# Background
Generally, metastatic colorectal cancer represents an incurable situation for which only palliative options (e.g.: best supportive care, palliative chemotherapy) should be considered. However, there are specific circumstances where an attempt at metastatectomy (surgical resection of a metastasis) may be possible and where five-year survivals may reach 40 percent.  In addition, cytoreductive surgery ("peritoneal stripping") and heated intra-peritoneal chemotherapy may be considered for limited intra-peritoneal metastases. 4 Such treatments require involvement of a multidisciplinary team that should include a hepatobiliary surgeon, thoracic surgeon, and surgical oncologist (see Appendix A ). Consider post-operative ("adjuvant") therapy (an extrapolation from Clinical Practice Guidelines for Early Stage Colon Cancer) along with careful surveillance for patients with no evidence of residual disease (also an extrapolation from Clinical Practice Guidelines for Colorectal Cancer Surveillance):

# Post-Metastatectomy Colorectal Cancer Surveillance Guidelines 5
If resection of another recurrence from liver and/or lung is clinically appropriate,
- Obtain a CEA every three months for five years (progressive rises warrant a workup for recurrent disease); and - Obtain a CT scan of the thorax, abdomen, and pelvis at the discretion of the treating physician.
Stereotactic body radiation (SBRT), radiofrequency ablation (RFA) 6 or other local therapies may be considered for patients with otherwise resectable liver metastases who are unable to consider surgery due to medical comorbidities (e.g.: lung disease, significant heart disease).
It is recommended that surgery (e.g.: colon resection, diverting colostomy) or endoscopic procedure (e.g. stent placement) be considered to relieve or prevent a bowel obstruction. Tumor resection or palliative radiation may be considered for bleeding. Surgery is not recommended for patients with an asymptomatic (or minimally symptomatic) primary colorectal cancer and clearly incurable metastatic disease.
Palliative chemotherapy regimens are generally continued as long as tumor shrinkage or stability is confirmed, the side effects remain manageable, the patient wishes to continue, and the treatment remains medically reasonable. Palliative radiotherapy may help control local problems (e.g. pain from bone metastases, bleeding from in situ rectal cancer).
Guideline Questions 

# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with metastatic colorectal cancer. Different principles may apply to pediatric patients.

# Recommendations
Goals of Therapy 1. To maintain or to improve the patient's quality of life (to control or to delay the onset of tumourrelated symptoms). 2. To prolong life, if possible.  9 Pooled retrospective analyses establish the predictive and prognostic value of primary tumor site using Cetuximab and Panitumumab. 10,11 In a retrospective evaluation of 38% of the 5,760 patients enrolled in the CRYSTAL, FIRE-3, PEAK, PRIME, 181, and CALGB 80405 studies (trials with different populations, control arms, treatments, etc.), primary tumor location confers both prognostic effect (outcomes are worse for disease that arises from the proximal colon, regardless of the treatment received) and predictive effect (first-line use of anti-EGFR therapy improves outcomes in RAS wild-type disease that arises from the distal colon but offers no benefit when disease arises from the proximal colon). 12 The Alberta Provincial Gastrointestinal Tumour Team supports the use of EGFR inhibitors in first-line treatment for patients with Ras wild-type, MSS/MMR proficient metastatic colorectal cancer (i.e. non-mutated Kras or Nras) with left sided primary tumors. Selection of first-line therapy should now consider the results of a rigorous molecular analysis as well as reference to the primary tumor location (in addition to patient preferences, extent of cancer, goals of care, mutations in RAS, medical comorbidities, performance status, etc.). 9. Mutations in Kras and Nras predict a lack of response in anti-Epidermal Growth Factor Receptor (EGFR) therapy in patients with metastatic colorectal cancer. 13 Patients with known Ras mutations should not be treated with either cetuximab or panitumumab. a. Note: The recommendation for Ras testing should not necessarily indicate a preference regarding regimen selection in the first-line setting. Rather, early identification of Ras status is intended to plan for the treatment continuum. b. When compared to best supportive care in patients with Kras wild-type colorectal cancer refractory or intolerant to a fluoropyrimidine (e.g.: 5-Fluorouracil, Capecitabine), Irinotecan, and Oxaliplatin, the use of monoclonal antibodies directed at the EGFR delays disease progression and deterioration in quality of life. Panitumumab prolongs progression-free survival compared to best supportive care . 14,15 Only Panitumumab is funded for patients with Kras wild-type disease on the Alberta Health Services Cancer Drug Benefit Program. Refer to the Panitumumab and Cetuximab: Toxicity Management Guidelines.

