Medication Summary
The fluoropyrimidine 5-fluorouracil (5-FU) remains the backbone of chemotherapy regimens for colon cancer, both in the adjuvant and metastatic setting. In addition to 5-FU, oral fluoropyrimidines such as capecitabine (Xeloda) and, outside the United States, tegafur are used as monotherapy or in combination with oxaliplatin (Eloxatin). Some of the standard combination regimens employ prolonged continuous infusion of 5-FU (FOLFIRI, FOLFOX) [177] or capecitabine (CAPOX, XELOX, XELIRI). [178, 179] For unresectable or metastatic colon cancer, treatment increasingly includes biologic agents, typically as targeted therapy based on genetic analysis of the tumor.
See also Colon Cancer Treatment Protocols
Antineoplastic Agent, Antimetabolite (pyrimidine analog)
Class Summary
These agents inhibit cell growth and proliferation.
5-Fluorouracil
Fluoropyrimidine analog. Cell cycle-specific with activity in the S-phase as single agent and has for many years been combined with biochemical modulator leucovorin. It inhibits DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. Classic antimetabolite anticancer drug with chemical structure similar to endogenous intermediates or building blocks of DNA or RNA synthesis. 5-FU inhibits tumor cell growth through at least 3 different mechanisms that ultimately disrupt DNA synthesis or cellular viability. These effects depend on intracellular conversion of 5-FU into 5-FdUMP, 5-FUTP, and 5-FdUTP. 5-FdUMP inhibits thymidylate synthase (key enzyme in DNA synthesis), which leads to accumulation of dUMP, which then gets misincorporated into the DNA in the form of 5-FdUTP resulting in inhibition of DNA synthesis and function with cytotoxic DNA strand breaks. 5-FUTP is incorporated into RNA and interferes with RNA processing.
Capecitabine (Xeloda)
Fluoropyrimidine carbamate prodrug from of 5-fluorouracil (5-FU). Capecitabine itself is inactive. Undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil), inhibiting thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. This step interferes with DNA and to a lesser degree with RNA synthesis.
Antidote, Folic Acid Antagonist
Class Summary
These agents counteract the toxic effects of the chemotherapeutic drug.
Leucovorin
Reduced form of folic acid that does not require enzymatic reduction reaction for activation. Allows for purine and pyrimidine synthesis, both of which are needed for normal erythropoiesis. Current standard therapy for colon cancer involves combination chemotherapy. Binds to and stabilizes ternary complex of FdUTP (intracellular active metabolite of fluoropyrimidines) and thymidylate synthetase (TS), augmenting cytotoxic effects of 5-fluorouracil. Used as an adjunct to fluorouracil.
Antineoplastic Agent, Miscellaneous
Class Summary
Irinotecan is a topoisomerase I inhibitor. Trifluridine is a thymidine-based nucleoside analog that is combined with the thymidine phosphorylase inhibitor, tipiracil.
Irinotecan (Camptosar)
Semisynthetic derivative of camptothecin, an alkaloid extract from the Camptotheca acuminate tree. Inactive in its parent form. Converted by the carboxylesterase enzyme to its active metabolite from, SN-38.
SN-38 binds to and stabilizes the topoisomerase I-DNA complex and prevents the relegation of DNA after it has been cleaved by topoisomerase I, inhibiting DNA replication. Current standard therapy for metastatic colon cancer involves combination of 5-FU/LV/CPT11 chemotherapy (see Standard Therapy).
Because of toxicity problems associated with Saltz regimen (5-FU/LV/CPT11), now standard first-line therapy for metastatic colon cancer, maximum of 400 mg/m2 of 5-FU and 100 mg/m2 of CPT11 can be used as starting dose.
Tipiracil/trifluridine (Lonsurf)
Trifluridine is a thymidine-based nucleoside analog that incorporates into DNA, interferes with DNA synthesis, and inhibits cell proliferation. Tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase. The combination product is indicated, as a single agent or in combination with bevacizumab, for metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.
Antineoplastic Agent, Alkylating Agent
Class Summary
Oxaliplatin is a platinum analog.
Oxaliplatin
Third-generation platinum-based antineoplastic agent used in combination with an infusion of 5-fluorouracil (5-FU) and leucovorin for treatment of metastatic colorectal cancer in patients with recurrence or progression following initial treatment with irinotecan, 5-FU, and leucovorin. Also indicated for previously untreated advanced colorectal cancer in combination with 5-FU and leucovorin. Covalently binds to DNA with preferential binding to the N-7 position of guanine and adenine. DNA mismatch repair enzymes are unable to recognize oxaliplatin-DNA adducts in contrast with other platinum-DNA adducts as a result of their bulkier size. Forms interstrand and intrastrand Pt-DNA crosslinks that inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific with activity in all phases of the cell cycle.
