Metastatic Colorectal Cancer: Biomarker-Driven Treatment Selection, Maintenance, and Sequencing

Authored by Natalia Gandur, published on 2026-07-18 01:46:14.0

  1. Metastatic / recurrent colorectal adenocarcinoma
    Confirmed metastatic or recurrent colorectal adenocarcinoma requiring treatment-intent assessment, molecular characterization, and multidisciplinary management planning. This pathway applies to adults with histologically confirmed colorectal adenocarcinoma and radiologically or pathologically confirmed metastatic or recurrent disease. Before entering the pathway: - Confirm colorectal origin and adenocarcinoma histology. - Review prior colorectal surgery, radiation therapy, adjuvant therapy, and timing of recurrence. - Distinguish colon from rectal primary and document primary tumor location. - Exclude appendiceal cancer, anal squamous carcinoma, neuroendocrine carcinoma, and other non-adenocarcinoma histologies requiring a dedicated pathway. - Identify immediately unstable presentations such as obstruction, perforation, major bleeding, sepsis, severe pain, or threatened organ function. Urgent clinical stabilization should not be delayed while completing molecular testing.
    • Initial Assessment and Disease Extent
      Define metastatic distribution, disease burden, symptoms, prior therapy, functional status, organ function, and whether urgent local or systemic intervention is required. Assess: Disease: - Primary tumor site: right colon, left colon, or rectum. - Sites of metastatic disease: liver, lung, peritoneum, lymph nodes, bone, ovary, brain, or other. - Number, size, distribution, and radiographic behavior of metastatic lesions. - Synchronous versus metachronous metastatic disease. - Symptoms from the primary tumor or metastatic sites. - Bowel obstruction, perforation, bleeding, biliary obstruction, pain, infection, or threatened organ function. Patient: - ECOG performance status. - Frailty, comorbidities, cognition, nutrition, and social support. - Renal, hepatic, marrow, and cardiovascular function. - Baseline neuropathy and prior oxaliplatin exposure. - Prior irinotecan, fluoropyrimidine, biologic, immunotherapy, or targeted therapy. - Time from completion of adjuvant therapy to recurrence. Work-up: - CT chest, abdomen, and pelvis. - Liver MRI when liver-limited disease, indeterminate liver lesions, or local-treatment planning requires greater definition. - Pelvic MRI for relevant rectal primary or pelvic recurrence. - Baseline CEA. - Colonoscopy or endoscopic reassessment when clinically indicated. - Multidisciplinary review when disease may be resectable, convertible, oligometastatic, or appropriate for local therapy.
      • Required Biomarker and Molecular Assessment
        Complete molecular characterization before treatment selection whenever clinically feasible. Obtain or confirm: Required: - MSI-H / dMMR versus MSS / pMMR. - Extended RAS testing: KRAS and NRAS exons 2, 3, and 4. - BRAF V600E. - Primary tumor sidedness: right-sided versus left-sided. Strongly recommended where available: - HER2 amplification or overexpression, particularly in RAS/BRAF wild-type disease. - KRAS G12C. - NTRK fusion and other rare actionable alterations through comprehensive genomic profiling. Specimen considerations: - Use adequate tumor tissue whenever available. - Plasma ctDNA may complement tissue testing when tissue is unavailable, inadequate, delayed, or when acquired resistance is being investigated. - A negative plasma result should not automatically exclude an alteration if tumor shedding is low; obtain tissue testing when clinically necessary. - Repeat molecular assessment may be relevant at progression, particularly before anti-EGFR rechallenge or when acquired resistance is suspected. Hereditary implications: - Refer for germline evaluation when age, family history, MMR loss pattern, polyposis phenotype, multiple cancers, or other features suggest hereditary cancer risk. Do not delay treatment of obstruction, perforation, major bleeding, sepsis, or another unstable presentation while awaiting the full panel.
        • Treatment Intent, Patient Fitness, and Goals
          Define whether the goal is cure, conversion to local therapy, durable disease control, symptom relief, or lower-intensity care. Integrate: Treatment intent: - Potentially curative. - Conversion to resectability or definitive local treatment. - Disease control / palliative treatment. - Symptom-directed or lower-intensity care. Patient factors: - ECOG performance status and frailty. - Comorbidities and organ function. - Baseline neuropathy. - Prior treatment toxicity. - Ability to tolerate doublet or triplet chemotherapy. - Immune-related contraindications. - Oral versus intravenous therapy feasibility. Clinical urgency: - Need for rapid tumor shrinkage. - Symptomatic or organ-threatening disease. - Impending obstruction or other local complication. - Potential for conversion to surgery, ablation, or stereotactic radiation. Patient priorities: - Survival. - Quality of life. - Avoidance of neuropathy, dermatologic toxicity, diarrhea, fatigue, or other treatment burden. - Treatment-free time. - Infusion frequency, travel, work, and caregiver support. - Financial and geographic access. - Clinical-trial participation. Document treatment intent and shared decision-making before selecting the systemic therapy pathway.
          • Resectability / Oligometastatic Classification
            Is the disease clearly resectable, borderline resectable with conversion potential, or unresectable / systemic-disease dominant? Classify through multidisciplinary review whenever feasible. Assess: - Ability to achieve complete local control of all known disease. - Number, size, and distribution of metastatic lesions. - Liver remnant, vascular anatomy, biliary anatomy, and technical liver resectability. - Pulmonary resectability or suitability for ablation/SBRT. - Presence and extent of extrahepatic disease. - Peritoneal disease distribution. - Symptomatic primary tumor. - Biological disease tempo. - Patient fitness for surgery or other definitive local therapy. Outgoing branches: 1. Clearly resectable / potentially curable. 2. Borderline resectable / conversion intent. 3. Unresectable / systemic-disease dominant.
            • CLEARLY RESECTABLE / POTENTIALLY CURABLE
              • MDT metastasis-directed strategy
                Plan surgery, ablation, SBRT, perioperative systemic therapy, and sequencing of the primary tumor and metastatic sites through MDT review. For clearly resectable or potentially curable metastatic disease: - Confirm that complete local control of all known disease is technically and clinically feasible. - Review the need for upfront systemic therapy versus upfront local treatment. - Consider surgery, thermal ablation, stereotactic body radiation therapy, or combined approaches. - Define sequencing of the primary tumor and metastatic sites. - Consider perioperative systemic therapy according to prior exposure, recurrence interval, disease burden, surgical plan, and MDT consensus. - Avoid unnecessary delay of definitive local therapy in clearly resectable disease. - Reassess pathology, margins, treatment response, residual disease, and postoperative systemic therapy needs after local treatment. - Discuss recurrence risk, surveillance, and future systemic options. Local treatment should be delivered in experienced centers when technically complex.