# Recommendations
The EGFR signaling pathway is activated in response to binding of the ligand to the extracellular domain of the EGFR. The resultant signaling cascade regulates genes that control progression through the cell cycle. Kras regulates this cascade. The Kras gene may be "wild-type" (in up to 65% of cases) or "mutated". Wild-type Kras remains active only transiently after interaction of EGFR with its ligand. Mutated Kras remains constitutively active irrespective of activation of EGFR. This permits unregulated proliferation and enhances survival, metastasis, and angiogenesis.
Monoclonal antibodies directed against EGFR block activation of the EGFR and, thereby, the downstream events. A constitutively active ("mutant") Kras would not be influenced by such therapy. Kras testing by quantitative PCR (or direct DNA sequencing) is highly specific for mutations known to confer constitutive activation.  17 They were randomized to encorafenib, binimetinib and cetuximab, encorafenib and cetuximab or dealer's choice of irinotecan+ cetuximab or FOLFIRI plus cetuximab (argued to be the standard treatment). The analysis was powered to compare the triplet regimen against the standard treatment arm. In an updated overall survival analysis, median OS was similar in patients treated with encorafenib + cetuximab with or without binimetinib (9.3 mo and 9.3 mo, respectively). Median OS in the standard treatment arm was 5.9 mo. Treatment with encorafenib + cetuximab with or without binimetinib was associated with longer maintenance of quality of life across different QOL assessment tools compared to the standard arm. 17 In Alberta, encorafenib is administered with panitumumab. pERC and clinical experts noted that concurrent administration with panitumumab instead of cetuximab would lead to less frequent chemotherapy sessions, and it is expected that patients who receive encorafenib in combination with panitumumab would respond similarly to patients treated with cetuximab. 11. Whether treatment is with combination chemotherapy or sequential monotherapy (with or without Bevacizumab) depends upon the patient's goals, their physical status, and other life circumstances, as assessed by their treating oncologist. Sequences of therapy may include: a.  12 - Involves the administration of Irinotecan (180 mg/m 2 IV) and Leucovorin (400 mg/m 2 IV) concurrently over two hours followed by 5-Fluorouracil (400 mg/m 2 IV bolus and then an IV infusion of 2,400 mg/m 2 over forty-six hours) in every two-week cycle. This regimen requires placement of a port, central venous catheter (CVC), or peripherally inserted central catheter (PICC). - For patients who have complications with, or contraindications to, placement of a port, CVC, or PICC along with the capacity to tolerate the potential for greater toxicity, consider CAPIRI (administers Irinotecan 200 mg/m 2 IV over ninety minutes followed by Capecitabine 800 mg/m 2 PO Q12h for fourteen days in every twenty-one day cycle). 24 - Supplement with Bevacizumab, where appropriate (see below).
- Consider a switch to FOLFOX6 (or CAPOX) at progression, provided it is medically reasonable and the patient wishes further therapy. The sequence of FOLFIRI followed by FOLFOX6 is equivalent to the sequence of FOLFOX6 followed by FOLFIRI. 25 - Due to Oxaliplatin's propensity to cause a cumulative peripheral sensory neuropathy, consider a non-Oxaliplatin-containing regimen before an Oxaliplatinbased regimen. Irinotecan should be considered relatively contraindicated (or consider a dose modification) for patients with an elevated bilirubin due to metastatic disease or Gilbert's syndrome Regimen Details - Gilbert's syndrome results from impaired activity of uridine diphosphate glucuronyltransferase isoform 1A1 (UGT1A1). It delays the metabolism of Irinotecan and thereby increases the risk of severe toxicity. CAPOX and mFOLFOX6  - CAPOX involves the administration of Oxaliplatin (130 mg/m 2 IV over two hours) and Capecitabine 1,000 mg/m 2 PO Q12h for fourteen days in every twenty-one day cycle. - mFOLFOX6 involves the administration of Oxaliplatin (85 mg/m 2 IV) and Leucovorin (400 mg/m 2 IV) concurrently over two hours followed by 5-Fluorouracil (400 mg/m 2 IV bolus and then an intravenous infusion of 2,400 mg/m 2 over forty-six hours) in every two-week cycle. This regimen requires placement of a port, central venous catheter (CVC), or peripherally inserted central catheter (PICC). - Supplement with Bevacizumab, where appropriate (see below).
- Consider a switch to FOLFIRI or Irinotecan at progression, provided it is medically reasonable and the patient wishes further therapy. The sequence of FOLFIRI followed by FOLFOX6 is equivalent to the sequence of FOLFOX6 followed by FOLFIRI. 25 - Due to Oxaliplatin's propensity to cause a cumulative peripheral sensory neuropathy, consider a non-Oxaliplatin-containing regimen before an Oxaliplatinbased regimen. - For patients with persistent grade  2 peripheral neuropathy, considering holding or reducing the doses of Oxaliplatin. FOLFOXIRI 15 - Involves the administration of a 90 minute infusion of Irinotecan (165 mg/m 2 ), a 120 minute infusion of Oxaliplatin (85 mg/m 2 ), and a concomitant 120 minute infusion of Leucovorin (400 mg/m 2 ), followed by a 48-hour continuous infusion 5-Fluorouracil (total dose 3200 mg/m 2 ) in every two-week cycle. This regimen requires placement of a port, central venous catheter (CVC), or peripherally inserted central catheter (PICC). - Supplement with Bevacizumab, where appropriate (see below).
- FOLFOXIRI is usually reserved for patients with excellent performance status as the progression free survival and overall survival improvement associated with FOLFOXIRI and Bevacizumab in the TRIBE study were accompanied with increased toxicity. 16 Capecitabine 16 - Involves the administration of Capecitabine 1,250 mg/m 2 PO Q12h for fourteen days in every twenty-one day cycle. Refer to "Capecitabine: A Guide for Patient Care." - Supplement with Bevacizumab, where appropriate (see below). Irinotecan 17 - Involves the administration of Irinotecan (350 mg/m 2 IV over ninety minutes) in every three-week cycle. - Decrease the dose by 20% for patients over seventy years of age or for patients who have received prior radiotherapy to the pelvis. - Irinotecan should be considered relatively contraindicated (or consider a dose modification) for patients with an elevated bilirubin due to metastatic disease or Gilbert's syndrome - Gilbert's syndrome results from impaired activity of uridine diphosphate glucuronyltransferase isoform 1A1 (UGT1A1). It delays the metabolism of Irinotecan and thereby increases the risk of severe toxicity. 5-Fluorouracil (simplified LV5FU2)
- Involves the administration of Leucovorin (400 mg/m 2 IV over two hours) followed by 5-Fluorouracil (400 mg/m 2 IV bolus and then an intravenous infusion of 2,400 mg/m 2 over forty-six hours) in every two-week cycle. - This regimen requires placement of a port, central venous catheter (CVC), or 
Patients who have progressed on all standard therapy should be encouraged to participate in clinical trials. The following trials have been conducted in patients who have progressed on or were intolerant to a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an EGFR inhibitor (if KRAS/NRAS wild type):
The phase III CORRECT trial randomized 760 patients who progressed on standard therapy to best supportive care with placebo or regorafenib.38 OS for patients on regorafenib was 6.4 months versus 5.0 months for the placebo arm (HR 0.77, 95% CI 0.64-0.94, p=0.005). PFS improved modestly but significantly (1.9 months versus 1.7 months; HR 0.49, 95% CI 0.42 -0.58, p<0.000001). The most common adverse events observed in the trial were hand-foot skin reactions (17%), fatigue (10%), hypertension (7%), diarrhea (7%) and rash/desquamation (6%). Regorafenib is currently not funded by the Alberta Health Services Outpatient Cancer Drug Benefit Program. The phase III RECOURSE trial randomized 800 patients to trifluridine-tipiracil or placebo. Median OS was significantly prolonged in patients treated with trifluridine-tipiracil compared to placebo (7.1 versus 5.3 months, HR 0.68, 95% CI 0.58-0.81; P<0.001), and this benefit was irrespective of prior regorafenib use. Trifluridine-tipiracil is currently not funded by the Alberta Health Services Outpatient Cancer Drug Benefit Program. 38 - For patients with metastatic colorectal cancer, optimal palliative chemotherapy offers two-year survivals under 40% and five-year survivals under 5% whereas resection of liver metastases offers two-year survivals of 60% to 70% and five-year survivals of 30%. - Resection of lung metastases offers a five-year overall survival of 48% (39.6% for R0 and 0% for R1 or R2 resections). 3 - Assigning one point to each factor (node-positive primary, disease-free interval under twelve months, two or more hepatic metastases, largest metastasis over 5 cm, and CEA level over 200 g/L) to generate a clinical risk ("Fong") score; it is highly predictive of outcome. 1.8 Years - The definition of resectable liver metastases continues to evolve. Currently, resection is considered possible if both an R0 resection and an adequate- future liver remnant are anticipated, and two contiguous liver segments can be preserved. - For patients with a normal liver, hepatic insufficiency is rare when the future liver remnant exceeds 20% of the total liver volume. 38 For patients extensively pre-treated with chemotherapy, a future liver remnant that exceeds 30% of the total liver volume is required.
For patients with underlying liver disease (e.g.: cirrhosis), a future liver remnant that exceeds 40% of the total liver volume is necessary to avoid cholestasis, fluid retention, and liver failure. - The use of EGFR inhibitors for resectable colorectal liver metastases is not recommended. The New EPOC trial randomized operable metastatic patients with KRAS wild-type metastatic colorectal cancer to FOLFOX with or without cetuximab. The addition of cetuximab was associated with significantly worse PFS (median 15.5 mo vs. 22.2 mo) and OS (median 81.0 mo vs. 55.4 mo; HR: 1.45; 95%CI: 1.02-2.05; p=0.036). 42 

