Metastatic Colorectal Cancer

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


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. [1][2][3] 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 [Link]). 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.

Search Strategy
This guideline was developed to outline the management recommendations for patients with metastatic colorectal cancer. It was compiled from the results of randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. The most recent update involved the following search criteria using the

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.

Recommendations
1. Consider treatment on a clinical trial, if available. 2. Patients with a new diagnosis of metastatic disease (stage IV diagnosis) should receive testing for activating mutations of Ras (Kras and Nras), BRAF, and evaluation of microsatellite instability or mismatch repair deficiency in tumour tissue. 3. In the absence of relevant comorbid medical problems, patients with metastatic colorectal cancer and a performance status of ECOG 0, 1, or 2 should be offered palliative chemotherapy.  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  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. 10. Patients with BRAF mutated metastatic colorectal cancer represent a distinct group of patients who have a poor prognosis and are typically resistant to traditional doublet chemotherapy regimens. The individual patient data meta-analysis of 5 trials compared FOLFOXIRI + bevacizumab versus doublet chemotherapy + bevacizumab, including n=115 patients with BRAF mutations. FOLFOXIRI + bevacizumab had increased response rates for patients with BRAF mutations. This regimen is associated with increased neutropenia, febrile neutropenia, and diarrhea. There was no significant improvement in OS or PFS with FOLFOXIRI + bevacizumab compared to doublet chemotherapy + bevacizumab. 16 In select patients with BRAF mutations, FOLFOXIRI + bevacizumab may be considered. For patients who have progressed on first or second line treatments (i.e. those that have been exposed to both irinotecan and oxaliplatin), the combination of BRAF, MEK and EGFR inhibition appears to be effective. The phase III open-label BEACON trial studied 665 patients with BRAF V600E mutated metastatic colorectal cancer [Level I]. Patients had progressed on 1 or 2 prior treatments. 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 ( 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 [12][13][14] • 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 • Bevacizumab interrupts VEGF-mediated angiogenesisa critical factor in tumor growth and progression. It is thought to decrease the interstitial pressure in tumors, to normalize tumor vasculature, and to improve the delivery of chemotherapy. • Bevacizumab is contraindicated in patients with: · Radiological or clinical evidence of invasion of the tumor into a major blood vessel; · Major surgical procedure or significant trauma within preceding twenty-eight days; · Major surgical procedure anticipated within forthcoming four to six weeks; · Uncontrolled hypertension; · Clinically significant cardio-or cerebro-vascular disease (e.g.: myocardial infarction or cerebrovascular accident within six months, unstable angina, congestive heart failure, use of a thrombolytic agent within six months, serious dysrhythmia); · Inherited bleeding diathesis, coagulopathy, or esophageal varices; · Significant proteinuria or renal dysfunction; · Non-healing wound, ulcer, or bone fracture; · Metastases within central nervous system or ophthalmologic abnormalities; and · Pregnancy, lactation, or childbearing potential without effective contraception.
• If the medical oncologist feels the benefits outweigh the risks, it may be combined with chemotherapy in patients with a good performance status (ECOG ≤2). It can be administered over ten minutes at 5 mg/kg IV (Q2week chemotherapy schedule) or over fifteen minutes at 7.5 mg/kg IV (Q3week chemotherapy schedule).

14.
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 ( • 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 µg/L) to generate a clinical risk ("Fong") score; it is highly predictive of outcome. 2

"Fong
Score" 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 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 µg/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 55-57 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 [Level II]
• 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 [59][60][61] 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 Guideline Resource Unit Last revision: April 2023 (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) [Level III]
• 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. [67][68][69][70][71][72][73] • Patients should be discussed at multidisciplinary rounds. SBRT can be considered for unresectable disease when alternative therapies have failed or are contraindicated.

Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GI Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GI Tumour Team who were not involved in the guideline's development, including surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in theGuideline Resource Unit Handbook.
This guideline was originally developed in 2010.

Levels of Evidence I
Evidence from at least one large randomized, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomized trials without heterogeneity II Small randomized trials or large randomized trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity III Prospective cohort studies IV Retrospective cohort studies or case-control studies V Studies without control group, case reports, expert opinion

Strength of Recommendations
A Strong evidence for efficacy with a substantial clinical benefit; strongly recommended B Strong or moderate evidence for efficacy but with a limited clinical benefit; generally recommended C Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, etc.); optional D Moderate evidence against efficacy or for adverse outcome; generally not recommended E Strong evidence against efficacy or for adverse outcome; never recommended

Maintenance
A formal review of the guideline will be conducted in 2024. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.

Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial GI Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.

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Funding Source
Financial support for the development of CancerCare Alberta's evidence-based clinical practice guidelines and supporting materials comes from the CancerCare Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.