                • Surveillance and follow-up
                  Use risk-adapted imaging, CEA, toxicity review, and multidisciplinary reassessment after definitive local therapy. Follow-up should include: - Clinical assessment and symptom review. - CEA when informative. - Cross-sectional imaging according to recurrence risk, disease distribution, and local guideline. - Monitoring of surgical, ablative, or radiation-related complications. - Management of neuropathy, bowel dysfunction, fatigue, nutritional issues, and quality of life. - Reassessment in MDT if recurrence is potentially amenable to further local therapy. - Molecular reassessment when recurrence or resistance may change treatment selection. - Supportive care, lifestyle counseling, and psychosocial support.
                  • First-line systemic therapy selection
                    Select first-line therapy sequentially according to MSI/MMR status, fitness, BRAF V600E, RAS status, primary tumor sidedness, treatment intent, and urgency of response. Use the following sequential decision order: 1. MSI-H / dMMR? 2. If MSS / pMMR: fit for combination therapy? 3. If fit: BRAF V600E mutation? 4. If BRAF wild-type: RAS mutation? 5. If RAS/BRAF wild-type: primary tumor sidedness? Do not treat frailty, high tumor burden, sidedness, and molecular alterations as equivalent parallel categories. Regulatory approval and access vary by country. Treatment selection should incorporate local approvals, reimbursement, patient preference, toxicity, and clinical-trial availability.
                    • MSI-H / dMMR?
                      Is the metastatic colorectal cancer microsatellite instability-high or mismatch repair deficient? Confirm MSI-H / dMMR using validated testing. YES: - Route to first-line checkpoint inhibitor-based therapy. NO — MSS / pMMR: - Route to fitness assessment and molecularly directed chemotherapy/biologic selection. PD-L1 expression is not required for treatment selection in MSI-H / dMMR colorectal cancer.
                      • YES — MSI-H / dMMR
                        • MSI-H / dMMR first-line therapy
                          Use nivolumab + ipilimumab or pembrolizumab according to approval, availability, immune-risk profile, disease context, and patient preference. First-line options: - Nivolumab + ipilimumab. - Pembrolizumab. Selection considerations: - Regulatory availability. - Need for combination versus single-agent immunotherapy. - Autoimmune disease. - Solid-organ transplant. - Prior immune-related adverse event. - Performance status and comorbidities. - Patient preference and infusion burden. - Toxicity profile. - Disease tempo and need for rapid clinical control. Before treatment: - Document baseline symptoms and organ function. - Review autoimmune, transplant, infectious, endocrine, pulmonary, hepatic, renal, neurologic, and cardiac history. - Counsel regarding immune-mediated toxicities. During therapy: - Monitor for colitis, hepatitis, pneumonitis, endocrinopathies, nephritis, dermatologic toxicity, neurologic toxicity, myocarditis, and infusion reactions. - Reassess clinically and radiographically. - Confirm apparent early progression when pseudoprogression is clinically plausible and the patient remains stable. Checkpoint inhibitor therapy should not be selected based on PD-L1 expression.
                          • Response assessment
                            Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                            • Progressive disease or intolerable toxicity
                              Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                              • Open: Progression and next-line sequencing pathway
                                Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                            • Disease control / no progressive disease
                              De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                              • Open: Maintenance and de-escalation pathway
                                Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                            • Conversion to resectability
                              Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                              • Open: Metastasis-directed therapy pathway
                                Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                      • NO — MSS / pMMR
                        • Fit for combination therapy?
                          Can the patient tolerate standard combination systemic therapy? Assess: - ECOG performance status. - Frailty and comorbidity burden. - Renal, hepatic, and marrow function. - Baseline neuropathy. - Prior treatment exposure. - Nutrition. - Cognition and social support. - Patient goals and willingness to accept toxicity. NO: - Route to adapted lower-intensity therapy. YES: - Proceed to BRAF V600E assessment.
                          • NO — FRAIL / MAJOR COMORBIDITY
                            • Adapted lower-intensity therapy
                              Use a tolerable fluoropyrimidine-based or otherwise individualized lower-intensity regimen, with biologic therapy when clinically appropriate. Potential approaches: - Fluoropyrimidine monotherapy. - Fluoropyrimidine + bevacizumab. - Dose-reduced doublet chemotherapy in selected patients. - Anti-EGFR monotherapy or reduced-intensity anti-EGFR-based therapy in highly selected RAS/BRAF wild-type, left-sided disease when chemotherapy is unsuitable. - Best supportive care when treatment burden outweighs expected benefit. Selection should consider: - Frailty and geriatric assessment. - Renal function and suitability for capecitabine. - DPD deficiency testing where standard locally. - Baseline neuropathy. - Bleeding, thrombotic, wound-healing, and gastrointestinal-perforation risk before bevacizumab. - Skin toxicity and electrolyte monitoring before anti-EGFR therapy. - Patient goals and treatment logistics. Reassess tolerance early and avoid undertreatment solely on chronological age.
                              • Response assessment
                                Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                • Progressive disease or intolerable toxicity
                                  Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                  • Open: Progression and next-line sequencing pathway
                                    Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                • Disease control / no progressive disease
                                  De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                  • Open: Maintenance and de-escalation pathway
                                    Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                • Conversion to resectability
                                  Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                  • Open: Metastasis-directed therapy pathway
                                    Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                          • YES — FIT
                            • BRAF V600E mutation?
                              Is a pathogenic BRAF V600E mutation present? YES: - Route to BRAF V600E-targeted first-line therapy. NO: - Proceed to RAS mutation assessment. If BRAF V600E is present together with MSI-H / dMMR, the MSI-H / dMMR immunotherapy branch generally takes priority in first line, with individualized MDT discussion.
                              • YES — BRAF V600E
                                • BRAF V600E first-line therapy
                                  Use encorafenib + cetuximab + fluorouracil-based chemotherapy where approved, available, and clinically appropriate. Preferred where approved and available: - Encorafenib + cetuximab + fluorouracil-based chemotherapy. Key considerations: - Confirm BRAF V600E with a validated assay. - Confirm MSI/MMR status. - Review fitness for oxaliplatin-based chemotherapy. - Monitor for cetuximab-related dermatologic toxicity, infusion reactions, diarrhea, and hypomagnesemia. - Monitor encorafenib-related gastrointestinal, hepatic, ocular, cardiac, and dermatologic adverse events. - Monitor chemotherapy-related neuropathy, cytopenias, diarrhea, and mucositis. - Reassess for conversion to local therapy when response creates a potentially resectable situation. If the targeted first-line regimen is unavailable: - Use an appropriate chemotherapy + bevacizumab strategy. - Consider FOLFOXIRI + bevacizumab only in selected fit patients. - Prioritize clinical-trial access. If encorafenib + cetuximab was not used first line, preserve it as an established later-line option.
