Systemic chemotherapy for metastatic colorectal cancer: General principles
- Jeffrey W Clark, MD
Jeffrey W Clark, MD
- Associate Professor of Medicine
- Harvard Medical School
- Axel Grothey, MD
Axel Grothey, MD
- Mayo Clinic College of Medicine
The majority of patients with metastatic colon or rectal cancer (mCRC) cannot be cured, although a subset of patients with liver and/or lung-isolated metastatic disease, local recurrence, or limited intraabdominal disease are potentially curable with surgery. For other patients with 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 "Locoregional methods for management and palliation in patients who present with stage IV colorectal cancer", section on 'Aggressive cytoreduction and intraperitoneal chemotherapy for peritoneal carcinomatosis'.)
This topic review will cover general principles that underlie chemotherapy treatment of mCRC, including the goals of therapy in patients with potentially resectable metastatic disease versus those with categorically unresectable disease, benefits of treatment compared with supportive care alone, issues related to timing and duration of treatment in patients with unresectable metastatic disease, and assessment during therapy. Data from clinical trials evaluating systemic therapy for nonresectable mCRC, specific treatment recommendations for patients with unresectable mCRC, issues relevant to treatment of mCRC in the elderly and those with a poor performance status, and the use of systemic therapy for the purpose of downsizing potentially resectable CRC liver metastases are discussed elsewhere. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations" and "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials" and "Therapy for metastatic colorectal cancer in elderly patients and those with a poor performance status" and "Management of potentially resectable colorectal cancer liver metastases", section on 'Conversion therapy for initially unresectable metastases'.)
For decades, fluorouracil (FU) was the sole active agent for advanced colorectal cancer (CRC). 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 (bevacizumab), the vascular endothelial growth factor receptor (VEGF; ramucirumab), and the epidermal growth factor receptor (cetuximab and panitumumab); intravenous aflibercept, a fully-humanized 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 (including the VEGF receptors 1 to 3), stromal, and oncogenic kinases; 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 anti-angiogenic properties as well. In addition, other orally active fluoropyrimidines (capecitabine, S-1, tegafur-uracil [UFT]) are also available.
The best way to combine and sequence these agents is still not established. A compilation of commonly used chemotherapy protocols for colorectal cancer is available. (See "Treatment protocols for small and large bowel cancer" and "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations".)
The goals of chemotherapy for metastatic colorectal cancer (mCRC) differ according to the clinical scenario. For most patients, treatment will be palliative and not curative (a fact that may not be understood by patients ), and the treatment goals are to prolong overall survival and maintain quality of life (QOL) for as long as possible.
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- CHEMOTHERAPY OPTIONS
- TREATMENT GOALS
- Potentially resectable disease
- Nonresectable disease
- CHEMOTHERAPY VERSUS SUPPORTIVE CARE
- TIMING OF CHEMOTHERAPY
- CHEMOTHERAPY DOSING IN OBESE PATIENTS
- CONTINUOUS VERSUS INTERMITTENT THERAPY
- - OPTIMOX trials
- - NO16966
- - MRC COIN trial
- - CONcePT trial
- - CAIRO3 trial
- - German AIO KRK 0207 trial
- - STOP and GO trial
- - Maintenance bevacizumab alone
- - Erlotinib plus bevacizumab
- - Maintenance cetuximab
- - Meta-analysis
- ASSESSMENT DURING THERAPY
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS
- Goals of therapy
- Timing and dosing of initial chemotherapy
- Duration of initial therapy
- Response assessment