Treatment Protocols

Treatment protocols for colon cancer are provided below, including adjuvant and neoadjuvant therapy for resectable disease and therapy for advanced or metastatic colon cancer.

Adjuvant chemotherapy for resectable colon cancer

Stage 0 and I:

Adjuvant chemotherapy is not recommended.

Stage II:

American Society of Clinical Oncologists (ASCO) guidelines recommend that adjuvant therapy should not be routinely offered to patients with stage II colon cancer at low risk of recurrence, but should be offered to patients with stage IIB and stage IIC colon cancer (ie, T4, lesions either penetrating visceral peritoneum or invasive of surrounding organ, respectively) and may be offered to patients with stage IIA (ie, T3) colon cancer with high-risk features.^[1]The value of adjuvant therapy in stage II disease is at best controversial; however, adjuvant therapy may be considered in patients with high-risk disease.

Common regimens include fluorouracil (5-FU) and leucovorin with or without oxaliplatin, or capecitabine with oxaliplatin, as follows:^[2]

mFOLFOX6: Oxaliplatin 85 mg/m² IV over 2 h on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-fluorouracil (5-FU) 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 hours) continuous infusion; repeat every 2 wk for up to 6 months perioperative treatment ^{[2, 3, 4]} or
FLOX: 5-FU 500 mg/m² IV weekly plus leucovorin 500 mg/m² IV weekly for 6 wk (days 1, 8, 15, 22, 29, and 36) of each 8-wk cycle plus oxaliplatin 85 mg/m² IV administered on days 1, 15, and 29 of each 8-wk cycle for three cycles^[5] or
CapeOx: Oxaliplatin 130 mg/m² over 2 hours on day 1 plus capecitabine 1000 mg/m² PO BID on days 1-14 every 3 wk for up to 6 months perioperative treatment ^{[2, 6]}or
Leucovorin 500 mg/m² given as a 2-h infusion and repeated weekly for 6 wk plus 5-FU 500 mg/m² given as a bolus 1 h after the start of leucovorin and repeated weekly for 6 wk; every 8 wk for four cycles or
Leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU bolus 400 mg/m², then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 hours) continuous infusion; repeat every 2 wk

Stage III (node-positive):

The following regimens are acceptable adjuvant therapies for resectable stage III colon cancer:^{[3, 7, 8, 9, 10, 5]}

mFOLFOX6: Oxaliplatin 85 mg/m² IV over 2 h on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 hours) continuous infusion; repeat every 2 wk or
FLOX: 5-FU 500 mg/m² IV weekly plus leucovorin 500 mg/m² IV weekly for 6 wk (days 1, 8, 15, 22, 29, and 36) of each 8-wk cycle plus oxaliplatin 85 mg/m² IV administered on days 1, 15, and 29 of each 8-wk cycle for three cycles or
Capecitabine 1000-1250 mg/m² PO BID on days 1-14; repeat cycle every 21 d for eight cycles or
CapeOx: Oxaliplatin 130 mg/m² over 2 hours on day 1 plus capecitabine 1000 mg/m² PO BID on days 1-14 every 3 wk for eight cycles or
Leucovorin 500 mg/m² given as a 2-hour infusion and repeated weekly for 6 wk followed by 5-FU 500 mg/m² given as a bolus 1 hour after the start of leucovorin and repeated six times weekly; every 8 wk for four cycles or
Leucovorin 400 mg/m² IV over 2 hours on day 1 plus 5-FU bolus 400 mg/m², then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 hours) continuous infusion; repeat every 2 wk

Duration of FOLFOX or CapeOx for low-risk and high risk stage III:^[2]

Results of the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) trial (n=12,834), based on 3-year disease-free survival (DFS), showed that FOLFOX narrowly failed to meet the prespecified noninferiority threshold. The 3-year DFS in the FOLFOX 3-month arm was lower than that in the 6-month arm by 0.9% (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.00 - 1.15). To show noninferiority, the upper limit of the 95% CI had to be 1.12 or less, so noninferiority was not established. However, the shorter 3-mo duration reduced neurotoxicity by 17% in patients on FOLFOX and 15% in those on CapeOx, compared with 6 months of treatment (48% and 45%, respectively; P < 0.0001).

