Colon Cancer Treatment Protocols 

Updated: Mar 28, 2018
  • Author: Khalid Matin, MD, FACP; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
  • Print
Sections

Treatment Protocols

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

See Benign or Malignant: Can You Identify These Colonic Lesions?, a Critical Images slideshow, to help identify the features of benign lesions as well as those with malignant potential.

Adjuvant chemotherapy for resectable colon cancer

Stage 0 and I:

Adjuvant chemotherapy is not recommended.

Stage IIA, B and C (node-negative):

The value of adjuvant therapy in stage II disease is at best controversial; however, the following regimens may be used: [1, 2, 3]

  • Capecitabine 1000-1250 mg/m2 PO BID on days 1-14; repeat cycle every 21 days for eight cycles or

  • Leucovorin 500 mg/m2 given as a 2-h infusion and repeated weekly for 6 wk plus 5-fluorouracil (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 II patients with high microsatellite instability (MSI-H) have a better prognosis and do not benefit from 5-FU adjuvant treatment. [4]

Stage II (high-risk or intermediate-risk patients):

Adjuvant therapy is an option for high-risk patients with stage II disease. In deciding whether to administer adjuvant therapy, the following should be considered:

  • Number of lymph nodes analyzed
  • Poor prognostic features
  • Other comorbidities and life expectancy

Common regimens include 5-FU and leucovorin with or without oxaliplatin or capecitabine, as follows: [1]

  • 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 [5, 6]  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 [7] or

  • Capecitabine 1000-1250 mg/m2 PO BID on days 1-14; repeat cycle every 21 d for eight cycles [8]

  • CapeOx: Oxaliplatin 130 mg/m2 over 2 h 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-h infusion and repeated weekly for 6 wk plus   5-fluorouracil (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: [5, 8, 9, 2, 3, 7]

  • 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: [1]

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. [10, 11, 12]  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 [13, 14, 15]  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 [3, 16]  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 [17]  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 [18, 19, 20]  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 [21]  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 [22, 23, 24]  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 [25, 24]  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 [26]   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 [21]  
  • 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-EGFR therapy. [27, 28]

Stage IV:

Chemotherapy for advanced or metastatic disease includes the use of multiple drugs as single agents or as combination regimens, as follows [16, 29, 30] :

  • Patients with right sided 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 5FU/LV with or without targeted agents are all considered appropriate first-line agents. 
  • For patients who are not candidates for intensive therapy, single-agent 5FU/LV, capecitabine, irinotecan, cetuximab or panitumumab, and nivolumab or pembrolizumab, can be used in the appropriate setting. 

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 [31] 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 [32]  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 [21] . 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 [17] 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 [33] 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 [30, 34]  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 [35]

First-line chemotherapy for patients who are not candidates for bevacizumab [36, 37, 38, 39, 40] :

  • 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 [13, 14, 15]  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 [41]

  • 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 [16, 3] 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 [42] 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 [43] 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 [35] 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 [29] 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 [25, 36, 37]  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 [44, 38]  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 d (total 2400 mg/m2 over 46-48 h) continuous infusion; repeat every 2 wk [40] 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 [40]

  • 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-d (total 2400 mg/m2 over 46 h) continuous infusion; repeat every 2 wk [45]

  • Referral for clinical trial

Second-line chemotherapy for metastatic disease [44, 46, 47] :

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 that 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-d (total 2400 mg/m2 over 46 h) continuous infusion; repeat every 2 wk [3] 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-d (total 2400 mg/m2 over 46 h) continuous infusion plus  bevacizumab 5mg/kg iv on day 1 or ziv-aflibercept 4mg/kg iv over 60 mins on day 1 or ramucirumab 8mg/kg iv over 60 mins on day 1, repeat every 2 wk [48, 49, 50] 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 mins 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 [45, 50] 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 [51]

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 4 cycles [52, 53]  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 4 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 2h 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 4 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 weeks 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 [44]

  • Cetuximab 500 mg/m2 IV over 2 h every 2 weeks 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 [54]  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 [55]

  • 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 [56]

  • 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 [57] 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; [1]  monitor hepatic function before and during treatment and interrupt, reduce, or discontinue drug accordingly [57]  or

  • Tipiracil/trifluridine 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 [58] or

  • Pembrolizumab 200 mg IV q3wk over 30 min, 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 [55]

  • 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. [56]

  • Referral for clinical trial

Summary of guiding principles in the treatment of metastatic colorectal cancer

See the list below:

  1. 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. [55]
  2. 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.

  3. 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. 
  4. The selection of oxaliplatin or irinotecan as part of the cytotoxic backbone upfront in metastatic disease is based primarily on toxicity profile.
  5. Bevacizumab improves survival when used as first-line and second-line therapy and works with irinotecan- and oxaliplatin-based therapy.

  6. The addition of bevacizumab to irinotecan, fluorouracil, and leucovorin (IFL) significantly improves the response rate, overall survival, and progression-free survival.

  7. 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.

  8. Interruption in therapy is not ideal for patients; some form of maintenance therapy is preferred after a stable disease state is obtained.

  9. Single-agent maintenance bevacizumab may be a feasible option for patients receiving bevacizumab + CapeOx as induction therapy.

  10. Anti-EGFR antibody therapy should be given only to patients with pan-RAS and BRAF V600E wild-type tumors.

  11. Anti-EGFR antibody therapy and bevacizumab should not be combined, due to increased toxicity.

  12. Optimal use of all therapeutic agents improves survival in patients with metastatic disease.

  13. 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.

  14. A multidisciplinary approach is necessary to deal with the complicated issue of potentially resectable or marginally resectable metastatic disease.

  15. Patients who receive bevacizumab-containing neoadjuvant therapy must not undergo surgery until at least 6-8 weeks afterward, in order to minimize perioperative complications.

  16. 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.