                                  • Response assessment
                                    Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                    • Progressive disease or intolerable toxicity
                                      Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                      • Open: Progression and next-line sequencing pathway
                                        Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                    • Disease control / no progressive disease
                                      De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                      • Open: Maintenance and de-escalation pathway
                                        Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                    • Conversion to resectability
                                      Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                      • Open: Metastasis-directed therapy pathway
                                        Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                              • NO — BRAF WILD-TYPE
                                • RAS mutation?
                                  Is a pathogenic KRAS or NRAS mutation present? YES — RAS-mutant: - Route to chemotherapy + anti-VEGF strategy. - Do not use standard anti-EGFR therapy as first-line treatment. NO — RAS/BRAF wild-type: - Route to primary tumor sidedness.
                                  • YES — RAS-MUTANT
                                    • RAS-mutant first-line therapy
                                      Use doublet chemotherapy + bevacizumab; consider triplet chemotherapy + bevacizumab in selected fit patients. Standard direction: - FOLFOX, CAPOX, or FOLFIRI + bevacizumab. Selected fit patients: - FOLFOXIRI + bevacizumab when maximal response, high tumor burden, or conversion is a major goal. Selection considerations: - Prior oxaliplatin exposure and recurrence interval. - Baseline neuropathy. - Diarrhea risk. - Renal and hepatic function. - Performance status and frailty. - Need for rapid tumor shrinkage. - Bevacizumab-related bleeding, thrombosis, hypertension, proteinuria, wound-healing, and perforation risk. - Planned surgery and appropriate bevacizumab washout interval. Anti-EGFR therapy should not be used as standard first-line treatment in RAS-mutant disease.
                                      • Response assessment
                                        Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                        • Progressive disease or intolerable toxicity
                                          Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                          • Open: Progression and next-line sequencing pathway
                                            Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                        • Disease control / no progressive disease
                                          De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                          • Open: Maintenance and de-escalation pathway
                                            Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                        • Conversion to resectability
                                          Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                          • Open: Metastasis-directed therapy pathway
                                            Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                                  • NO — RAS/BRAF WILD-TYPE
                                    • Primary tumor sidedness?
                                      For RAS/BRAF wild-type disease, is the primary tumor left-sided or right-sided? Left-sided:- Distal transverse colon, descending colon, sigmoid colon, or rectum.- Route to chemotherapy + anti-EGFR. Right-sided:- Cecum, ascending colon, hepatic flexure, or proximal transverse colon.- Route to chemotherapy + bevacizumab as the usual first-line direction. Document primary tumor location clearly. Sidedness is a treatment-selection factor only after confirming RAS/BRAF wild-type status.
                                      • Left-sided RAS/BRAF wild-type therapy
                                        Use doublet chemotherapy + cetuximab or panitumumab, particularly when depth of response or conversion is important. Preferred direction: - FOLFOX or FOLFIRI + cetuximab or panitumumab. Best fit: - Left-sided primary. - Extended RAS wild-type. - BRAF wild-type. - Fit for combination therapy. - Need for response depth, tumor shrinkage, or conversion. Monitoring: - Acneiform rash. - Paronychia. - Diarrhea. - Mucositis. - Hypomagnesemia and other electrolyte abnormalities. - Infusion reaction. - Ocular toxicity. - Quality-of-life impact. Clinical notes: - Consider prophylactic skin care according to local practice. - Avoid anti-EGFR therapy if a RAS mutation is present. - HER2 amplification may indicate reduced anti-EGFR sensitivity and supports later HER2-directed planning. - Bevacizumab-based therapy remains an alternative when anti-EGFR is unsuitable or not preferred.
                                        • Response assessment
                                          Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                          • Progressive disease or intolerable toxicity
                                            Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                            • Open: Progression and next-line sequencing pathway
                                              Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                          • Disease control / no progressive disease
                                            De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                            • Open: Maintenance and de-escalation pathway
                                              Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                          • Conversion to resectability
                                            Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                            • Open: Metastasis-directed therapy pathway
                                              Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                                      • Right-sided RAS/BRAF wild-type therapy
                                        Use doublet chemotherapy + bevacizumab as the usual first-line direction. Preferred direction: - FOLFOX, CAPOX, or FOLFIRI + bevacizumab. Selected fit patients: - Consider FOLFOXIRI + bevacizumab when high burden, symptomatic disease, or conversion is a major goal. Clinical notes: - Anti-EGFR therapy is generally not preferred in first-line right-sided disease. - An anti-EGFR-based strategy may be discussed only in highly selected cases when maximal shrinkage is required and alternative options are unsuitable. - Confirm that the tumor is RAS and BRAF wild-type. - Monitor bevacizumab-related hypertension, bleeding, thrombosis, proteinuria, impaired wound healing, and gastrointestinal perforation risk.
                                        • Response assessment
                                          Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                          • Progressive disease or intolerable toxicity
                                            Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                            • Open: Progression and next-line sequencing pathway
                                              Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                          • Disease control / no progressive disease
                                            De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                            • Open: Maintenance and de-escalation pathway
                                              Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                          • Conversion to resectability
                                            Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                            • Open: Metastasis-directed therapy pathway
                                              Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
            • BORDERLINE RESECTABLE / CONVERSION INTENT
              • Biomarker-driven conversion therapy
                Select the most active tolerable regimen according to molecular profile, sidedness, disease distribution, patient fitness, and the goal of maximal tumor shrinkage. For borderline resectable disease, choose systemic therapy with an explicit conversion goal. Preferred direction by biology: MSI-H / dMMR: - Use checkpoint inhibitor-based therapy when clinically appropriate. - Discuss response kinetics and timing of reassessment in MDT. BRAF V600E: - Use encorafenib + cetuximab + fluorouracil-based chemotherapy where approved and available. RAS/BRAF wild-type, left-sided: - Doublet chemotherapy + anti-EGFR is generally favored when maximal response depth is important. RAS-mutant or right-sided RAS/BRAF wild-type: - Doublet chemotherapy + bevacizumab. - Consider FOLFOXIRI + bevacizumab in selected fit patients when maximal response is required. Implementation: - Establish measurable baseline disease. - Define the local-treatment target before starting therapy. - Reassess radiographically approximately every 2 months or after the planned initial treatment interval. - Return to MDT early; do not continue conversion therapy indefinitely after resectability has been achieved. - Balance tumor shrinkage against cumulative neuropathy, marrow toxicity, liver injury, and surgical timing.
                • Converted to resectable / local-therapy candidate
                  Proceed to MDT-planned local therapy when complete local disease control becomes feasible. When conversion is achieved: - Confirm resectability or suitability for ablation/SBRT in MDT. - Re-stage all known disease before local treatment. - Define timing of surgery relative to chemotherapy and biologic therapy. - Allow appropriate interval after anti-VEGF therapy before major surgery. - Review chemotherapy-associated liver injury and cumulative toxicity. - Plan treatment of the primary tumor and metastatic sites. - Aim for complete local control of all active disease. - Reassess postoperative systemic therapy according to prior treatment duration, response, pathology, toxicity, and recurrence risk.
