Individualizing Therapy for Metastatic Colorectal Cancer November

The past decade has seen exciting developments in the field of colorectal cancer, particularly in the setting of advanced disease. The developments of new treatment options have translated into impressive gains in response rates, progression-free survival, overall survival, and, in certain situations, potential cure. In this issue of ONCOLOGY, Drs. Davies and Goldberg have provided an excellent review of the history of the development of newer therapies for metastatic colorectal cancer (mCRC), presenting the data and rationale behind each new therapeutic approach. The article eloquently details how multiple studies have investigated the use of cytotoxic chemotherapeutic agents (fluorouracil [5-FU], oxaliplatin [Eloxatin], and irinotecan) in attempts to determine the best combination and the ideal order in which to administer them. Doublet chemotherapy regimens (FOLFOX [leucovorin (folinic acid), 5-FU, oxaliplatin] and FOLFIRI [leucovorin, 5-FU, irinotecan]) have improved efficacy over 5-FU/leucovorin alone. [1,2] It does not appear to change outcomes whether FOLFOX or FOLFIRI are used as firstor second-line therapy,[3] and ultimately it was shown that survival is improved with exposure to all three drugs. [4] Capecitabine (Xeloda) appears to be an acceptable alternative for 5-FU,[5,6] although this agent has not gained the popularity in the United States that it has in Europe. Targeted therapies have provided an additional mechanism with which to attack advanced colorectal cancer. Bevacizumab (Avastin), a vascular endothelial growth factor (VEGF) inhibitor, and epidermal growth factor receptor (EGFR) inhibitors (cetuximab [Erbitux] and panitumumab [Vectibix]) can lead to increased response rates, progression-free survival, and—in the case of bevacizumab—overall survival, particularly when used in combination with cytotoxic chemotherapy. [7-11] Ongoing trials are aimed at determining the optimal combinations of cytotoxic and targeted therapies. With the treatment options we have available, the challenge is the following: How do we best utilize these therapies to provide the greatest benefit to our patients with advanced colorectal cancer? The focus now should be to tailor each therapeutic option to the individual, minimizing toxicity while obtaining the maximum efficacy our treatments can provide. Biomarker-Driven Treatment Decisions The latest breakthrough in the individualization of therapy for mCRC involves determining whether the patient’s tumor has a mutation in K-ras. As outlined by Drs. Davies and Goldberg, a large body of evidence shows that only individuals with K-ras wild-type status stand to benefit from the use of EGFR inhibitors. These agents provide no survival advantage to patients with K-ras mutant tumors and, in fact, have the potential to harm this subset of patients. [12,13] To determine whether a given patient might benefit from the use of an EGFR inhibitor, tumors should be tested for K-ras mutation status. Ideally, this should be done at the time of diagnosis for all patients with colorectal cancer. Testing can also be performed on tissue from previously resected lesions or biopsies. Recurrent and metastatic lesions retain their K-ras status; therefore, knowledge of K-ras status initially, even in patients without advanced disease, will indicate whether EGFR inhibitors will be an option for treatment in the event of recurrence. Beyond K-ras, further biomarkers such as B-raf (V600E) mutations, intact expression of PTEN,[14] and expression levels of EGFR ligands (amphiregulin, epiregulin) will conceivably allow us to more specifically identify patients who will benefit from EGFR-targeted therapies. [15-17] The ideal patient for cetuximab or panitumumab therapy would have a K-ras wild-type colorectal cancer without B-raf mutations, intact PTEN, and high expression levels of amphiregulin and/or epiregulin. Curative vs Palliative Approach Another question to ask when considering treatment for advanced colorectal cancer is: What is the