# Marginally resectable liver metastases
- Pre-operative chemotherapy can downsize tumors, 43,44 identify responders (progression predicts for a poor outcome), 44 and improve three-year progression-free survival (42.4% versus 33.2% in resected patients, HR 0.73, CI95% 0.55-0.97, p = 0.025). 20 - In the situation where a liver metastatectomy could be facilitated by reduction in the size of the liver metastasis, patients should be treated with Oxaliplatin-based chemotherapy to optimal resectability rather than to maximal response or progression. The general approach for consideration of a biologic agent for non-liver limited mCRC should be used. Kras wild type, left sided primary, consider panitumumab; 22 Kras mutant, consider bevacizumab. 23 - As the post-operative morbidity increases with the number of cycles of chemotherapy administered pre-operatively, only a limited number of cycles of chemotherapy should be delivered. 45 The type of hepatic injury is regimen specific: 46 - 5-Fluorouracil predisposes to steatosis, a typically indolent manifestation of non-alcoholic fatty liver disease (NAFLD) that can increase the risks of post-operative infectious complications. - Irinotecan predisposes to non-alcoholic steatohepatitis (NASH), a serious complication of non-alcoholic fatty liver disease that includes fatty infiltration, inflammation, and hepatocyte damage. This can affect the hepatic reserve and increase morbidity and mortality after partial hepatectomy (ninety-day mortality of 1.6% versus 14.7%, p = 0.001). 21 - Oxaliplatin predisposes to sinusoidal obstruction (characterized by peri-sinusoidal inflammation, congestion, fibrosis, and venous occlusion). Some studies 21 suggest that it fails to increase the risk of peri-operative death while others 47 suggest that it increases morbidity (from 6.3% to 40.0%, p < 0.026) and prolongs length-of-stay (from 10.9 days to 17.0 days, p < 0.006) after hepatectomy. - Bevacizumab reduces the sinusoidal dilation induced by Oxaliplatin (all grades: from 53.5% to 27.4%; moderate or severe grades: from 27.9% to 8.1%, p < 0.01) as well as the degree of tumor viability when used in combination with 5-Fluorouracil and Leucovorin (32.9% versus 45.3%, p = 0.02). 48 Bevacizumab fails to impair liver regeneration after portal vein embolization. 49 - In a retrospective analysis of patients with initially unresectable metastatic disease, 50 12.5% became resectable after pre-operative FOLFOX. This was associated with a five-year survival of 33% -similar to the results achieved in "initially operable" patients. - In a retrospective analysis of patients who underwent pre-operative chemotherapy and resection of colorectal liver metastases, the degree of pathologic response correlated with outcome (five-year survival of 75% for complete response, 56% for major response, and 33% for minor response). The predictors for complete or major response were CEA  5 g/L, tumor size  3 cm, and chemotherapy with fluoropyrimidine, Oxaliplatin, and Bevacizumab. 51 - Portal vein occlusion by pre-operative embolization or intra-operative ligation can increase the volume of the left lobe by 30 to 40%. Metastases in the future liver remnant should be resected before portal vein embolization. 52 - The addition of Oxaliplatin 53,54 but not Irinotecan  to 5-Fluorouracil and Leucovorin in the adjuvant treatment of stage III colon cancer improves outcomes. Therefore, if the metastatic disease is resected, give subsequent consideration to "adjuvant" chemotherapy to complete a total course of therapy equivalent to six months (see Clinical Practice Guidelines for Early Stage Colon Cancer). 58 