                  • First-line systemic therapy selection
                    Select first-line therapy sequentially according to MSI/MMR status, fitness, BRAF V600E, RAS status, primary tumor sidedness, treatment intent, and urgency of response. Use the following sequential decision order: 1. MSI-H / dMMR? 2. If MSS / pMMR: fit for combination therapy? 3. If fit: BRAF V600E mutation? 4. If BRAF wild-type: RAS mutation? 5. If RAS/BRAF wild-type: primary tumor sidedness? Do not treat frailty, high tumor burden, sidedness, and molecular alterations as equivalent parallel categories. Regulatory approval and access vary by country. Treatment selection should incorporate local approvals, reimbursement, patient preference, toxicity, and clinical-trial availability.
                    • MSI-H / dMMR?
                      Is the metastatic colorectal cancer microsatellite instability-high or mismatch repair deficient? Confirm MSI-H / dMMR using validated testing. YES: - Route to first-line checkpoint inhibitor-based therapy. NO — MSS / pMMR: - Route to fitness assessment and molecularly directed chemotherapy/biologic selection. PD-L1 expression is not required for treatment selection in MSI-H / dMMR colorectal cancer.
                      • YES — MSI-H / dMMR
                        • MSI-H / dMMR first-line therapy
                          Use nivolumab + ipilimumab or pembrolizumab according to approval, availability, immune-risk profile, disease context, and patient preference. First-line options: - Nivolumab + ipilimumab. - Pembrolizumab. Selection considerations: - Regulatory availability. - Need for combination versus single-agent immunotherapy. - Autoimmune disease. - Solid-organ transplant. - Prior immune-related adverse event. - Performance status and comorbidities. - Patient preference and infusion burden. - Toxicity profile. - Disease tempo and need for rapid clinical control. Before treatment: - Document baseline symptoms and organ function. - Review autoimmune, transplant, infectious, endocrine, pulmonary, hepatic, renal, neurologic, and cardiac history. - Counsel regarding immune-mediated toxicities. During therapy: - Monitor for colitis, hepatitis, pneumonitis, endocrinopathies, nephritis, dermatologic toxicity, neurologic toxicity, myocarditis, and infusion reactions. - Reassess clinically and radiographically. - Confirm apparent early progression when pseudoprogression is clinically plausible and the patient remains stable. Checkpoint inhibitor therapy should not be selected based on PD-L1 expression.
                          • Response assessment
                            Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                            • Progressive disease or intolerable toxicity
                              Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                              • Open: Progression and next-line sequencing pathway
                                Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                            • Disease control / no progressive disease
                              De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                              • Open: Maintenance and de-escalation pathway
                                Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                            • Conversion to resectability
                              Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                              • Open: Metastasis-directed therapy pathway
                                Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                      • NO — MSS / pMMR
                        • Fit for combination therapy?
                          Can the patient tolerate standard combination systemic therapy? Assess: - ECOG performance status. - Frailty and comorbidity burden. - Renal, hepatic, and marrow function. - Baseline neuropathy. - Prior treatment exposure. - Nutrition. - Cognition and social support. - Patient goals and willingness to accept toxicity. NO: - Route to adapted lower-intensity therapy. YES: - Proceed to BRAF V600E assessment.
                          • NO — FRAIL / MAJOR COMORBIDITY
                            • Adapted lower-intensity therapy
                              Use a tolerable fluoropyrimidine-based or otherwise individualized lower-intensity regimen, with biologic therapy when clinically appropriate. Potential approaches: - Fluoropyrimidine monotherapy. - Fluoropyrimidine + bevacizumab. - Dose-reduced doublet chemotherapy in selected patients. - Anti-EGFR monotherapy or reduced-intensity anti-EGFR-based therapy in highly selected RAS/BRAF wild-type, left-sided disease when chemotherapy is unsuitable. - Best supportive care when treatment burden outweighs expected benefit. Selection should consider: - Frailty and geriatric assessment. - Renal function and suitability for capecitabine. - DPD deficiency testing where standard locally. - Baseline neuropathy. - Bleeding, thrombotic, wound-healing, and gastrointestinal-perforation risk before bevacizumab. - Skin toxicity and electrolyte monitoring before anti-EGFR therapy. - Patient goals and treatment logistics. Reassess tolerance early and avoid undertreatment solely on chronological age.
                              • Response assessment
                                Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                • Progressive disease or intolerable toxicity
                                  Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                  • Open: Progression and next-line sequencing pathway
                                    Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                • Disease control / no progressive disease
                                  De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                  • Open: Maintenance and de-escalation pathway
                                    Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                • Conversion to resectability
                                  Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                  • Open: Metastasis-directed therapy pathway
                                    Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                          • YES — FIT
                            • BRAF V600E mutation?
                              Is a pathogenic BRAF V600E mutation present? YES: - Route to BRAF V600E-targeted first-line therapy. NO: - Proceed to RAS mutation assessment. If BRAF V600E is present together with MSI-H / dMMR, the MSI-H / dMMR immunotherapy branch generally takes priority in first line, with individualized MDT discussion.
                              • YES — BRAF V600E
                                • BRAF V600E first-line therapy
                                  Use encorafenib + cetuximab + fluorouracil-based chemotherapy where approved, available, and clinically appropriate. Preferred where approved and available: - Encorafenib + cetuximab + fluorouracil-based chemotherapy. Key considerations: - Confirm BRAF V600E with a validated assay. - Confirm MSI/MMR status. - Review fitness for oxaliplatin-based chemotherapy. - Monitor for cetuximab-related dermatologic toxicity, infusion reactions, diarrhea, and hypomagnesemia. - Monitor encorafenib-related gastrointestinal, hepatic, ocular, cardiac, and dermatologic adverse events. - Monitor chemotherapy-related neuropathy, cytopenias, diarrhea, and mucositis. - Reassess for conversion to local therapy when response creates a potentially resectable situation. If the targeted first-line regimen is unavailable: - Use an appropriate chemotherapy + bevacizumab strategy. - Consider FOLFOXIRI + bevacizumab only in selected fit patients. - Prioritize clinical-trial access. If encorafenib + cetuximab was not used first line, preserve it as an established later-line option.
                                  • Response assessment
                                    Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                    • Progressive disease or intolerable toxicity
                                      Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                      • Open: Progression and next-line sequencing pathway
                                        Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                    • Disease control / no progressive disease
                                      De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                      • Open: Maintenance and de-escalation pathway
                                        Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                    • Conversion to resectability
                                      Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                      • Open: Metastasis-directed therapy pathway
                                        Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                              • NO — BRAF WILD-TYPE
                                • RAS mutation?
                                  Is a pathogenic KRAS or NRAS mutation present? YES — RAS-mutant: - Route to chemotherapy + anti-VEGF strategy. - Do not use standard anti-EGFR therapy as first-line treatment. NO — RAS/BRAF wild-type: - Route to primary tumor sidedness.
