Colon Cancer Treatment Protocols
No Results
No Results
processing….
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.
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:
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:
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
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] :
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
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
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] 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 [56] 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 q3Weeks for up to 4 doses, THEN administer nivolumab 250 mg IV q2Weeks until disease progression or unacceptable toxicity. [59]
Referral for clinical trial
See the list below:
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.
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.
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 + 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.
[Guideline] NCCN Clinical Practice Guidelines in Oncology: Colon Cancer Version 2.2018 – March 14, 2018. Available at http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed: March 27, 2018.
Haller DG, Catalano PJ, Macdonald JS, O’Rourke MA, Frontiera MS, Jackson DV, et al. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005 Dec 1. 23(34):8671-8. [Medline].
André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer. 1999 Sep. 35(9):1343-7. [Medline].
Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010 Jul 10. 28(20):3219-26. [Medline].
André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009, Jul 1. 27(19):3109-16. [Medline].
André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3. 350(23):2343-51. [Medline].
Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007 Jun 1. 25(16):2198-204. [Medline].
Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005 Jun 30. 352(26):2696-704. [Medline].
Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011 Apr 10. 29(11):1465-71. [Medline].
Adam, R.; Avisar, E.; Ariche, A.; Giachetti, S.; Azoulay, D.; Castaing, et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann.Surg.Oncol. 2001. 8(4):347-353. [Medline].
Kesmodel SB, Ellis LM, Lin E, et al. Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases. J Clin Oncol. 2008 Nov 10. 26(32):5254-60. [Medline].
Tamandl D, Gruenberger B, Klinger M, et al. Liver resection remains a safe procedure after neoadjuvant chemotherapy including bevacizumab: a case-controlled study. Ann Surg. 2010 Jul. 252(1):124-30. [Medline].
Maindrault-Goebel F, de Gramont A, Louvet C, André T, Carola E, Gilles V, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Oncology Multidisciplinary Research Group (GERCOR). Ann Oncol. 2000 Nov. 11(11):1477-83. [Medline].
de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug. 18(16):2938-47. [Medline].
Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, et al. A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002 Aug 12. 87(4):393-9. [Medline].
Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20. 25(30):4779-86. [Medline].
Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20. 26(12):2013-9. [Medline].
Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol. 2008 Apr 10. 26(11):1830-5. [Medline].
Okines A, Puerto OD, Cunningham D, et al. Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO16966 trial. Br J Cancer. 2009 Oct 6. 101(7):1033-8. [Medline]. [Full Text].
Reddy SK, Morse MA, Hurwitz HI, et al. Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases. J Am Coll Surg. 2008 Jan. 206(1):96-106. [Medline].
Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct. 16 (13):1306-15. [Medline].
Adam R, Aloia T, Lévi F, et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol. 2007 Oct 10. 25(29):4593-602. [Medline].
Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2. 360(14):1408-17. [Medline].
Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010 Jan. 11(1):38-47. [Medline].
Alan P. Venook, Donna Niedzwiecki, Heinz-Josef Lenz, Federico Innocenti, Michelle R. Mahoney, Bert H. O’Neil, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). ASCO meeting abstracts. 2014. 32:LBA3:
Falcone A, Masi G, Brunetti I, et al. The Triplet Combination of Irinotecan, Oxaliplatin and 5FU/LV (FOLFOXIRI) vs the Doublet of Irinotecan and 5FU/LV (FOLFIRI) as First-Line Treatment of Metastatic Colorectal Cancer (MCRC): Results of a Randomized Phase III Trial by the Gruppo Oncologico Nord Ovest (G.O.N.O.). Proceedings from the 42nd Annual Meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 3513:
Tran NH, Cavalcante LL, Lubner SJ, Mulkerin DL, LoConte NK, Clipson L, et al. Precision medicine in colorectal cancer: the molecular profile alters treatment strategies. Ther Adv Med Oncol. 2015 Sep. 7 (5):252-62. [Medline]. [Full Text].
Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008 Dec 10. 26(35):5705-12. [Medline].
Cassidy J, Tabernero J, Twelves C, et al. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol. 2004 Jun 1. 22(11):2084-91. [Medline].
Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003 Jan 1. 21(1):60-5. [Medline].
Emmanouilides C, Sfakiotaki G, Androulakis N, Kalbakis K, Christophylakis C, Kalykaki A, et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007 May 30. 7:91:[Medline].
Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep. 15(10):1065-75.
Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Oct. 14(11):1077-85. [Medline].
Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005 May 20. 23(15):3502-8. [Medline].
Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993 Oct. 11(10):1879-87. [Medline].
Bokemeyer C, Bondarenko I, Makhson A, et al. Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the first-line treatment of metastatic colorectal cancer (mCRC): OPUS, a randomized phase II study. J Clin Oncol. 2007 (June 20 suppl). 25:18s.
Bokemeyer C, Bondarenko I, Hartmann J T, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. J Clin Oncol. 2008. 26:(May 20 suppl; abstr 4000).