Antineoplastic Agent, Monoclonal Antibody
Class Summary
These agents target factors responsible for deregulated cell proliferation.
Cetuximab (Erbitux)
Recombinant, human/mouse chimeric monoclonal antibody that specifically binds to the extracellular domain of human epidermal growth factor receptors (EGFR, HER1, c-ErbB-1). Cetuximab-bound EGF receptor inhibits activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased production of matrix metalloproteinase and vascular endothelial growth factor.
Indicated for treatment of KRAS mutation-negative (wild-type) EGFR-expressing, metastatic colorectal cancer for the following: 1) in combination with FOLFIRI for first-line treatment, 2) in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, and 3) as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan.
Bevacizumab (Avastin, Mvasi)
Murine derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting vascular endothelial growth factor (VEGF). Inhibiting new blood vessel formation denies blood, oxygen, and other nutrients needed for tumor growth. Bevacizumab is indicated in combination with a fluoropyrimidine-based chemotherapy as a first-line or second-line treatment for metastatic colorectal cancer. It is also indicated for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen. For continuation therapy, use bevacizumab in combination with a fluoropyrimidine (eg, 5-FU, capecitabine) plus irinotecan or oxaliplatin-based chemotherapy. Mvasi has been FDA-approved as a biosimilar to Avastin but not as an interchangeable product.
Panitumumab (Vectibix)
Recombinant human IgG2 kappa monoclonal antibody that binds to human epidermal growth factor receptor (EGFR). Indicated for wild-type KRAS (exon 2 in codons 12 or 13) metastatic colororectal carcinoma, as determined by an FDA-approved test. Indicated as second-line, monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. Also indicated as first-line therapy in combination with FOLFOX.
Ipilimumab (Yervoy)
Recombinant human cytotoxic T-lymphocyte antigen 4 (CTLA-4) - blocking antibody. It is indicated in combination with nivolumab for adults with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) which progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Antineoplastics, Tyrosine Kinase Inhibitors
Class Summary
VEGF induces endothelial cell proliferation and blood vessel permeability. Inhibiting VEGF prevents tyrosine kinase stimulation.
Ziv-aflibercept (Zaltrap)
Vascular endothelial growth factor (VEGF) inhibitor; prevents VEGF from stimulating cellular responses by binding to tyrosine kinase receptors (ie, the VEGF receptors). Indicated in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin regimen.
Regorafenib (Stivarga)
Regorafenib is a tyrosine kinase inhibitor. It is indicated for metastatic colorectal cancer in patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therapy (eg, bevacizumab, ziv-aflibercept); and, if KRAS wild type, an anti-EGFR therapy (eg, cetuximab, panitumumab).
Tucatinib (Tukysa)
Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro and in vivo, tucatinib inhibits the antitumor activity of HER2-expressing tumor cells and inhibits the growth of HER2-expressing tumors. The combination of tucatinib with trastuzumab showed an increase in antitumor activity in vitro and in vivo. The FDA granted accelerated approval for tucatinib in combination with trastuzumab for adults with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed after treatment with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy.
Antineoplastics, VEGF Inhibitor
Class Summary
Vascular endothelial growth factor (VEGF) receptor antagonists disrupt ligand-induced proliferation and migration of human endothelial cells. Angiogenesis requires the binding of signaling molecules (eg, VEGF) to receptors on the surface of normal endothelial cells. When VEGF and other endothelial growth factors bind to their receptors on endothelial cells, signals within these cells are initiated that promote the growth and survival of new blood vessels. When VEGF is bound, angiogenesis is inhibited.
Ramucirumab (Cyramza)
Ramucirumab specifically binds VEGF receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. It is indicated for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first-line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen.
Fruquintinib (Fruzaqla)
Fruquintinib is a selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is indicated for metastatic colorectal cancer (mCRC) in adults who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.
PD-1/PD-L1 Inhibitors
Class Summary
Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells.
Pembrolizumab (Keytruda)
Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. It is indicated for unresectable or metastatic colon cancer that has tested positive for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR), and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan.
Nivolumab (Opdivo)
Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor to block the ligands PD-L1 and PD-L2 from binding. The negative PD-1 receptor signaling that regulates T-cell activation and proliferation is therefore disrupted. This releases PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response. It is indicated for unresectable or metastatic colon cancer that has tested positive for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR), and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan in patients ≥ 12 years. Additionally, it is also indicated in combination with ipilimumab for adults.