                                  • YES — RAS-MUTANT
                                    • RAS-mutant first-line therapy
                                      Use doublet chemotherapy + bevacizumab; consider triplet chemotherapy + bevacizumab in selected fit patients. Standard direction: - FOLFOX, CAPOX, or FOLFIRI + bevacizumab. Selected fit patients: - FOLFOXIRI + bevacizumab when maximal response, high tumor burden, or conversion is a major goal. Selection considerations: - Prior oxaliplatin exposure and recurrence interval. - Baseline neuropathy. - Diarrhea risk. - Renal and hepatic function. - Performance status and frailty. - Need for rapid tumor shrinkage. - Bevacizumab-related bleeding, thrombosis, hypertension, proteinuria, wound-healing, and perforation risk. - Planned surgery and appropriate bevacizumab washout interval. Anti-EGFR therapy should not be used as standard first-line treatment in RAS-mutant disease.
                                      • Response assessment
                                        Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                        • Progressive disease or intolerable toxicity
                                          Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                          • Open: Progression and next-line sequencing pathway
                                            Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                        • Disease control / no progressive disease
                                          De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                          • Open: Maintenance and de-escalation pathway
                                            Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                        • Conversion to resectability
                                          Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                          • Open: Metastasis-directed therapy pathway
                                            Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                                  • NO — RAS/BRAF WILD-TYPE
                                    • Primary tumor sidedness?
                                      For RAS/BRAF wild-type disease, is the primary tumor left-sided or right-sided? Left-sided:- Distal transverse colon, descending colon, sigmoid colon, or rectum.- Route to chemotherapy + anti-EGFR. Right-sided:- Cecum, ascending colon, hepatic flexure, or proximal transverse colon.- Route to chemotherapy + bevacizumab as the usual first-line direction. Document primary tumor location clearly. Sidedness is a treatment-selection factor only after confirming RAS/BRAF wild-type status.
                                      • Left-sided RAS/BRAF wild-type therapy
                                        Use doublet chemotherapy + cetuximab or panitumumab, particularly when depth of response or conversion is important. Preferred direction: - FOLFOX or FOLFIRI + cetuximab or panitumumab. Best fit: - Left-sided primary. - Extended RAS wild-type. - BRAF wild-type. - Fit for combination therapy. - Need for response depth, tumor shrinkage, or conversion. Monitoring: - Acneiform rash. - Paronychia. - Diarrhea. - Mucositis. - Hypomagnesemia and other electrolyte abnormalities. - Infusion reaction. - Ocular toxicity. - Quality-of-life impact. Clinical notes: - Consider prophylactic skin care according to local practice. - Avoid anti-EGFR therapy if a RAS mutation is present. - HER2 amplification may indicate reduced anti-EGFR sensitivity and supports later HER2-directed planning. - Bevacizumab-based therapy remains an alternative when anti-EGFR is unsuitable or not preferred.
                                        • Response assessment
                                          Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                          • Progressive disease or intolerable toxicity
                                            Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                            • Open: Progression and next-line sequencing pathway
                                              Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                          • Disease control / no progressive disease
                                            De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                            • Open: Maintenance and de-escalation pathway
                                              Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                          • Conversion to resectability
                                            Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                            • Open: Metastasis-directed therapy pathway
                                              Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                                      • Right-sided RAS/BRAF wild-type therapy
                                        Use doublet chemotherapy + bevacizumab as the usual first-line direction. Preferred direction: - FOLFOX, CAPOX, or FOLFIRI + bevacizumab. Selected fit patients: - Consider FOLFOXIRI + bevacizumab when high burden, symptomatic disease, or conversion is a major goal. Clinical notes: - Anti-EGFR therapy is generally not preferred in first-line right-sided disease. - An anti-EGFR-based strategy may be discussed only in highly selected cases when maximal shrinkage is required and alternative options are unsuitable. - Confirm that the tumor is RAS and BRAF wild-type. - Monitor bevacizumab-related hypertension, bleeding, thrombosis, proteinuria, impaired wound healing, and gastrointestinal perforation risk.
                                        • Response assessment
                                          Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                          • Progressive disease or intolerable toxicity
                                            Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                            • Open: Progression and next-line sequencing pathway
                                              Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                          • Disease control / no progressive disease
                                            De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                            • Open: Maintenance and de-escalation pathway
                                              Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                          • Conversion to resectability
                                            Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                            • Open: Metastasis-directed therapy pathway
                                              Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                • Not convertible / progressive disease
                  Redirect to the unresectable systemic-treatment pathway when conversion is not achieved or disease progresses. If the disease remains unresectable or progresses: - Confirm progression and exclude inadequate exposure, adherence issues, or treatment interruption. - Reassess molecular profile and prior therapy. - Reassess symptoms, performance status, organ function, and treatment goals. - Determine whether isolated progression is amenable to local therapy. - Redirect to biomarker-driven systemic treatment for unresectable disease. - Consider clinical trial participation. - Integrate supportive and palliative care early.
                  • Patient fitness and urgency of response
                    Can the patient tolerate combination therapy, and is rapid tumor shrinkage required? Assess: Fitness: - ECOG performance status. - Frailty and geriatric vulnerabilities. - Renal, hepatic, marrow, and cardiac function. - Baseline neuropathy. - Nutritional status. - Prior treatment toxicity. - Ability to tolerate doublet or triplet chemotherapy. Urgency: - Symptomatic bulky disease. - Threatened organ function. - Rapidly progressive disease. - High tumor burden. - Need for conversion to local therapy. - Obstruction, bleeding, or severe pain. Categories: - Frail / major comorbidities: use adapted lower-intensity therapy. - Fit for combination therapy: proceed through molecularly defined treatment selection. - Fit with high-burden or conversion intent: consider the most active tolerable regimen based on molecular subgroup.
                    • First-line systemic therapy selection
                      Select first-line therapy sequentially according to MSI/MMR status, fitness, BRAF V600E, RAS status, primary tumor sidedness, treatment intent, and urgency of response. Use the following sequential decision order: 1. MSI-H / dMMR? 2. If MSS / pMMR: fit for combination therapy? 3. If fit: BRAF V600E mutation? 4. If BRAF wild-type: RAS mutation? 5. If RAS/BRAF wild-type: primary tumor sidedness? Do not treat frailty, high tumor burden, sidedness, and molecular alterations as equivalent parallel categories. Regulatory approval and access vary by country. Treatment selection should incorporate local approvals, reimbursement, patient preference, toxicity, and clinical-trial availability.
                      • MSI-H / dMMR?
