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Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials

Authors
Jeffrey W Clark, MD
Axel Grothey, MD
Section Editor
Richard M Goldberg, MD
Deputy Editor
Diane MF Savarese, MD

INTRODUCTION

The majority of patients with metastatic colon or rectal cancer cannot be cured, although a subset with liver and/or lung-isolated disease is potentially curable with surgery. For other patients with metastatic colorectal cancer (mCRC), treatment is palliative and generally consists of systemic chemotherapy. (See "Management of potentially resectable colorectal cancer liver metastases" and "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation and techniques".)

For decades, fluorouracil (FU) was the sole active agent. This has changed markedly since the year 2000, with the approval of irinotecan, oxaliplatin, three humanized monoclonal antibodies (MoAbs) that target the vascular endothelial growth factor (VEGF; bevacizumab) and epidermal growth factor receptor (EGFR; cetuximab and panitumumab), intravenous aflibercept, a recombinant fusion protein consisting of VEGF binding portions from the human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1, regorafenib, an orally active inhibitor of angiogenic tyrosine kinases (including the VEGF receptors 1, 2, and 3) as well as several other membrane-bound and intracellular kinases that are involved in normal cellular function and in pathologic processes, and trifluridine-tipiracil (TAS-102), an oral cytotoxic agent that consists of the nucleoside analog trifluridine (a cytotoxic antimetabolite that inhibits thymidylate synthetase and, after modification within tumor cells, is incorporated into DNA causing strand breaks) and tipiracil, a potent thymidine phosphorylase inhibitor, which inhibits trifluridine metabolism and has antiangiogenic properties as well. The best way to combine and sequence these agents is still not established.

The best way to combine and sequence all of these agents is not known. Increasingly, biomarker expression is driving therapeutic decision-making. However, the biologic targets for most of the agents that are active against mCRC are unknown, with the exception of agents targeting the EGFR. Benefit from monoclonal antibodies targeting the EGFR is restricted to patients whose tumors do not contain mutated RAS genes. Furthermore, evidence increasingly suggests that response to EGFR-targeted agents is highly unlikely in patients whose tumors harbor BRAF mutations (particularly the BRAF V600E mutation).

This topic review will cover the data from clinical trials evaluating systemic chemotherapy for nonresectable mCRC. General principles of treatment and specific treatment recommendations, including the use of biomarkers to select therapy and a compilation of treatment protocols, are presented elsewhere, as is the use of systemic therapy for the purpose of downstaging potentially resectable CRC liver metastases. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles" and "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations" and "Treatment protocols for small and large bowel cancer" and "Management of potentially resectable colorectal cancer liver metastases", section on 'Therapy after resection of liver metastases'.)

FLUOROPYRIMIDINES

Until the development of combination regimens of leucovorin (LV)-modulated fluorouracil (FU) with either irinotecan or oxaliplatin, FU/LV was the standard first-line therapy for metastatic colorectal cancer (mCRC), and it is still used in patients who cannot tolerate these triple-drug regimens. If it is to be used alone, because of the more favorable toxicity profile, we recommend short-duration infusional FU/LV (ie, the de Gramont regimen) [1] rather than the Mayo regimen of treatment for five consecutive days once per month. An acceptable alternative is weekly FU (500 mg/m2) plus LV (500 mg/m2) for six of every eight weeks [2].

                                                               

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Literature review current through: Nov 2016. | This topic last updated: Thu Oct 20 00:00:00 GMT+00:00 2016.
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