# Radiofrequency ablation 
- Radiofrequency ablation applies multiple four-to six-minute cycles of current to create irreversible damage and protein coagulation around a percutaneously-placed needle. It can be applied to liver metastases under 5 cm (preferably under 3 cm) that are located away from large blood vessels ("heat sinks"). Although hemorrhage, bile leak, and infection can occur, major complications arise in only about 2% of patients treated. Incomplete ablation is identified in 20 to 30% of cases. While needle-track recurrences occur, this is reduced by ablation upon withdrawal. Retrospective studies  suggest that radiofrequency ablation is associated with a higher local recurrence rate and a lower recurrence-free and overall survival when compared to resection of a hepatic metastasis. Peritoneal carcinomatosis - Cytoreductive surgery in combination with heated intra-peritoneal chemotherapy (HIPEC) followed by systemic 5-Fluorouracil and Leucovorin provides superior outcomes when compared to the same systemic chemotherapy regimen with or without palliative surgery (median survival 22.3 months versus 12.6 months, HR 0.55, CI95% 0.32-0.95, p = 0.032). 4 Patients with involvement of zero to five of the seven regions of the abdominal cavity have a significantly better survival than patients with six or seven affected regions. Macroscopically complete cytoreduction (R1) confers a significantly superior survival than patients with residual disease (R2). - Cytoreductive surgery 62 involves the complete removal of macroscopic disease (e.g.: peritonectomy, omentectomy, cholecystectomy, splenectomy, abdominal organs involved with tumor), lysis of intra-abdominal adhesions (to permit optimal exposure to heated intraperitoneal chemotherapy), and reconstitution of the gastrointestinal tract. Hyperthermia exerts a direct cytotoxic effect that impairs DNA repair, denatures proteins, induces heat-shock proteins, induces apoptosis, inhibits angiogenesis, and blocks oxidative metabolism 64 . Hyperthermia is synergistic with cytotoxic agents. 63 The process is associated with a reported morbidity and mortality rates of 22.9% and 4%, respectively. 64 Unresectable disease
- Consider palliative chemotherapy. click here for more details - Resection of an asymptomatic primary colorectal cancer provides only minimal palliative benefit, risks morbidity and mortality, and delays initiation of systemic therapy. 65,66 Obstruction and bleeding complicate only 13.9% and 3.0% of cases treated with palliative chemotherapy when the primary tumor is left in situ. Therefore, when a patient presents with an unequivocally unresectable metastatic disease and an asymptomatic primary colorectal cancer, palliative chemotherapy can be initiated; resection of the primary tumor can be reserved for the small proportion of patients who develop a complication related to the primary tumor. Resection, diversion, placement of a stent, or radiation is indicated for a symptomatic primary colorectal cancer.