                        Is the metastatic colorectal cancer microsatellite instability-high or mismatch repair deficient? Confirm MSI-H / dMMR using validated testing. YES: - Route to first-line checkpoint inhibitor-based therapy. NO — MSS / pMMR: - Route to fitness assessment and molecularly directed chemotherapy/biologic selection. PD-L1 expression is not required for treatment selection in MSI-H / dMMR colorectal cancer.
                        • YES — MSI-H / dMMR
                          • MSI-H / dMMR first-line therapy
                            Use nivolumab + ipilimumab or pembrolizumab according to approval, availability, immune-risk profile, disease context, and patient preference. First-line options: - Nivolumab + ipilimumab. - Pembrolizumab. Selection considerations: - Regulatory availability. - Need for combination versus single-agent immunotherapy. - Autoimmune disease. - Solid-organ transplant. - Prior immune-related adverse event. - Performance status and comorbidities. - Patient preference and infusion burden. - Toxicity profile. - Disease tempo and need for rapid clinical control. Before treatment: - Document baseline symptoms and organ function. - Review autoimmune, transplant, infectious, endocrine, pulmonary, hepatic, renal, neurologic, and cardiac history. - Counsel regarding immune-mediated toxicities. During therapy: - Monitor for colitis, hepatitis, pneumonitis, endocrinopathies, nephritis, dermatologic toxicity, neurologic toxicity, myocarditis, and infusion reactions. - Reassess clinically and radiographically. - Confirm apparent early progression when pseudoprogression is clinically plausible and the patient remains stable. Checkpoint inhibitor therapy should not be selected based on PD-L1 expression.
                            • Response assessment
                              Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                              • Progressive disease or intolerable toxicity
                                Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                • Open: Progression and next-line sequencing pathway
                                  Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                              • Disease control / no progressive disease
                                De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                • Open: Maintenance and de-escalation pathway
                                  Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                              • Conversion to resectability
                                Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                • Open: Metastasis-directed therapy pathway
                                  Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                        • NO — MSS / pMMR
                          • Fit for combination therapy?
                            Can the patient tolerate standard combination systemic therapy? Assess: - ECOG performance status. - Frailty and comorbidity burden. - Renal, hepatic, and marrow function. - Baseline neuropathy. - Prior treatment exposure. - Nutrition. - Cognition and social support. - Patient goals and willingness to accept toxicity. NO: - Route to adapted lower-intensity therapy. YES: - Proceed to BRAF V600E assessment.
                            • NO — FRAIL / MAJOR COMORBIDITY
                              • Adapted lower-intensity therapy
                                Use a tolerable fluoropyrimidine-based or otherwise individualized lower-intensity regimen, with biologic therapy when clinically appropriate. Potential approaches: - Fluoropyrimidine monotherapy. - Fluoropyrimidine + bevacizumab. - Dose-reduced doublet chemotherapy in selected patients. - Anti-EGFR monotherapy or reduced-intensity anti-EGFR-based therapy in highly selected RAS/BRAF wild-type, left-sided disease when chemotherapy is unsuitable. - Best supportive care when treatment burden outweighs expected benefit. Selection should consider: - Frailty and geriatric assessment. - Renal function and suitability for capecitabine. - DPD deficiency testing where standard locally. - Baseline neuropathy. - Bleeding, thrombotic, wound-healing, and gastrointestinal-perforation risk before bevacizumab. - Skin toxicity and electrolyte monitoring before anti-EGFR therapy. - Patient goals and treatment logistics. Reassess tolerance early and avoid undertreatment solely on chronological age.
                                • Response assessment
                                  Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                  • Progressive disease or intolerable toxicity
                                    Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                    • Open: Progression and next-line sequencing pathway
                                      Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                  • Disease control / no progressive disease
                                    De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                    • Open: Maintenance and de-escalation pathway
                                      Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                  • Conversion to resectability
                                    Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                    • Open: Metastasis-directed therapy pathway
                                      Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                            • YES — FIT
                              • BRAF V600E mutation?
                                Is a pathogenic BRAF V600E mutation present? YES: - Route to BRAF V600E-targeted first-line therapy. NO: - Proceed to RAS mutation assessment. If BRAF V600E is present together with MSI-H / dMMR, the MSI-H / dMMR immunotherapy branch generally takes priority in first line, with individualized MDT discussion.
                                • YES — BRAF V600E
                                  • BRAF V600E first-line therapy
                                    Use encorafenib + cetuximab + fluorouracil-based chemotherapy where approved, available, and clinically appropriate. Preferred where approved and available: - Encorafenib + cetuximab + fluorouracil-based chemotherapy. Key considerations: - Confirm BRAF V600E with a validated assay. - Confirm MSI/MMR status. - Review fitness for oxaliplatin-based chemotherapy. - Monitor for cetuximab-related dermatologic toxicity, infusion reactions, diarrhea, and hypomagnesemia. - Monitor encorafenib-related gastrointestinal, hepatic, ocular, cardiac, and dermatologic adverse events. - Monitor chemotherapy-related neuropathy, cytopenias, diarrhea, and mucositis. - Reassess for conversion to local therapy when response creates a potentially resectable situation. If the targeted first-line regimen is unavailable: - Use an appropriate chemotherapy + bevacizumab strategy. - Consider FOLFOXIRI + bevacizumab only in selected fit patients. - Prioritize clinical-trial access. If encorafenib + cetuximab was not used first line, preserve it as an established later-line option.
                                    • Response assessment
                                      Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                      • Progressive disease or intolerable toxicity
                                        Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                        • Open: Progression and next-line sequencing pathway
                                          Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                      • Disease control / no progressive disease
                                        De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                        • Open: Maintenance and de-escalation pathway
                                          Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                      • Conversion to resectability
                                        Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                        • Open: Metastasis-directed therapy pathway
                                          Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                                • NO — BRAF WILD-TYPE
                                  • RAS mutation?
                                    Is a pathogenic KRAS or NRAS mutation present? YES — RAS-mutant: - Route to chemotherapy + anti-VEGF strategy. - Do not use standard anti-EGFR therapy as first-line treatment. NO — RAS/BRAF wild-type: - Route to primary tumor sidedness.
                                    • YES — RAS-MUTANT
                                      • RAS-mutant first-line therapy
                                        Use doublet chemotherapy + bevacizumab; consider triplet chemotherapy + bevacizumab in selected fit patients. Standard direction: - FOLFOX, CAPOX, or FOLFIRI + bevacizumab. Selected fit patients: - FOLFOXIRI + bevacizumab when maximal response, high tumor burden, or conversion is a major goal. Selection considerations: - Prior oxaliplatin exposure and recurrence interval. - Baseline neuropathy. - Diarrhea risk. - Renal and hepatic function. - Performance status and frailty. - Need for rapid tumor shrinkage. - Bevacizumab-related bleeding, thrombosis, hypertension, proteinuria, wound-healing, and perforation risk. - Planned surgery and appropriate bevacizumab washout interval. Anti-EGFR therapy should not be used as standard first-line treatment in RAS-mutant disease.