Recommendations differ depending on stage III risk status:

Low-risk stage III: CapeOx for 3 mo or FOLFOX for 3-6 mo
High risk stage III: CapeOx for 3-6 mo or FOLFOX for 6 mo

Neoadjuvant therapy for resectable metastatic disease

Neoadjuvant therapy for resectable metastatic disease is usually administered for approximately 2-3 months, limiting the development of hepatotoxicity.^{[11, 12, 13]} Regimens for adjuvant and neoadjuvant therapy are similar:

mFOLFOX6: Oxaliplatin 85 mg/m² IV over 2 h on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 hours) continuous infusion; repeat every 2 wk^{[14, 15, 16]} or
FOLFIRI: Irinotecan 180 mg/m² IV over 30-90 min on day 1 plus leucovorin 400 mg/m² IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 hours) continuous infusion; repeat every 2 wk^{[10, 17]} or
CapeOx with or without bevacizumab: Oxaliplatin 130 mg/m² over 2 h on day 1 plus capecitabine 1000 mg/m² PO BID for 14 d; repeat every 3 wk plus bevacizumab 7.5 mg/kg IV every 3 wk^[18] or
mFOLFOX6 plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 min on day 1 plus oxaliplatin 85 mg/m² IV over 2 h on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 hours) continuous infusion; repeat every 2 wk for four to six cycles with reevaluation for maintenance therapy^{[19, 20, 21]} or
FOLFIRI plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 min on day 1 plus irinotecan 180 mg/m² IV over 30-90 min on day 1 plus leucovorin 400 mg/m² IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 hours) continuous infusion; repeat every 2 wk for 4-6 cycles^[22] or
mFOLFOX6 plus cetuximab (only for pan-RAS wild-type tumors): Cetuximab 400 mg/m² loading dose over 2 h on day 1, then cetuximab 250 mg/m² weekly plus oxaliplatin 85 mg/m² IV over 2 h on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2-d continuous infusion; repeat every 2 wk for 4-6 cycles^{[23, 24, 25]} or
FOLFIRI plus cetuximab (only for pan-RAS wild-type tumors): Cetuximab 400 mg/m² loading dose over 2 hours on day 1, then cetuximab 250 mg/m² over 1 hour weekly plus irinotecan 180 mg/m² IV over 30-90 min on day 1 plus leucovorin 400 mg/m² IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 hours) continuous infusion; repeat every 2 wk for 4-6 cycles^{[26, 25]} or
FOLFOXIRI: Irinotecan 165 mg/m ² over 60 minutes then oxaliplatin 85 mg/m ² plus leucovorin 400 mg/m ² concurrently over 120 minutes then 5-FU 1600 mg/m ²/day for 2 days (total 3200 mg/m ² over 48 hours); repeat every 2 wk for 4-6 cycles ^[27] or
FOLFOXIRI plus bevacizumab: Bevacizumab 5 mg/kg IV over 30-90 min plus irinotecan 165 mg/m ² over 60 minutes then oxaliplatin 85 mg/m ² plus leucovorin 400 mg/m ² concurrently over 120 minutes then 5-FU 1600 mg/m ²/day for 2 days (total 3200 mg/m ² over 48 hours); repeat every 2 wk for 4-6 cycles ^[22]
Please read comment 16 in the "Guiding Principles" section below

Chemotherapy for advanced or metastatic disease

In patients with metastatic colon cancer, testing of the tumor for KRAS mutations at exons 2, 3, and 4; NRAS mutations at exons 2, 3, and 4 (ie, pan-RAS or all-RAS testing) and BRAF V600E mutation should guide the decision whether to use biologic agents that target epidermal growth factor receptor (EGFR). Patients with wild-type pan-RAS and no BRAF V600E typically respond to anti–epidermal growth factor receptor (EGFR) therapy.^{[28, 29]}

Stage IV:

Chemotherapy for advanced or metastatic disease includes the use of multiple drugs as single agents or as combination regimens, as follows^{[17, 30, 31]}:

Patients with right-side tumors are less likely to respond to EGFR therapy with cetuximab or panitumumab.
BRAF V600E mutation makes response to anti-EGFR therapy less likely.
Choice of initial therapy for advanced disease is based on goals of treatment, location of tumor, mutational profile, toxicity profile of the drugs, and patient's performance status.
mFOLFOX6, FOLFIRI, CapeOx, FOLFOXIRI, capecitabine, and infusional 5-FU/LV with or without targeted agents are all considered appropriate first-line agents.
For patients who are not candidates for intensive therapy, single-agent 5-FU/LV, capecitabine, irinotecan, cetuximab or panitumumab, and nivolumab or pembrolizumab, can be used in the appropriate setting.

