Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study.
ABSTRACT The randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients receiving cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer (mCRC).
The biomarker analysis was extended through the use of additional DNA samples extracted from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data are presented.
Of 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%) KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4 significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551, P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed.
These results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.
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ABSTRACT: Colorectal cancer (CRC) is a common neoplasia in the Western countries, with considerable morbidity and mortality. Every fifth patient with CRC presents with metastatic disease, which is not curable with radical intent in roughly 80% of cases. Traditionally approached surgically, by resection of the primitive tumor or stoma, the management to incurable stage IV CRC patients has significantly changed over the last three decades and is nowadays multidisciplinary, with a pivotal role played by chemotherapy (CHT). This latter have allowed for a dramatic increase in survival, whereas the role of colonic and liver surgery is nowadays matter of debate. Although any generalization is difficult, two main situations are considered, asymptomatic (or minimally symptomatic) and severely symptomatic patients needing aggressive management, including emergency cases. In asymptomatic patients, new CHT regimens allow today long survival in selected patients, also exceeding two years. The role of colonic resection in this group has been challenged in recent years, as it is not clear whether the resection of primary CRC may imply a further increase in survival, thus justifying surgery-related morbidity/mortality in such a class of short-living patients. Secondary surgery of liver metastasis is gaining acceptance since, under new generation CHT regimens, an increasing amount of patients with distant metastasis initially considered non resectable become resectable, with a significant increase in long term survival. The management of CRC emergency patients still represents a major issue in Western countries, and is associated to high morbidity/mortality. Obstruction is traditionally approached surgically by colonic resection, stoma or internal by-pass, although nowadays CRC stenting is a feasible option. Nevertheless, CRC stent has peculiar contraindications and complications, and its long-term cost-effectiveness is questionable, especially in the light of recently increased survival. Perforation is associated with the highest mortality and remains mostly matter for surgeons, by abdominal lavage/drainage, colonic resection and/or stoma. Bleeding and other CRC-related symptoms (pain, tenesmus, etc.) may be managed by several mini-invasive approaches, including radiotherapy, laser therapy and other transanal procedures.World journal of gastroenterology : WJG. 06/2014; 20(24):7602-7621.
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ABSTRACT: Panitumumab (Pmab) is generally considered to be ineffective after the failure of cetuximab (Cmab) therapy in metastatic colorectal cancer (mCRC) patients. However, a few studies have demonstrated that Pmab is an effective treatment for disease progression following Cmab-based regimens in the USA. In the present study, we evaluated the safety and efficacy of Pmab therapy following the failure of Cmab therapy in Japanese patients with mCRC. We performed a retrospective review of the treatment of 16 mCRC patients who tolerated Pmab with clinical benefits after the failure of Cmab therapy between August 2010 and September 2011 at Shiga University of Medical Science. Fourteen of the 16 patients were administered standard Pmab monotherapy (6 mg/kg) intravenously every 2 weeks and the remaining two patients received Pmab with mFOLFOX6 intravenously every 2 weeks. All patients received Pmab chemotherapy until the occurrence of disease progression. Partial radiographic responses (PR) were observed in 2 of the 16 patients and stable disease (SD) was observed in 5 patients. Nine patients had evidence of progressive disease (PD). According to the KRAS status, 7 of the 13 (53.8%) patients who had wild-type KRAS achieved a high disease control rate (PR + SD). The median progression-free survival (PFS) and overall survival (OS) in the wild-type KRAS patients was 96 and 245 days, respectively. Pmab may be an alternative treatment strategy for Japanese patients with mCRC who have experienced failure with standard Cmab-based therapeutic regimens.Oncology letters 04/2013; 5(4):1331-1334. · 0.24 Impact Factor
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ABSTRACT: Initially unresectable colorectal liver metastases can be resected after response to chemotherapy. While cetuximab has been shown to increase response and resection rates, the survival outcome for this conversion strategy needs further evaluation. Patients with technically unresectable and/or ≥5 liver metastases were treated with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated with regard to resectability every 2 months. Tumour response and secondary resection data have been reported previously. A final analysis of overall survival (OS) and progression-free survival (PFS) was performed in December 2012. Between December 2004 and March 2008, 56 patients were randomised to arm A, 55 to arm B. The median OS was 35.7 [95% CI: 27.2-44.2] months (arm A: 35.8 [95% CI: 28.1- 43.6], arm B: 29.0 [95% CI: 16.0-41.9] months, HR 1.03 [95% CI: 0.66-1.61], p=0.9). The median PFS was 10.8 [95% CI: 9.3-12.2] months (arm A: 11.2 [95% CI: 7.2-15.3], arm B: 10.5 [95% CI: 8.9-12.2] months, HR 1.18 [95% CI: 0.79-1.74], p=0.4). Patients who underwent R0 resection (n=36) achieved a better median OS (53.9 [95% CI: 35.9-71.9] months) than those who did not (21.9 [95% CI:17.1-26.7] months, p<0.001). The median disease-free survival for R0 resected patients was 9.9 [95% CI: 5.8-14.0] months, and the 5-year OS rate was 46.2 [95% CI: 29.5-62.9] %. This study confirms a favourable long-term survival for patients with initially suboptimal or unresectable colorectal liver metastases who respond to conversion therapy and undergo secondary resection. Both FOLFOX/FOLFIRI plus cetuximab, appear to be appropriate regimens for "conversion" treatment in patients with K-RAS codon 12/13/61 wild-type tumours. Thus, liver surgery can be considered curative or alternatively as an additional "line of therapy" in those patients who are not cured. NCT00153998, www.clinicaltrials.gov.Annals of Oncology 02/2014; · 7.38 Impact Factor