Tag: Rectal Cancer

SUMMARY: Treatment of metastatic colorectal cancer with a combination of chemotherapy given along with AVASTIN® is well established. However the duration of therapy remains unclear and it is common to give drug holidays to patients. The outcome in patients who are given these drug holidays remains unclear. The CAIRO3 study is a phase III trial in which patients with previously untreated, unresectable metastatic colorectal cancer received induction treatment with six cycles of Capecitabine (XELODA®)/Oxaliplatin (ELOXATIN®) plus Bevacizumab (AVASTIN®) – CAPOX-B. Patients who had not progressed during induction and had reponses or had stable disease (N=558) were then randomized to receive either XELODA® at 625 mg/m2 twice daily along with AVASTIN® at 7.5 mg/kg every 3 weeks or be observed. Upon first progression, patients in both treatment groups were treated with CAPOX-B until second progression and this was considered the primary endpoint for this study. Secondary endpoints included Overall Survival (OS). Median follow up was 40 months. The median time to second progression from randomization was 19.8 months in the maintenance group and 15 months in the observation group (HR=0.63; P<0.001) The time to first progression in the maintenance treatment group was 8.5 months versus 4.1 months in the observation group (HR 0.41; P<0.001). The time to second progression following treatment with CAPOX-B was 11.8 months in the maintenance group versus 10.5 months for the observation group (HR 0.77; P=0.007), representing a 23% reduction in the risk of progression. The adjusted median OS was 21.7 months with maintenance treatment and 18.2 months in the observation group (HR=0.80; P=0.035). Treatment was well tolerated with slight increase in hand-foot syndrome and neurotoxicity in the maintenance group. Based on this data, the authors recommended maintenance treatment with XELODA® and AVASTIN® until progression or unacceptable toxicity, following 6 cycles of efficacious treatment with CAPOX-B. It is important to note that in the SAKK 41/06 trial conducted by the Swiss Group, observation alone was non-inferior to single agent maintenance AVASTIN® following initial chemotherapy, suggesting that the addition of fluoropyrimidine (XELODA®) chemotherapy to AVASTIN® as maintenance treatment, improves time to progression and median OS in patients with metastatic colorectal cancer. Koopman M, Simkens LH, Ten Tije, AJ et al. J Clin Oncol 31, 2013 (suppl; abstr 3502)

ZALTRAP® (Aflibercept) is a soluble fusion protein that is capable of binding with high affinity to pro-angiogenic factors such as all VEGF-A isoforms, VEGF-B, and PlGF. This is unlike bevacizumab, which is a monoclonal antibody that only targets all isoforms of VEGF-A.  In the VELOUR trial, second-line chemotherapy in combination with ZALTRAP® (Aflibercept) demonstrated significant improvement in the progression-free survival  as well as overall survival compared to chemotherapy alone. This benefit was seen irrespective of prior bevacizumab therapy. This data was presented at the 13th ESMO world congress.

The CORRECT trial is a randomized phase III  study which demonstrated improved survival with Regorafenib, an oral multikinase inhibitor when compared to placebo, in individuals with advanced colorectal cancer, who had progressed on all available standard therapies. This important study gives a new option for individuals with advanced colorectal cancer. Additional data will be presented at ASCO 2012 meeting.

As we understand the molecular biology of colon cancer, it is becoming clear that tumors with MisMatch Repair Deficiency (MMR-D) and high MicroSatellite Instability (MSI) tend to have a favorable prognosis and do not benefit from chemotherapy and on the contrary, 5-FU based chemotherapy may potentially result in a detrimental effect. The Oncotype DX colon cancer 12 gene assay is a valuable tool that can provide additional information in the decision making process.

Testing for KRAS mutations is presently the standard of care prior to treatment with anti EGFR monoclonal antibodies such as cetuximab and panitumumab, as KRAS mutant colorectal tumors do not respond to anti EGFR monoclonal antibodies. However it is becoming clear that BRAF which is involved in intracellular signaling and cell growth and a principal downstream mediator of KRAS, when mutated resulted in shorter progression free survival and overall survival regardless of KRAS status. Targeted therapy may be taking a turn for the better making treatment more personalized.