evaluate the efficacy and toxicities of concomitant boost intensity-modulated radiation therapy (IMRT) along with capecitabine and oxaliplatin, followed by a cycle of Xelox, in neoadjuvant course for locally advanced rectal cancer.Materials and methods: Patients with histologically confirmed, newly diagnosed, locally advanced rectal adenocarcinoma (cT3-T4 and/or cN+) located within 12 cm of the anal verge were included in this study. Patients received IMRT to the pelvis of 50 Gy and a concomitant boost of 5 Gy to the primary tumor in 25 fractions, and concurrent with oxaliplatin (50 mg/m2 d1 weekly) and capecitabine (625 mg/m2 bid d1-5 weekly). One cycle of Xelox (oxaliplatin 130 mg/m2 on d1 and capecitabine 1000 mg/m2 twice daily d1-14) was given two weeks after the completion of chemoradiation, and radical surgery was scheduled eight weeks after chemoradiation. Tumor response was evaluated by tumor regression grade (TRG) system and acute toxicities were evaluated by NCI-CTC 3.0 criteria. Survival curves were estimated using the Kaplan-Meier method and compared with Log-rank test. A total of 78 patients were included between March 2009 and May 2011 (median age 54 years; 62 male). Seventy-six patients underwent surgical resection. Twenty-eight patients underwent sphincter-sparing lower anterior resection and 18 patients (23.7%) were evaluated as pathological complete response (pCR). The incidences of grade 3 hematologic toxicity, diarrhea, and radiation dermatitis were 3.8%, 10.3%, and 17.9%, respectively. The three-year LR (local recurrence), DFS (disease-free survival) and OS (overall survival) rates were 14.6%, 63.8% and 77.4%, respectively. Initial clinical T stage and tumor regression were independent prognostic factors to DFS. An intensified regimen of concomitant boost radiotherapy plus concurrent capecitabine and oxaliplatin, followed by one cycle of Xelox, can be safely administered in patients with locally advanced rectal cancer, and produces a high rate of pCR. A prognostic score model is helpful to distinguish different long-term prognosis groups in early stage.
    Radiation Oncology 03/2014; 9(1):70. DOI:10.1186/1748-717X-9-70 · 2.55 Impact Factor
Show more


43 Reads
Available from