Colon Cancer Treatment Protocols 

Updated: May 26, 2017
  • Author: Lewis J Rose, MD; 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:

Patients do not require adjuvant therapy

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 1250 mg/m 2 PO BID on days 1-14; repeat cycle every 21 d for eight cycles or
  • Leucovorin 500 mg/m 2 given as a 2-h infusion and repeated weekly for 6 wk plus  5-fluorouracil (5-FU) 500 mg/m 2 given as a bolus 1 h after the start of leucovorin and repeated six times weekly; every 8 wk for four cycles or
  • Leucovorin 400 mg/m 2 IV over 2 h on day 1 plus  5-FU bolus 400 mg/m 2, then  1200 mg/m 2/day for 2 d (total 2400 mg/m 2 over 46-48 h) continuous infusion; repeat every 2 wk

Stage II in high-risk or intermediate-risk patients:

Adjuvant therapy for high-risk patients with stage II is an option. Common regimens include 5-FU and leucovorin with or without oxaliplatin or capecitabine, as follows [1] :

  • mFOLFOX6: Oxaliplatin 85 mg/m 2 IV over 2 h on day 1 plus  leucovorin 400 mg/m 2 IV over 2 h on day 1 plus  5-FU 400 mg/m 2 IV bolus on day 1, then  1200 mg/m 2/day for 2 d continuous infusion; repeat every 2 wk or
  • FLOX: 5-FU 500 mg/m 2 IV weekly plus  leucovorin 500 mg/m 2 IV weekly for 6 wk (days 1, 8, 15, 22, 29, and 36) of each 8-wk cycle plus  oxaliplatin 85 mg/m 2 IV administered on days 1, 15, and 29 of each 8-wk cycle for three cycles or
  • Capecitabine 1250 mg/m 2 PO BID on days 1-14; repeat cycle every 21 d for eight cycles

Stage III (node-positive):

The following regimens are acceptable adjuvant therapies for stage III disease for resectable colon cancer [2, 3] :

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

Neoadjuvant therapy for resectable metastatic disease

Neoadjuvant therapy for resectable metastatic disease is usually administered for approximately 2-3 mo, limiting the development of hepatotoxicity. [3] Regimens for adjuvant and neoadjuvant therapy are similar.

  • mFOLFOX6: Oxaliplatin 85 mg/m 2 IV over 2 h on day 1 plus  leucovorin 400 mg/m 2 IV over 2 h on day 1 plus  5-FU 400 mg/m 2 IV bolus on day 1, then  1200 mg/m 2/day for 2-d continuous infusion; repeat every 2 wk or
  • FOLFIRI: 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 46-48h) continuous infusion; repeat every 2 wk
  • CapeOx with or without bevacizumab: Oxaliplatin 130 mg/m 2 over 2 h on day 1 plus  capecitabine 1000 mg/m 2 PO BID for 14 d; repeat every 3 wk plus  bevacizumab 7.5 mg/kg IV every 3 wk
  • mFOLFOX6 plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 min on day 1 plus  oxaliplatin 85 mg/m 2 IV over 2 h on day 1 plus  leucovorin 400 mg/m 2 IV over 2 h on day 1 plus  5-FU 400 mg/m 2 IV bolus on day 1, then  1200 mg/m 2/day for 2-d continuous infusion; repeat every 2 wk for four to six cycles with reevaluation for maintenance therapy (1 g of calcium gluconate and 1 g of magnesium sulfate may be given over 15 min preinfusion and postinfusion to reduce the risk of neurotoxicity) [4, 5, 6, 7, 8]
  • FOLFIRI plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 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 four to six cycles
  • mFOLFOX6 plus cetuximab (only for pan-RAS wild-type tumors): Cetuximab 400 mg/m 2 loading dose on day 1, then  cetuximab 250 mg/m 2 weekly plus  oxaliplatin 85 mg/m 2 IV over 2 h on day 1 plus  leucovorin 400 mg/m 2 IV over 2 h on day 1 plus  5-FU 400 mg/m 2 IV bolus on day 1, then  1200 mg/m 2/day for 2-d continuous infusion; repeat every 2 wk for four to six cycles [9, 10, 11]
  • FOLFIRI plus cetuximab (only for pan-RAS wild-type tumors): Cetuximab 400 mg/m 2 loading dose over 2 h on day 1, then  cetuximab 250 mg/m 2 over 1 h weekly 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 four to six cycles [31]
  • FOLFOXIRI: Irinotecan 165 mg/m 2 over 60 minutes then  oxaliplatin 85 mg/m 2 plus  leuovorin 200 mg/m 2 concurrently over 120 minutes then  5-FU 3200 mg/m 2 over 48 hours; repeat every 2 wk for four to six cycles [32]
  • 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 200 mg/m 2 concurrently over 120 minutes then  5-FU 3200 mg/m 2 over 48 hours; repeat every 2 wk for four to six cycles [31]