Antineoplastics, Other
Class Summary
Larotrectinib selectively inhibits tropomyosin receptor kinases (TRKs). Entrectinib and its major metabolite TRKs, proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK). [180]
Larotrectinib (Vitrakvi)
Highly selective inhibitor of tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In tumor models, larotrectinib demonstrates antitumor activity in cells by activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK overexpression
Entrectinib (Rozlytrek)
Selectively inhibits TRKA, TRKB, and TRKC. Indicated for adults and children aged 12 years or older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation.
Antineoplastics, BRAF Kinase Inhibitor
Class Summary
This pathway regulates several key cellular activities, including proliferation, differentiation, survival, and angiogenesis; inappropriate activation of proteins in this pathway has been shown to occur in many cancers.
Encorafenib (Braftovi)
Encorafenib inhibits in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. It is indicated in combination with cetuximab for metastatic colorectal cancer (CRC) in patients with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.
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Standard colectomies for adenocarcinoma of the colon.
Tables
Primary tumor (T) |
|
TX |
Primary tumor cannot be assessed |
T0 |
No evidence of primary tumor |
Tis |
Carcinoma in situ: intraepithelial or intramucosal carcinoma (involvement of lamina propria with no extension through the muscularis mucosa) |
T1 |
Tumor invades submucosa (through the muscularis mucosa but not into the muscularis propria) |
T2 |
Tumor invades muscularis propria |
T3 |
Tumor invades through the muscularis propria into the pericolorectal tissues |
T4 |
Tumor invades the visceral peritoneum or invades or adheres to adjacent organ or structure |
T4a |
Tumor invades through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum) |
T4b |
Tumor directly invades or is adherent to other organs or structures |
| T Suffix | Definition |
| (m) | Select if synchronous primary tumors are found in a single organ |
Definition of Regional lymph nodes (N) |
|
NX |
Regional lymph nodes cannot be assessed |
N0 |
No regional lymph node metastasis |
N1 |
Metastasis in 1-3 regional lymph nodes (tumor in lymph nodes measuring ≥0.2 mm) or any number of tumor deposits are present and all identifiable nodes are negative |
N1a |
Metastasis in 1 regional lymph node |
N1b |
Metastasis in 2-3 regional lymph nodes |
N1c |
Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized, pericolic, or perirectal/mesorectal tissues without regional nodal metastasis |
N2 |
Metastasis in 4 or more lymph nodes |
N2a |
Metastasis in 4-6 regional lymph nodes |
N2b |
Metastasis in 7 or more regional lymph nodes |
| N Suffix | Definition |
| (sn) | Select if regional lymph node metastasis identified by sentinel lymph node biopsy only |
| (f) | Select if regional lymph node metastasis identified by fine needle aspiration or core needle biopsy |
Definition of Distant metastasis (M) The terms pM0 and Mx are not valid categories in the TNM system. Assignment of the M category for clinical classification may be cM0, cM1 or pM1. Any of the categories (cM0, CM1 or pM1) may be used with pathological stage grouping. |
|
| M Category | M Criteria |
cM0 |
No distant metastasis by imaging or other studies, no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.) |
cM1 |
Metastasis to one or more distant sites or organs or peritoneal metastasis is identified |
cM1a |
Metastasis confined to 1 organ or site is identified without peritoneal metastasis |
cM1b |
Metastasis to two or more sites or organs is identified without peritoneal metastasis |
M1c |
Metastasis to the peritoneal surface alone or with other site or organ metastases |
| pM1 | Metastasis to one or more distant sites or organs or peritoneal metastasis is identified and microscopically confirmed |
| pM1a | Metastasis to one site or organ is identified without peritoneal metastasis and microscopically confirmed |
| pM1b | Metastasis to two or more sites or organs is identified without peritoneal metastasis and microscopically confirmed. |