                                        • Response assessment
                                          Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                          • Progressive disease or intolerable toxicity
                                            Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                            • Open: Progression and next-line sequencing pathway
                                              Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                          • Disease control / no progressive disease
                                            De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                            • Open: Maintenance and de-escalation pathway
                                              Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                          • Conversion to resectability
                                            Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                            • Open: Metastasis-directed therapy pathway
                                              Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                                    • NO — RAS/BRAF WILD-TYPE
                                      • Primary tumor sidedness?
                                        For RAS/BRAF wild-type disease, is the primary tumor left-sided or right-sided? Left-sided:- Distal transverse colon, descending colon, sigmoid colon, or rectum.- Route to chemotherapy + anti-EGFR. Right-sided:- Cecum, ascending colon, hepatic flexure, or proximal transverse colon.- Route to chemotherapy + bevacizumab as the usual first-line direction. Document primary tumor location clearly. Sidedness is a treatment-selection factor only after confirming RAS/BRAF wild-type status.
                                        • Left-sided RAS/BRAF wild-type therapy
                                          Use doublet chemotherapy + cetuximab or panitumumab, particularly when depth of response or conversion is important. Preferred direction: - FOLFOX or FOLFIRI + cetuximab or panitumumab. Best fit: - Left-sided primary. - Extended RAS wild-type. - BRAF wild-type. - Fit for combination therapy. - Need for response depth, tumor shrinkage, or conversion. Monitoring: - Acneiform rash. - Paronychia. - Diarrhea. - Mucositis. - Hypomagnesemia and other electrolyte abnormalities. - Infusion reaction. - Ocular toxicity. - Quality-of-life impact. Clinical notes: - Consider prophylactic skin care according to local practice. - Avoid anti-EGFR therapy if a RAS mutation is present. - HER2 amplification may indicate reduced anti-EGFR sensitivity and supports later HER2-directed planning. - Bevacizumab-based therapy remains an alternative when anti-EGFR is unsuitable or not preferred.
                                          • Response assessment
                                            Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                            • Progressive disease or intolerable toxicity
                                              Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                              • Open: Progression and next-line sequencing pathway
                                                Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                            • Disease control / no progressive disease
                                              De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                              • Open: Maintenance and de-escalation pathway
                                                Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                            • Conversion to resectability
                                              Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                              • Open: Metastasis-directed therapy pathway
                                                Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                                        • Right-sided RAS/BRAF wild-type therapy
                                          Use doublet chemotherapy + bevacizumab as the usual first-line direction. Preferred direction: - FOLFOX, CAPOX, or FOLFIRI + bevacizumab. Selected fit patients: - Consider FOLFOXIRI + bevacizumab when high burden, symptomatic disease, or conversion is a major goal. Clinical notes: - Anti-EGFR therapy is generally not preferred in first-line right-sided disease. - An anti-EGFR-based strategy may be discussed only in highly selected cases when maximal shrinkage is required and alternative options are unsuitable. - Confirm that the tumor is RAS and BRAF wild-type. - Monitor bevacizumab-related hypertension, bleeding, thrombosis, proteinuria, impaired wound healing, and gastrointestinal perforation risk.
                                          • Response assessment
                                            Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                            • Progressive disease or intolerable toxicity
                                              Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                              • Open: Progression and next-line sequencing pathway
                                                Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                            • Disease control / no progressive disease
                                              De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                              • Open: Maintenance and de-escalation pathway
                                                Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                            • Conversion to resectability
                                              Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                              • Open: Metastasis-directed therapy pathway
                                                Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
            • UNRESECTABLE / SYSTEMIC-DISEASE DOMINANT
              • Patient fitness and urgency of response
                Can the patient tolerate combination therapy, and is rapid tumor shrinkage required? Assess: Fitness: - ECOG performance status. - Frailty and geriatric vulnerabilities. - Renal, hepatic, marrow, and cardiac function. - Baseline neuropathy. - Nutritional status. - Prior treatment toxicity. - Ability to tolerate doublet or triplet chemotherapy. Urgency: - Symptomatic bulky disease. - Threatened organ function. - Rapidly progressive disease. - High tumor burden. - Need for conversion to local therapy. - Obstruction, bleeding, or severe pain. Categories: - Frail / major comorbidities: use adapted lower-intensity therapy. - Fit for combination therapy: proceed through molecularly defined treatment selection. - Fit with high-burden or conversion intent: consider the most active tolerable regimen based on molecular subgroup.
                • First-line systemic therapy selection
                  Select first-line therapy sequentially according to MSI/MMR status, fitness, BRAF V600E, RAS status, primary tumor sidedness, treatment intent, and urgency of response. Use the following sequential decision order: 1. MSI-H / dMMR? 2. If MSS / pMMR: fit for combination therapy? 3. If fit: BRAF V600E mutation? 4. If BRAF wild-type: RAS mutation? 5. If RAS/BRAF wild-type: primary tumor sidedness? Do not treat frailty, high tumor burden, sidedness, and molecular alterations as equivalent parallel categories. Regulatory approval and access vary by country. Treatment selection should incorporate local approvals, reimbursement, patient preference, toxicity, and clinical-trial availability.
                  • MSI-H / dMMR?
                    Is the metastatic colorectal cancer microsatellite instability-high or mismatch repair deficient? Confirm MSI-H / dMMR using validated testing. YES: - Route to first-line checkpoint inhibitor-based therapy. NO — MSS / pMMR: - Route to fitness assessment and molecularly directed chemotherapy/biologic selection. PD-L1 expression is not required for treatment selection in MSI-H / dMMR colorectal cancer.
                    • YES — MSI-H / dMMR
                      • MSI-H / dMMR first-line therapy
                        Use nivolumab + ipilimumab or pembrolizumab according to approval, availability, immune-risk profile, disease context, and patient preference. First-line options: - Nivolumab + ipilimumab. - Pembrolizumab. Selection considerations: - Regulatory availability. - Need for combination versus single-agent immunotherapy. - Autoimmune disease. - Solid-organ transplant. - Prior immune-related adverse event. - Performance status and comorbidities. - Patient preference and infusion burden. - Toxicity profile. - Disease tempo and need for rapid clinical control. Before treatment: - Document baseline symptoms and organ function. - Review autoimmune, transplant, infectious, endocrine, pulmonary, hepatic, renal, neurologic, and cardiac history. - Counsel regarding immune-mediated toxicities. During therapy: - Monitor for colitis, hepatitis, pneumonitis, endocrinopathies, nephritis, dermatologic toxicity, neurologic toxicity, myocarditis, and infusion reactions. - Reassess clinically and radiographically. - Confirm apparent early progression when pseudoprogression is clinically plausible and the patient remains stable. Checkpoint inhibitor therapy should not be selected based on PD-L1 expression.