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 and NRAS mutations at exons 2, 3, and 4 (ie, pan-RAS or all-RAS testing) should guide the decision whether to use biologic agents that target epidermal growth factor receptor (EGFR). Patients with wild-type pan-RAS typically respond to anti-EGFR therapy. [12]

Stage IV:

Chemotherapy for advanced or metastatic disease includes the use of multiple drugs as single agents or as combination regimens. [13, 14, 15, 16, 17, 18]

First-line chemotherapy for bevacizumab candidates:

  • mFOLFOX6 plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 min on day 1 plus  oxaliplatin 85 mg/m 2 IV over 2h on day 1 plus  leucovorin 400 mg/m 2 IV over 2 h on day 1 plus  5-FU 400 mg/m 2 IV bolus on day 1, then  1200 mg/m 2/day for 2-d continuous infusion; repeat every 2 wk for four to six cycles with reevaluation for maintenance therapy (1 g of calcium gluconate and 1 g of magnesium sulfate may be given over 15 min preinfusion and postinfusion to reduce the risk of neurotoxicity) or
  • FLOX plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 min on days 1, 15, and 29 plus  oxaliplatin 85 mg/m 2 on days 1, 15, and 29 plus  leucovorin 500 mg/m 2 on days 1, 8, 15, 22, 29, and 36 plus  5-FU 500 mg/m 2 on days 1, 8, 15, 22, 29, and 39 for two cycles, followed by reevaluation or
  • FOLFIRI plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 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 2d (total 2400 mg/m 2 over 46-48 h) continuous infusion; repeat every 2 wk for four to six cycles with reevaluation for maintenance therapy or
  • CAPEOX plus bevacizumab: Bevacizumab 7.5 mg/kg over 30-90 min on day 1 plus  oxaliplatin 130 mg/m 2 over 2 h on day 1 plus  capecitabine 1000 mg/m 2 PO BID for 14 d; repeat every 21 d for four cycles followed by reevaluation for maintenance therapy 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 1250 mg/m 2 PO BID for 14 d; repeat cycle every 21 d for eight cycles, then  reevaluate for maintenance 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/m 2 IV over 2 h on day 1 plus  5-FU bolus 400 mg/m 2, 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 four to six cycles with reevaluation for maintenance therapy or
  • Bevacizumab plus 5-FU and leucovorin (Roswell Park) (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/m 2 over 2 h plus  5-FU 500 mg/m 2 bolus every 2 wk for four to six cycles with reevaluation for maintenance therapy

First-line chemotherapy for patients who are not candidates for bevacizumab [16, 17, 18, 19, 20] :

  • mFOLFOX6: Oxaliplatin 85 mg/m 2 IV over 2 h on day 1 plus  leucovorin 400 mg/m 2 IV over 2 h on day 1 plus  5-FU 400 mg/m 2 IV bolus on day 1, then  1200 mg/m 2/day for 2-d continuous infusion; repeat every 2 wk for four cycles or
  • FLOX: Oxaliplatin 85 mg/m 2 on days 1, 15, and 29 plus  leucovorin 500 mg/m 2 on days 1, 8, 15, 22, 29, and 36, followed by 5-FU 500 mg/m 2 on days 1, 8, 15, 22, 29, and 39 for two cycles followed by reevaluation or
  • FOLFIRI: 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 four cycles 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 for four cycles
  • Capecitabine: Capecitabine 1250 mg/m 2 PO BID on days 1-14; repeat cycle every 21 d until progression or
  • Roswell Park regimen: Leucovorin 500 mg/m 2 IV weekly for 6 wk over 2 h followed by 5-FU 500 mg/m 2 IV bolus weekly for 6 wk; repeat cycle every 8 wk or
  • CapeOx: Oxaliplatin 130 mg/m 2 over 2 h on day 1 plus  capecitabine 1000 mg/m 2 BID for 14 d every 21 d for four cycles, followed by reevaluation for maintenance therapy or
  • mFOLFOX6 plus cetuximab (only for pan-RAS wild-type tumors): Cetuximab 400 mg/m 2 loading dose on day 1, then  cetuximab 250 mg/m 2 weekly plus  oxaliplatin 85 mg/m 2 IV over 2 h on day 1 plus  leucovorin 400 mg/m 2 IV over 2 h on day 1 plus  5-FU 400 mg/m 2 IV bolus on day 1, then  1200 mg/m 2/day for 2-d continuous infusion; repeat every 2 wk for four cycles, then reevaluate or
  • FOLFIRI plus cetuximab (only for pan-RAS wild-type tumors): Cetuximab 400 mg/m 2 loading dose over 2 h on day 1, then  cetuximab 250 mg/m 2 over 1 h weekly 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 four cycles, then reevaluate or
  • FOLFOX4 plus panitumumab (only for pan-RAS wild-type tumors): Panitumumab 6 mg/kg IV infusion over 1 h on day 1, then  oxaliplatin 85 mg/m 2 IV infusion on day 1, then  leucovorin 200 mg/m 2 (or equivalent) IV infusion, then  5-FU 400 mg/m 2 IV bolus and 600 mg/m 2 22-hour continuous IV infusion on days 1 and 2; repeat every 2 wk or
  • Referral for clinical trial