Pembrolizumab is indicated for the first-line treatment of unresectable or metastatic high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer^[32]:

200 mg IV q3Weeks or 400 mg IV q6wk; continue until disease progression, unacceptable toxicity, or up to 24 months

First-line chemotherapy for bevacizumab candidates:

mFOLFOX6 plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 min on day 1 plus oxaliplatin 85 mg/m² IV over 2h on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 2400 mg/m² over 46 hours continuous infusion; repeat every 2 wk for 4-6 six cycles with reevaluation for maintenance therapy^[33] or
FOLFIRI plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 min on day 1 plus irinotecan 180 mg/m² IV over 30-90 min on day 1 plus leucovorin 400 mg/m² IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2d (total 2400 mg/m² over 46 h) continuous infusion; repeat every 2 wk for 4-6 cycles with reevaluation for maintenance therapy^[34] or
FOLFOXIRI plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 min on day 1 plus irinotecan 165 mg/m² IV over 60 min on day 1 plus oxaliplatin 85 mg/m² IV over 2h on day 1 plus leucovorin 400 mg/m² IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 1600 mg/m²/day for 2d (total 3200 mg/m² over 48 h) continuous infusion; repeat every 2 wk^[22]. Please read comment 16 in the "Guiding Principles" section below.
CAPEOX plus bevacizumab: Bevacizumab 7.5 mg/kg over 30-90 min on day 1 plus oxaliplatin 130 mg/m² over 2 h on day 1 plus capecitabine 1000 mg/m² PO BID for 14 d; repeat every 21 d for four cycles followed by reevaluation for maintenance therapy^[18] or
Capecitabine plus bevacizumab (in patients not able to undergo treatment with oxaliplatin or irinotecan): Bevacizumab 7.5 mg/kg on day 1 plus capecitabine 850-1250 mg/m² PO BID for 14 d; repeat cycle every 21 d for eight cycles, then reevaluate for maintenance^[35] or
DeGramont regimen plus bevacizumab (in patients not able to undergo treatment with oxaliplatin or irinotecan): Bevacizumab 5 mg/kg over 30-90 min on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU bolus 400 mg/m², then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 h) continuous infusion; repeat every 2 wk for 4-6 cycles with reevaluation for maintenance therapy^{[31, 36]} or
5-FU and leucovorin (Roswell Park) with bevacizumab (in patients unable to undergo treatment with oxaliplatin or irinotecan): Bevacizumab 5 mg/kg over 30-90 min on day 1 plus leucovorin 500 mg/m² over 2 h plus 5-FU 500 mg/m² bolus every 2 wk for 4-6 cycles with reevaluation for maintenance therapy^[37]

First-line chemotherapy for patients who are not candidates for bevacizumab^{[38, 39, 40, 41, 42]}:

