Introduction
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, experts opinions |
Grades of recommendation |
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,…), optional |
D. Moderate evidence against efficacy or for adverse outcome, generally not recommended |
E. Strong evidence against efficacy or for adverse outcome, never recommended |
Diagnosis and staging
History including familial history of tumors and syndromes associated with hereditary disease |
Physical examination must include the general condition (performance status, PS), and digital rectal exam |
Laboratory tests including liver and renal function and prognostic markers (white blood cell count, alkaline phosphatase, lactate dehydrogenase (LDH), bilirubin, and albumin) |
Carcinoembryonic antigen (CEA) |
Pathological review of a tumor biopsy should at least provide histological subtype, tumor grade, and KRAS and NRAS mutational status. BRAF genotyping may be considered in RAS wild-type tumors for prognostic information |
Computed tomography (CT) scan of the chest, abdomen and pelvis. Magnetic resonance imaging (MRI) of the liver could be considered in cases of hepatic metastases |
Complete colonoscopy to locate the primary tumor, to obtain tissue for histological diagnosis, and to detect potential synchronous colorectal lesions. Virtual colonoscopy could be useful in case of tumors that impede the progression of the endoscopic tube |
Other tests such as a bone scan or a brain CT scan should be performed only if clinically indicated |
Additional examinations, as clinically needed, are recommended prior to major abdominal or thoracic surgery with potentially curative intent |
Abdominal MRI with intravenous contrast may be considered in patients with potentially resectable liver metastases and for patients with iodine allergy |
A fluorodeoxyglucose (FDG)-positron emission tomography (PET–CT) scan should be performed, if available, when metastatic disease is or may potentially become resectable |
Needle biopsy of a patient with known histologic diagnosis is only recommended when it may change the therapeutic strategy |
Prognostic classifications
Biomarkers
The European Society of Medical Oncology (ESMO) proposes assigning patients to one of 4 groups to guide first-line therapeutic strategies (V, C) |
The expanded RAS mutation analysis needs to be known before anti-EGFR treatment in mCRC, performed on tumor DNA from any location, as long as the performing lab complies with nationally or internationally qualified quality assurance programs (I, A) |
Plasma can be a surrogate source tissue for mutational analysis when no tumor sample is available or for testing secondary resistance (III, C) |
Patients with asymptomatic primary tumor and unresectable disease should start initial palliative chemotherapy. Resection of the primary tumor should only be performed in patients who develop serious complications (II, B) |
Surgical R0 resection should be performed for solitary or confined liver or pulmonary metastases (II, A) |
CS and HIPEC by experienced expert teams may improve progression-free survival (PFS) and overall survival (OS) for selected patients with PC (IV, B) |
For most patients with good PS status and no significant comorbidities, the combination of infused regimens of 5-FU/leucovorin (LV) with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) remains the recommended chemotherapy backbone for first-line treatment (I, A) |
First-line chemotherapy selection should be based on prior oxaliplatin-based adjuvant treatment, clinical conditions and comorbidities, biologic drug to be combined, and patient’s preferences |
Oxaliplatin and capecitabine combination is an alternative first-line treatment option for patients with mCRC (I, B) |
Anti-EGFR antibodies should not be used without prior determination of RAS status. Expanded RAS analysis is superior to conventional RAS analysis (I, A) |
Addition of anti-EGFR therapy to FOLFIRI and to FOLFOX improves PFS and OS in first-line treatment of patients with mCRC (II, A) |
The addition of bevacizumab to chemotherapy is beneficial with respect to chemotherapy alone (I, B) |
There is no clear evidence of the superiority of anti-EGFR over bevacizumab in combination with chemotherapy in the first-line treatment of mCRC |
Anti-EGFR agents should not be combined with bevacizumab (I, B) |
First-line treatment for fit patients with WT RAS mCRC should include a combination of chemotherapy doublet and a monoclonal antibody (anti-EGFR or bevacizumab) |
First-line treatment for fit patients with mutant RAS mCRC should include a combination of chemotherapy doublet and bevacizumab (I, B) |
Second and successive treatment lines should be individualized according to prior therapy, RAS status and clinical condition (II, C) |
Patients with completely resected metastases should receive perioperatively 6 months of an active, preferably oxaliplatin-based chemotherapy regimen (I, B) |
Fit patients with borderline resectable metastases should receive intensive induction therapy with chemotherapy doublets and a monoclonal antibody, or chemotherapy triplets with or without bevacizumab. In RAS WT tumors, anti-EGFR may be more effective than bevacizumab in terms of tumor shrinkage (II, B) |
Fit patients with technically unresectable metastases and bulky, symptomatic or biologically aggressive disease, should receive intensive first-line therapy with chemotherapy doublets and a monoclonal antibody. In RAS WT tumors, bevacizumab may be subjectively better tolerated and allow the patient to receive more lines of therapy. Anti-EGFR agents, however, may be preferred in patients with significant tumor-related symptoms (IV, B) |
Treatment de-escalation after induction therapy is often required due to cumulative toxicity, and is also acceptable once disease control is achieved (II, B) |
Patients with unresectable metastases who are either unfit or asymptomatic and have limited risk for rapid clinical deterioration, should receive non-intensive/sequential therapy (I, B) |
Role of surgery
First-line systemic treatment: chemotherapy
First-line systemic treatment: targeted therapies
Management of patients with wild-type (WT) mCRC after expanded RAS analysis
Management of patients with mutated mCRC after expanded RAS analysis
Second- and successive treatment lines
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It may also be appropriate adding bevacizumab to chemotherapy if it was not used in initial therapy, preferably in combination with oxaliplatin-based therapy [43].
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For patients previously treated with oxaliplatin-based therapy, FOLFIRI plus aflibercept is an option, particularly if they did not receive prior bevacizumab therapy [44].
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Other alternative after progression to FOLFOX plus bevacizumab in first line is FOLFIRI plus ramucirumab [45].
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For patients with expanded RAS WT mCRC, cetuximab, or panitumumab plus preferably irinotecan-based therapy [46, 47] is recommended in second-line treatment. They may also be employed as single agents in third or subsequent lines of therapy in patients naive of anti-EGFR therapy [48, 49]. Cetuximab and panitumumab appear to have comparable efficacy when used as single agents for salvage therapy in patients with chemotherapy-refractory mCRC [50]. The reintroduction of EGFR inhibitors in subsequent treatment lines is not recommended for previously exposed patients.