Second-line chemotherapy for metastatic disease [21, 22, 23, 24, 25] :

  • 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
  • FOLFIRI (if FOLFOX, CapeOx, CapeOx plus bevacizumab or FOLFOX plus bevacizumab used as first-line chemotherapy): 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 four cycles, then reevaluate or
  • FOLFIRI plus cetuximab (only for pan-RAS wild-type tumors and if FOLFOX, CapeOx, CapeOx plus bevacizumab or FOLFOX plus bevacizumab used as first–line chemotherapy): Cetuximab 400 mg/m 2 loading dose over 2 h on day 1, then  cetuximab 250 mg/m 2 over 1 h weekly 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 four cycles, then reevaluate or
  • Ramucirumab plus FOLFIRI: Ramucirumab 8 mg/kg IV infusion over 60 min before  FOLFIRI - irinotecan 180 mg/m 2 IV infusion over 90 min plus  folinic acid 400 mg/m 2 IV simultaneously over 120 min, followed by  5-FU 400 mg/m 2 IV bolus over 2-4 min, followed by  2400 mg/m 2 IV continuous infusion over 46-48 h; repeat cycle every 2 wk or
  • mFOLFOX6 (if FOLFIRI or FOLFIFI plus bevacizumab used as first-line chemotherapy): Oxaliplatin 85 mg/m 2 IV over 2 h on day 1 plus  leucovorin 400 mg/m 2 IV over 2 h on day 1 plus  5-FU 400 mg/m 2 IV bolus on day 1, then  1200 mg/m 2/day for 2-d continuous infusion; repeat every 2 wk for four cycles or
  • CapeOx: Oxaliplatin 130 mg/m 2 over 2 h on day 1 plus  capecitabine 1000 mg/m 2 BID for 14 d every 21 d for four cycles, followed by reevaluation for maintenance therapy or
  • mFOLFOX6 plus cetuximab (only for pan-RAS wild-type tumors and if FOLFIRI or FOLFIRI plus bevacizumab used as first-line chemotherapy): Cetuximab 400 mg/m 2 loading dose on day 1 over 2 h, then  cetuximab 250 mg/m 2 over 1 h weekly plus  oxaliplatin 85 mg/m 2 IV over 2 h on day 1 plus  leucovorin 400 mg/m 2 IV over 2 h on day 1 plus  5-FU 400 mg/m 2 IV bolus on day 1, then  1200 mg/m 2/day for 2-d continuous infusion; repeat every 2 wk for four cycles and then reevaluate or
  • Irinotecan 125 mg/m 2 over 90 min weekly with reevaluation after 8 wk or
  • Cetuximab 400 mg/m 2 over 2 h on day 1, then  250 mg/m 2 over 1 h weekly with reevaluation after 8 wk or
  • Panitumumab 6 mg/kg over 60-90 min every 2wk with reevaluation after 8 wk or
  • Modified FOLFOX6 plus bevacizumab (if FOLFIRI used upfront and bevacizumab never used as first-line chemotherapy; note higher dose of bevacizumab as second-line chemotherapy): Bevacizumab 10 mg/kg over 30-90 min on day 1 plus  oxaliplatin 85 mg/m 2 over 2 h on day 1 plus  leucovorin 400 mg/m 2 over 2h plus  5-FU 400 mg/m 2 IV bolus on day 1, followed by 5-FU 2400 mg/m 2 IV continuous infusion over 46 h every 2 wk for four to six cycles with reevaluation for maintenance therapy (1 g of calcium gluconate and 1 g of magnesium sulfate may be given over 15 min preinfusion and postinfusion to reduce the risk of neurotoxicity) or
  • CAPEOX plus bevacizumab (if FOLFIRI used upfront and bevacizumab never used as first-line chemotherapy; note higher dose of bevacizumab as second-line chemotherapy): Bevacizumab 15 mg/kg over 30-90 min on day 1 plus  oxaliplatin 130 mg/m 2 over 2 h on day 1 plus  capecitabine 1000 mg/m 2 BID for 14d every 21 d for four cycles, followed by reevaluation for maintenance therapy or
  • FOLFIRI plus bevacizumab (if FOLFOX or CAPEOX used upfront and bevacizumab never used as first-line chemotherapy): Bevacizumab 10 mg/kg over 30-90 min on day 1 plus  irinotecan 180 mg/m 2 over 90 min on day 1 plus  leucovorin 400 mg/m 2 over 2 h on day 1 plus  5-FU 400 mg/m 2 IV bolus on day 1 followed by 5-FU 2400 mg/m 2 IV continuous infusion over 46 h every 2 wk for four to six cycles with reevaluation for maintenance therapy or
  • Ziv-aflibercept 4 mg/kg IV infused over 1 h q2 wk plus FOLFIRI in metastatic disease that is resistant to or has progressed after an oxaliplatin regimen; administer before any component of FOLFIRI regimen on the day of treatment
  • Pembrolizumab 200 mg IV q3wk 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 [33]
  • Referral for clinical trial