mFOLFOX6: Oxaliplatin 85 mg/m² IV over 2 h on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 2400 mg/m² over 46 hours continuous infusion; repeat every 2 wk^{[14, 15, 16]} or
mFOLFOX7: Oxaliplatin 85 mg/m² IV over 2 h on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU 1200mg/m²/day (total 2400 mg/m² over 46-48 hours) continuous infusion; repeat every 2 wk^[43]
FOLFIRI: Irinotecan 180 mg/m² IV over 30-90 min on day 1 plus leucovorin 400 mg/m² IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2-d (total 2400 mg/m² over 46 h) continuous infusion; repeat every 2 wk^{[17, 10]} or
FOLFOXIRI: Irinotecan 165 mg/m ² over 60 minutes then oxaliplatin 85 mg/m ² plus leucovorin 200 mg/m ² concurrently over 120 minutes, then 5-FU 3200 mg/m ² over 48 hours; repeat every 2 wk ^[44]Please read comment 16 in the "Guiding Principles" section below.
Capecitabine: Capecitabine 850-1250 mg/m² PO BID on days 1-14; repeat cycle every 21 d until progression^[45] or
Roswell Park regimen: Leucovorin 500 mg/m² IV weekly for 6 wk over 2 h followed by 5-FU 500 mg/m² IV bolus weekly for 6 wk; repeat cycle every 8 wk^[37]or
CapeOx: Oxaliplatin 130 mg/m² over 2 h on day 1 plus capecitabine 1000 mg/m² BID for 14 d every 21 d for four cycles, followed by reevaluation for maintenance therapy^[30] or
mFOLFOX6 plus cetuximab (only for pan-RAS and BRAF V600E wild-type tumors): Cetuximab 500 mg/mg/m² IV over 2 h every 2 weeks or cetuximab 400 mg/m² loading dose on day 1, then cetuximab 250 mg/m² weekly plus oxaliplatin 85 mg/m² IV over 2 h on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2-d (total 2400 mg/m² over 46 h) continuous infusion; repeat every 2 wk^{[26, 38, 39]} or
FOLFIRI plus cetuximab (only for pan-RAS and BRAF V600E wild-type tumors): Cetuximab 500 mg/m² IV over 2 hr every 2 weeks or cetuximab 400 mg/m² loading dose over 2 h on day 1, then cetuximab 250 mg/m² over 1 h weekly plus irinotecan 180 mg/m² IV over 30-90 min on day 1 plus leucovorin 400 mg/m² IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2-d (total 2400 mg/m² over 46 h) continuous infusion; repeat every 2 wk^{[46, 40]} or
FOLFOX plus panitumumab (only for pan-RAS and BRAF V600E wild-type tumors): Panitumumab 6 mg/kg IV infusion over 1 h on day 1, then oxaliplatin 85 mg/m² IV infusion on day 1, then leucovorin 400 mg/m² IV infusion, plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 h) continuous infusion; repeat every 2 wk^[42] or
FOLFOX4 plus panitumumab (only for pan-RAS and BRAF V600E wild-type tumors): Panitumumab 6 mg/kg IV infusion over 1 h on day 1, then oxaliplatin 85 mg/m² IV infusion on day 1 then leucovorin 200 mg/m² (or equivalent) IV infusion plus 5-FU 400 mg/m² IV bolus and 600 mg/m² 22-hour continuous infusion on days 1 and 2^[42]
FOLFIRI plus panitumumab (only for pan-RAS and BRAF V600E wild-type tumors): Panitumumab 6 mg/kg IV infusion over 1 h on day 1 plus irinotecan 180 mg/m² IV over 30-90 min on day 1 plus leucovorin 400 mg/m² IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46 h) continuous infusion; repeat every 2 wk^[47]
Referral for clinical trial

Second-line chemotherapy for metastatic disease^{[46, 48, 49]}:

Subsequent therapy primarily depends on the initial therapy—oxaliplatin vs irinotecan based—as follows:

Bevacizumab is indicated for second-line treatment in patients whose disease has progressed on a first-line bevacizumab-containing regimen; use bevacizumab in combination with a fluoropyrimidine (eg, 5-FU, capecitabine) plus irinotecan or oxaliplatin-based chemotherapy; bevacizumab dose is either 5 mg/kg IV q2 wk or 7.5 mg/kg IV q3 wk for continuation
Ziv-aflibercept and ramucirumab are effective only in combination with FOLFIRI, in patients who have not previously received treatment with FOLFIRI.
Cetuximab and panitumumab (anti-EGFR) can also be used as single agents for patients who cannot tolerate chemotherapy.

For patients with previous oxaliplatin-based therapy as first-line treatment (ie, FOLFOX, CapeOx, CapeOx plus bevacizumab, or FOLFOX plus bevacizumab), one of the following regimens can be used:

FOLFIRI: Irinotecan 180 mg/m² IV over 30-90 min on day 1 plus leucovorin 400 mg/m² IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46 h) continuous infusion; repeat every 2 wk^[10] or
FOLFIRI + bevacizumab or ziv-aflibercept or ramucirumab: Irinotecan 180 mg/m² IV over 30-90 min on day 1 plus leucovorin 400 mg/m² IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46 h) continuous infusion plus bevacizumab 5 mg/kg IV on day 1 or ziv-aflibercept 4 mg/kg iv over 60 min on day 1 or ramucirumab 8 mg/kg IV over 60 mins on day 1, repeat every 2 wk^{[50, 51, 52]} or
FOLFIRI plus cetuximab or panitumumab (only for pan- RAS and BRAF V600E wild-type tumors): Cetuximab 400 mg/m ² loading dose IV over 2 h on day 1, then cetuximab 250 mg/m ² IV over 1 h weekly or panitumumab 6 mg/kg IV over 60 min on day 1 plus irinotecan 180 mg/m ² IV over 30-90 min on day 1 plus leucovorin 400 mg/m ² IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m ² IV bolus on day 1, then 1200 mg/m ²/day for 2-d (total 2400 mg/m ² over 46-48 h) continuous infusion; repeat every 2 wk for 4-6 cycles, then reevaluate ^{[47, 52]} or
Irinotecan plus cetuximab or panitumumab (only for pan-RAS and BRAF V600E wild-type tumors): Irinotecan 180 mg/m² IV over 30-90 min on day 1 plus cetuximab 400 mg/m² loading dose over 2 h on day 1, then cetuximab 250 mg/m² over 1 h weekly or panitumumab 6 mg/kg iv over 60 min on day 1; repeat every 2 wk^[53]
Encorafenib plus cetuximab or panitumumab (only for BRAF V600E mutation positive tumors): Encorafenib 300 mg PO daily plus cetuximab 400 mg/m² loading dose over 2 h on day 1, then cetuximab 250 mg/m² over 1 h weekly^{[2, 54]}
Encorafenib plus panitumumab (only for BRAF V600E mutation positive tumors): Encorafenib 300 mg PO daily plus panitumumab 6 mg/kg IV over 60 min on day 1; repeat every 2 wk^[2]