| pM1c | Metastasis to the peritoneal surface is identified alone or with other site or organ metastasis and microscopically confirmed |
0 |
Tis |
N0 |
M0 |
I |
T1 |
N0 |
M0 |
|
T2 |
N0 |
M0 |
IIA |
T3 |
N0 |
M0 |
IIB |
T4a |
N0 |
M0 |
IIC |
T4b |
N0 |
M0 |
IIIA |
T1-T2 |
N1/N1c |
M0 |
|
T1 |
N2a |
M0 |
IIIB |
T3-T4a |
N1/N1c |
M0 |
|
T2-T3 |
N2a |
M0 |
|
T1-T2 |
N2b |
M0 |
IIIC |
T4a |
N2a |
M0 |
|
T3-T4a |
N2b |
M0 |
|
T4b |
N1-N2 |
M0 |
IVA |
Any T |
Any N |
M1a |
IVB IVC |
Any T Any T |
Any N Any T |
M1b M1c |
Parameter |
Organization |
||
ESMO [JSMO](2013) |
ASCO (2013) |
NCCN (2016) |
|
History and physical exam |
Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y |
Every 3-6 mo for 3 y, then every 6 mo to 5 y |
Every 3-6 mo for 2 y, then every 6 mo to 5 y |
CEA |
Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y |
Every 3 mo for 3 y* |
Every 3-6 mo for 2 y, then every 6 mo to 5 y |
Chest CT* |
Every 6-12 mo for first 3 y |
Every 1 y for 3 y |
Every 1 y for 5 y |
Colonoscopy** |
At y 1 after surgery, and every 3-5 y thereafter |
At 1 y, then every 5 y, dictated by the findings on the previous colonoscopy |
At 1 y, 3 y, then every 5 y if negative |
Abdominal CT* |
Every 6-12 mo for first 3 y |
Every 1 y for 3 y |
Every 6-12 mo for up to 5 y; scans to include chest and pelvis |
ESMO = European Society of Medical Oncology; JSMO = Japanese Society of Medical Oncology; ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network; CEA = carcinoembryonic antigen; CT = computed tomography * For patients at high risk for recurrence (eg, lymphatic or venous invasion, or poorly differentiated tumors). **Colonoscopy should be performed 3-6 mo postoperatively if preoperative colonoscopy was not done, due to an obstructing lesion; otherwise, colonoscopy in 1 y; if abnormal, repeat in 1 year; if no advanced adenoma (ie, villous polyp, polyp > 1 cm, or high-grade dysplasia), repeat in 3 y, then every 5 y. |
|||
Parameter |
Organization |
|||
ESMO (2013) [145] |
ASCO (2013) [144] |
NCCN (2022) [97] |
ASCRS (2015) [173] |
|
History and physical exam |
Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y |
Every 3-6 mo for 3 y, then every 6 mo to 5 y |
Every 3-6 mo for 2 y, then every 6 mo to 5 y |
Every 3-6 mo for 2 y, then every 6 mo to 5 y |
CEA |
Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y |
Every 3 mo for 3 y* |
Every 3-6 mo for 2 y, then every 6 mo to 5 y |
Every 3-6 mo for 2 y, then every 6 mo to 5 y |
Chest CT* |
Every 6-12 mo for first 3 y |
Every 1 y for 3 y |
Every 6-12 mo for 5 y |
Every 1 y for 5 y |
Colonoscopy** |
At y 1 after surgery, and every 3-5 y thereafter |
At 1 y, then every 5 y, dictated by the findings on the previous colonoscopy |
At 1 y; if advanced adenoma, repeat in 1 y; if no advanced adenoma, repeat in 3 y, then every 5 y |
At y 1 after surgery, and every 3-5 y dictated by the findings on the first postoperative examination |
Abdominal CT* |
Every 6-12 mo for first 3 y |
Every 1 y for 3 y |
Every 6-12 mo for 5 y; scans to include pelvis |
Every 1 y for 5 y |
ESMO = European Society of Medical Oncology; ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network; American Society of Colon and Rectal Surgeons = ASCRS CEA = carcinoembryonic antigen; CT = computed tomography * For patients at high risk for recurrence (eg, lymphatic or venous invasion, or poorly differentiated tumors). **Colonoscopy should be performed 3-6 mo postoperatively if preoperative colonoscopy was not done, due to an obstructing lesion; otherwise, colonoscopy in 1 y; if abnormal, repeat in 1 year; if no advanced adenoma (ie, villous polyp, polyp >1 cm, or high-grade dysplasia), repeat in 3 y, then every 5 y. |
||||
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Guidelines
- Medication
- Medication Summary
- Antineoplastic Agent, Antimetabolite (pyrimidine analog)
- Antidote, Folic Acid Antagonist
- Antineoplastic Agent, Miscellaneous
- Antineoplastic Agent, Alkylating Agent
- Antineoplastic Agent, Monoclonal Antibody
- Antineoplastics, Tyrosine Kinase Inhibitors
- Antineoplastics, VEGF Inhibitor
- PD-1/PD-L1 Inhibitors
- Antineoplastics, Other
- Antineoplastics, BRAF Kinase Inhibitor
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- Questions & Answers
- Tables
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