Van Cutsem E, Nowacki M, Lang I, et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial. J Clin Oncol. 2007 (June 20 suppl). 25:18s.
Van Cutsem E, Lang I, D’haens G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: the CRYSTAL experience. J Clin Oncol. 2008. 26:(May 20 suppl; abstr 2).
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1. 28(31):4697-705. [Medline].
Hochster HS, Grothey A, Hart L, Rowland K, Ansari R, Alberts S, et al. Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT. Ann Oncol. 2014 Jun. 25(6):1172-8. [Medline].
Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1. 25(13):1670-6. [Medline].
Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001 Nov 1. 19(21):4097-106. [Medline].
Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22. 351(4):337-45. [Medline].
Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1. 28(31):4706-13. [Medline].
Amado R, Wolf M, Freeman D, et al. Panitumumab efficacy and patient-reported outcomes in MCRC patients with wild-type KRAS tumor status. J Clin Oncol. 2007. 25:1658–64.
Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013 Jan. 14(1):29-37. [Medline].
Van Cutsem E, Tabernero J, Lakomy R, Prausova J, Ruff P, Van Hazel G, et al. Intravenous (IV) aflibercept versus placebo in combination with irinotecan/5-FU (FOLFIRI) for secondline treatment of metastatic colorectal cancer (mCRC): Results of a multinational phase III trial. Ann Oncol. 2011/06. 22(5):0-0024.
Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 Apr 10. [Medline].
Hecht JR, Cohn A, Dakhil S, Saleh M, Piperdi B, Cline-Burkhardt M, et al. SPIRITT: A Randomized, Multicenter, Phase II Study of Panitumumab with FOLFIRI and Bevacizumab with FOLFIRI as Second-Line Treatment in Patients with Unresectable Wild Type KRAS Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2015 Jun. 14(2):72-80. [Medline].
Van Cutsem E, Tejpar S, Vanbeckevoort D, Peeters M, Humblet Y, Gelderblom H, et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012 Aug 10. 30(23):2861-8. [Medline].
Maindrault-Goebel F, Louvet C, André T, et al. Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer. 1999 Sep. 35(9):1338-42. [Medline].
Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15. 22(2):229-37. [Medline].
Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1. 25(13):1658-64. [Medline].
Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25. 372 (26):2509-20. [Medline]. [Full Text].
Michael J. Overman, Scott Kopetz, Raymond S. McDermott, Joseph Leach, Sara Lonardi, Heinz-Josef Lenz, et al. Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results. J Clin Oncol. 2016. 34,:(suppl; abstr 3501).
Grothey A, Sobrero AF, Salvatore S, Falcone A, Ychou M, Heinz-Josef L, et al. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. J Clin Oncol 30, 2012 (suppl 4; abstr LBA385). [Full Text].
Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14. 372 (20):1909-19. [Medline].
Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol. 2018 Mar 10. 36 (8):773-779. [Medline].
Siena S, Tabernero J, Burkes R L, et al. Phase III study (PRIME/20050203) of panitumumab (pmab) with FOLFOX compared with FOLFOX alone in patients (pts) with previously untreated metastatic colorectal cancer (mCRC): pooled safety data. J Clin Oncol. 2008 (May 20 suppl). 26:15s.
Crane CH, Ellis LM, Abbruzzese JL, et al. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol. 2006 Mar 1. 24(7):1145-51. [Medline].
Alberts SR, Donhoe JH, Mahoney MR, et al. Liver resection after 5-fluorouracil, leucovorin and oxaliplatin for patients with metastatic colorectal cancer (MCRC) limited to the liver: A North Central Cancer Treatment Group (NCCTG) phase II study. Proc Am Soc Clin Oncol. 2003. 22:263,:(abstr 1053).
Khalid Matin, MD, FACP Associate Professor of Medicine, Virginia Commonwealth University School of Medicine; Medical Director of Community Oncology and Clinical Research Affiliations, Massey Cancer Center, VCU Medical Center
Khalid Matin, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology
Disclosure: Nothing to disclose.
Arushi Khurana, MBBS, MD Fellow in Hematology/Oncology, Virginia Commonwealth University School of Medicine
Arushi Khurana, MBBS, MD is a member of the following medical societies: Alliance for Academic Internal Medicine, American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Society of General Internal Medicine
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee
Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology
Disclosure: Nothing to disclose.
N Joseph Espat, MD, MS, FACS Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center
N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral Nutrition, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Association for Academic Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas Club, Sigma Xi, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress, Southern Medical Association, Surgical Infection Society
Disclosure: Nothing to disclose.
Lewis J Rose, MD Clinical Associate Professor of Medical Oncology, Division of Regional Cancer Care, Kimmel Cancer Center, Thomas Jefferson University Hospital; Consulting Staff, LRCRZ Associates
Lewis J Rose, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Hematology, Pennsylvania Medical Society, Phi Beta Kappa, Philadelphia County Medical Society
Disclosure: Nothing to disclose.
Colon Cancer Treatment Protocols
Research & References of Colon Cancer Treatment Protocols |A&C Accounting And Tax Services
Source
0 Comments