For patients who had irinotecan therapy as first-line treatment (ie, FOLFIRI plus bevacizumab), the following regimens can be used:

mFOLFOX6: Oxaliplatin 85 mg/m² IV over 2 h on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day for 2 days (total 2400 mg/m² over 46-48 hr) continuous infusion; repeat every 2 wk for four cycles^{[55, 56]} or
CapeOx: Oxaliplatin 130 mg/m² over 2 h on day 1 plus capecitabine 1000 mg/m² BID for 14 d every 21 d for four cycles, followed by reevaluation for maintenance therapy or
FOLFOX plus bevacizumab: Bevacizumab 5 mg/kg on day 1 plus oxaliplatin 85 mg/m² over 2 h on day 1 plus leucovorin 400 mg/m² over 2 h plus 5-FU 400 mg/m² IV bolus on day 1, followed by 5-FU 2400 mg/m² IV continuous infusion over 46 h every 2 wk or
CapeOx plus bevacizumab: Bevacizumab 7.5 mg/kg on day 1 plus oxaliplatin 130 mg/m² over 2 h on day 1 plus capecitabine 1000 mg/m² BID for 14 d every 21 d or
mFOLFOX6 plus cetuximab or panitumumab (only for pan-RAS and BRAF V600E wild-type tumors): Cetuximab 500 mg/m² IV over 2 h every 2 weeks or cetuximab 400 mg/m² loading dose on day 1 over 2 h, then cetuximab 250 mg/m² over 1 h weekly, or panitumumab 6 mg/kg IV over 60 min on day 1 plus oxaliplatin 85 mg/m² IV over 2 h on day 1 plus leucovorin 400 mg/m² IV over 2 h on day 1 plus 5-FU 400 mg/m² IV bolus on day 1, then 5-FU 2400 mg/m² IV continuous infusion over 46-48 h; repeat every 2 wk for four cycles and then reevaluate or
Irinotecan plus cetuximab or panitumumab (only for pan-RAS and BRAF V600E wild-type tumors, and if anti-EGFR therapy was not used in combination with FOLFIRI): Irinotecan 180 mg/m² IV over 30-90 min on day 1 plus cetuximab 500 mg/m² IV over 2 h every 2 wk or cetuximab 400 mg/m² loading dose IV over 2 h on day 1, then cetuximab 250 mg/m² IV over 1 h weekly or panitumumab 6 mg/kg IV over 60 min on day 1; repeat every 2 wk^[46]
Cetuximab 500 mg/m² IV over 2 h every 2 wk or cetuximab 400 mg/m² IV over 2 h on day 1, then 250 mg/m² IV over 1 h weekly with reevaluation after 8 wk or
Panitumumab 6 mg/kg over 60-90 min every 2 wk with reevaluation after 8 wk^[57] or
Pembrolizumab 200 mg IV q3wk, in adults with unresectable or metastatic colon cancer that has tested positive for MSI-H or deficient mismatch repair (dMMR) and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan^[58]
Nivolumab 240 mg IV q2wk, for unresectable or metastatic colon cancer that has tested positive for MSI-H or dMMR and has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan^[59]
Referral for clinical trial

Third-line chemotherapy for metastatic disease:

Panitumumab 6 mg/kg over 60-90 min every 2 wk only for pan-RAS and BRAF V600E wild-type tumors, with reevaluation after 8 wk or
Any regimen incorporating an EGFR antibody for patients with pan-RAS wild-type disease, using a cytotoxic backbone not previously tried or
Regorafenib 160 mg PO qd for first 21 days of each 28-day cycle^[60] or
First cycle: Regorafenib 80 mg PO qd on days 1-7, then 120 mg qd on days 8-14, then 160 mg PO qd on days 15-21 of each 28-day cycle; for subsequent cycles give 160 mg qd on days 1-21;^[2] monitor hepatic function before and during treatment and interrupt, reduce, or discontinue drug accordingly^[60] or
Trifluridine/tipiracil 35 mg/m² PO BID on days 1-5 and days 8-12 of each 28-day cycle; not to exceed 80 mg/dose; for use in patients previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti–vascular endothelial growth factor (VEGF) biological therapy, and (if pan-RAS wild-type), an anti-EGFR therapy^[61] or
Trifluridine/tipiracil 35 mg/m² PO BID on days 1-5 and days 8-12; not to exceed 80 mg/dose, plus bevacizumab 5 mg/kg IV on day 1 and day 15 in a 28-day cycle until disease progression or unacceptable toxicity, for metastatic colorectal cancer in adults previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan–based chemotherapy; an anti-VEGF biological therapy; and, if RAS wild-type, an anti-EGFR therapy^[62]
Pembrolizumab 200 mg IV q3wk or 400 mg IV q6wk, for adults with unresectable or metastatic colon cancer that has tested positive for MSI-H or dMMR and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan^[58] ^[63]or
Nivolumab 240 mg IV q2wk over 30 min, for unresectable or metastatic colon cancer that has tested positive for MSI-H or dMMR and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan^[59] or
Nivolumab 3 mg/kg IV over 30 min, followed by ipilimumab 1 mg/kg IV over 30 min on the same day; repeat combination q3wk for up to 4 doses, then nivolumab 250 mg IV q2wk until disease progression or unacceptable toxicity.^[64]
Trastuzumab 8 mg/kg IV loading dose on day 1 of cycle 1, followed by 6 mg/kg IV every 21 days plus tucatinib 300 mg PO BID; continue until disease progression or unacceptable toxicity; 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 ^[65]
Referral for clinical trial

Summary of guiding principles in the treatment of metastatic colorectal cancer

See the list below:

Patients with stage IV disease should be tested for MSI-H. If MSI-H is documented, consider pembrolizumab or nivolumab for unresectable or metastatic colon cancer that has tested positive for MSI-H or dMMR, and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan.^[58]
Differentiating M1a (metastatic disease at one organ site) from M1b (metastasis at more than one organ site) is important, in view of the curative potential of M1a disease.
All patients with metastatic disease should have pan-RAS testing and BRAF V600E mutation testing. Data suggest that even in the setting of KRAS wild-type tumors, BRAF mutation abrogates the effect of anti-EGFR antibody therapy; it is, however, prognostic of a worse outcome.
The selection of oxaliplatin or irinotecan as part of the cytotoxic backbone upfront in metastatic disease is based primarily on toxicity profile.
Bevacizumab improves survival when used as first-line and second-line therapy and works with irinotecan- and oxaliplatin-based therapy.
The addition of bevacizumab to irinotecan, fluorouracil, and leucovorin (IFL) significantly improves the response rate, overall survival, and progression-free survival.
The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.^[66]
Interruption in therapy is not ideal for patients; some form of maintenance therapy is preferred after a stable disease state is obtained.
Single-agent maintenance bevacizumab may be a feasible option for patients receiving bevacizumab plus CapeOx as induction therapy.
Anti-EGFR antibody therapy should be given only to patients with pan-RAS and BRAF V600E wild-type tumors.
Anti-EGFR antibody therapy and bevacizumab should not be combined, due to increased toxicity.
Optimal use of all therapeutic agents improves survival in patients with metastatic disease.
It is reasonable to leave the primary therapy in place when starting treatment for metastatic disease, if the patient has no urgent complication such as obstruction or uncontrolled bleeding.
A multidisciplinary approach is necessary to deal with the complicated issue of potentially resectable or marginally resectable metastatic disease.
Patients who receive bevacizumab-containing neoadjuvant therapy must not undergo surgery until at least 6-8 weeks afterward, in order to minimize perioperative complications.
With FOLFOXIRI, a lower dose of infusional 5-FU at 2400 mg/m² should be considered in North American patients. This regimen has the advantage of increased response rate, R0 resection margin of metastatic disease, progression-free survival, and overall survival compared with FOLFIRI and should be used selectively in patients with good performance status, particularly when the goal is to render the patient cancer free with neoadjuvant therapy. The same is true if bevacizumab is to be added.

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