# Stereotactic Body Radiotherapy (SBRT) 
- Liver SBRT is used to deliver high doses of radiation accurately to ablate and destroy all normal and tumour cells within a small geographic area. SBRT can provide moderate rates of local control for patients with liver metastases (50-100% at 1 year, 45-80% at 2 years), however, literature is limited to single institution retrospective studies.  - Patients should be discussed at multidisciplinary rounds. SBRT can be considered for unresectable disease when alternative therapies have failed or are contraindicated.
- Liver SBRT is currently under investigation in Phase II clinical trials open at the TBCC and CCI. Consider referral of patients with good liver function (Child Pugh A, B) and a limited number of metastases of an amenable size for participation in these studies.
- Continued clinical trials in the use of liver SBRT are recommended. Enrollment of patients into clinical trials or investigational protocols should be encouraged.

# Appendix A: Approach to Metastatic Colorectal Cancer
Resectable lung or liver metastases - Consider upfront resection especially for patients with favorable criteria: metachronous, fewer lesions, unilobar disease, no extra-hepatic disease. 39 - Perioperative oxaliplatin based chemotherapy, with 3 months pre-hepatic resection and 3 months post-hepatic resection can be considered for patients with resectable liver metastases, especially when the prognosis is unclear. This strategy improved three-year progression-free survival (423.4% versus 33.2% in resected patients, HR=0.73;95%CI: 0.55-0.97; p=00.025) in EORTC 40983, however, overall survival was not improved (Level II). 20,40 - The optimal role of adjuvant chemotherapy after upfront resection is unclear. Postoperative oxaliplatin based chemotherapy for 6 months improved disease-free survival HR 0.67, 95% CI (0.50-0.92, one sided p = 0.006) but not overall survival HR 1.25 (0.78-2.00) two sided P=0.42. 41 - The use of chemotherapy in this setting may be influenced by the clinical presentation: synchronous versus metachronous presentation, technical criteria for resectability, and/or number and size of metastases. 39

# Appendix B -Synchronous Metastatic Rectal Cancer Paradigm
Emerging evidence suggests that it may be important to consider the following approaches to potentially resectable metastatic disease, especially for rectal cancer. 

# Synchronous Metastatic