Note: In the above regimens, cetuximab can be replaced with panitumumab at 6 mg/kg every 2 wk if the patient experiences anaphylaxis with cetuximab.

Third-line chemotherapy for metastatic disease [26]

  • Panitumumab 6 mg/kg over 60-90 min every 2 wk for KRAS wild-type tumors only, with reevaluation after 8 wk or
  • Any regimen incorporating an epidermal growth factor receptor (EGFR) antibody for patients with KRAS 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; monitor hepatic function before and during treatment and interrupt, reduce, or discontinue drug accordingly or
  • Tipiracil/trifluridine 35 mg/m 2 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 chemotherap, an anti-VEGF biological therapy, and (if RAS wild-type), an anti-EGFR therapy [27] or
  • Referral for clinical trial

Summary of guiding principles in the treatment of metastatic colorectal cancer

See the list below:

  1. Patients with node-negative disease should be tested for microsatellite instability-high (MSI-H). If MSI-H is documented, consider pembrolizumab for 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. [33]
  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.
  4. Consideration should be given for BRAF testing for prognosis. The data on BRAF status are still preliminary in terms of predictive value, but there is a suggestion 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. Nevertheless, pharmacogenomic profiling beyond pan-RAS mutation status is not yet standard of care.
  5. Selection of oxaliplatin or irinotecan as part of the cytotoxic backbone upfront in metastatic disease is based primarily on toxicity profile.
  6. Bevacizumab improves survival as first-line and second-line therapy and works with irinotecan- and oxaliplatin-based therapy.
  7. The addition of bevacizumab to irinotecan, fluorouracil, and leucovorin (IFL) significantly improves the response rate, overall survival, and progression-free survival.
  8. 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.
  9. Interruption in therapy is not ideal for patients; some form of maintenance therapy is preferred after a stable disease state is obtained.
  10. Single-agent maintenance bevacizumab may be a feasible option for patients receiving bevacizumab + CapeOx as induction therapy.
  11. There are no data on maintenance anti-EGFR therapy.
  12. Anti-EGFR antibody therapy should be given only to patients with KRAS wild-type tumors.
  13. Anti-EGFR antibody therapy and bevacizumab should never be combined.
  14. In randomized clinical trials using both FOLFOX and FOLFIRI cytotoxic backbones, only patients with KRAS wild-type tumors have shown improvement in progression-free survival (PFS) and overall survival (OS)
  15. Optimal use of all therapeutic agents improves survival in patients with metastatic disease.
  16. It is reasonable to leave the primary therapy in place when starting treatment for metastatic disease, if there is no urgent situation such as obstruction or uncontrolled bleeding.
  17. A multidisciplinary approach is necessary to deal with the complicated issue of potentially resectable or marginally resectable metastatic disease.
  18. Patients who receive bevacizumab-containing neoadjuvant therapy must not undergo surgery until at least 6-8 weeks afterward, in order to minimize perioperative complications
  19. 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 RR, R0 resection 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.
  20. FOLFOXIRI plus bevacizumab provides benefit versus FOLFIRI plus bevacizumab in subset retrospective analysis regardless of RAS or BRAF mutational status. [31] It may be considered in patients with RAS and BRAF mutations, particularly those with metastatic disease in whom reduction in tumor burden could improve quality of life by providing symptom relief, or permit R0 resection with neoadjuvant use.