                        • Response assessment
                          Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                          • Progressive disease or intolerable toxicity
                            Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                            • Open: Progression and next-line sequencing pathway
                              Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                          • Disease control / no progressive disease
                            De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                            • Open: Maintenance and de-escalation pathway
                              Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                          • Conversion to resectability
                            Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                            • Open: Metastasis-directed therapy pathway
                              Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                    • NO — MSS / pMMR
                      • Fit for combination therapy?
                        Can the patient tolerate standard combination systemic therapy? Assess: - ECOG performance status. - Frailty and comorbidity burden. - Renal, hepatic, and marrow function. - Baseline neuropathy. - Prior treatment exposure. - Nutrition. - Cognition and social support. - Patient goals and willingness to accept toxicity. NO: - Route to adapted lower-intensity therapy. YES: - Proceed to BRAF V600E assessment.
                        • NO — FRAIL / MAJOR COMORBIDITY
                          • Adapted lower-intensity therapy
                            Use a tolerable fluoropyrimidine-based or otherwise individualized lower-intensity regimen, with biologic therapy when clinically appropriate. Potential approaches: - Fluoropyrimidine monotherapy. - Fluoropyrimidine + bevacizumab. - Dose-reduced doublet chemotherapy in selected patients. - Anti-EGFR monotherapy or reduced-intensity anti-EGFR-based therapy in highly selected RAS/BRAF wild-type, left-sided disease when chemotherapy is unsuitable. - Best supportive care when treatment burden outweighs expected benefit. Selection should consider: - Frailty and geriatric assessment. - Renal function and suitability for capecitabine. - DPD deficiency testing where standard locally. - Baseline neuropathy. - Bleeding, thrombotic, wound-healing, and gastrointestinal-perforation risk before bevacizumab. - Skin toxicity and electrolyte monitoring before anti-EGFR therapy. - Patient goals and treatment logistics. Reassess tolerance early and avoid undertreatment solely on chronological age.
                            • Response assessment
                              Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                              • Progressive disease or intolerable toxicity
                                Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                • Open: Progression and next-line sequencing pathway
                                  Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                              • Disease control / no progressive disease
                                De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                • Open: Maintenance and de-escalation pathway
                                  Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                              • Conversion to resectability
                                Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                • Open: Metastasis-directed therapy pathway
                                  Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                        • YES — FIT
                          • BRAF V600E mutation?
                            Is a pathogenic BRAF V600E mutation present? YES: - Route to BRAF V600E-targeted first-line therapy. NO: - Proceed to RAS mutation assessment. If BRAF V600E is present together with MSI-H / dMMR, the MSI-H / dMMR immunotherapy branch generally takes priority in first line, with individualized MDT discussion.
                            • YES — BRAF V600E
                              • BRAF V600E first-line therapy
                                Use encorafenib + cetuximab + fluorouracil-based chemotherapy where approved, available, and clinically appropriate. Preferred where approved and available: - Encorafenib + cetuximab + fluorouracil-based chemotherapy. Key considerations: - Confirm BRAF V600E with a validated assay. - Confirm MSI/MMR status. - Review fitness for oxaliplatin-based chemotherapy. - Monitor for cetuximab-related dermatologic toxicity, infusion reactions, diarrhea, and hypomagnesemia. - Monitor encorafenib-related gastrointestinal, hepatic, ocular, cardiac, and dermatologic adverse events. - Monitor chemotherapy-related neuropathy, cytopenias, diarrhea, and mucositis. - Reassess for conversion to local therapy when response creates a potentially resectable situation. If the targeted first-line regimen is unavailable: - Use an appropriate chemotherapy + bevacizumab strategy. - Consider FOLFOXIRI + bevacizumab only in selected fit patients. - Prioritize clinical-trial access. If encorafenib + cetuximab was not used first line, preserve it as an established later-line option.
                                • Response assessment
                                  Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                  • Progressive disease or intolerable toxicity
                                    Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                    • Open: Progression and next-line sequencing pathway
                                      Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                  • Disease control / no progressive disease
                                    De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                    • Open: Maintenance and de-escalation pathway
                                      Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                  • Conversion to resectability
                                    Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                    • Open: Metastasis-directed therapy pathway
                                      Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                            • NO — BRAF WILD-TYPE
                              • RAS mutation?
                                Is a pathogenic KRAS or NRAS mutation present? YES — RAS-mutant: - Route to chemotherapy + anti-VEGF strategy. - Do not use standard anti-EGFR therapy as first-line treatment. NO — RAS/BRAF wild-type: - Route to primary tumor sidedness.
                                • YES — RAS-MUTANT
                                  • RAS-mutant first-line therapy
                                    Use doublet chemotherapy + bevacizumab; consider triplet chemotherapy + bevacizumab in selected fit patients. Standard direction: - FOLFOX, CAPOX, or FOLFIRI + bevacizumab. Selected fit patients: - FOLFOXIRI + bevacizumab when maximal response, high tumor burden, or conversion is a major goal. Selection considerations: - Prior oxaliplatin exposure and recurrence interval. - Baseline neuropathy. - Diarrhea risk. - Renal and hepatic function. - Performance status and frailty. - Need for rapid tumor shrinkage. - Bevacizumab-related bleeding, thrombosis, hypertension, proteinuria, wound-healing, and perforation risk. - Planned surgery and appropriate bevacizumab washout interval. Anti-EGFR therapy should not be used as standard first-line treatment in RAS-mutant disease.
                                    • Response assessment
                                      Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                      • Progressive disease or intolerable toxicity
                                        Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                        • Open: Progression and next-line sequencing pathway
                                          Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                      • Disease control / no progressive disease
                                        De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                        • Open: Maintenance and de-escalation pathway
                                          Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                      • Conversion to resectability
                                        Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                        • Open: Metastasis-directed therapy pathway
                                          Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                                • NO — RAS/BRAF WILD-TYPE
                                  • Primary tumor sidedness?
                                    For RAS/BRAF wild-type disease, is the primary tumor left-sided or right-sided? Left-sided:- Distal transverse colon, descending colon, sigmoid colon, or rectum.- Route to chemotherapy + anti-EGFR. Right-sided:- Cecum, ascending colon, hepatic flexure, or proximal transverse colon.- Route to chemotherapy + bevacizumab as the usual first-line direction. Document primary tumor location clearly. Sidedness is a treatment-selection factor only after confirming RAS/BRAF wild-type status.
                                    • Left-sided RAS/BRAF wild-type therapy
                                      Use doublet chemotherapy + cetuximab or panitumumab, particularly when depth of response or conversion is important. Preferred direction: - FOLFOX or FOLFIRI + cetuximab or panitumumab. Best fit: - Left-sided primary. - Extended RAS wild-type. - BRAF wild-type. - Fit for combination therapy. - Need for response depth, tumor shrinkage, or conversion. Monitoring: - Acneiform rash. - Paronychia. - Diarrhea. - Mucositis. - Hypomagnesemia and other electrolyte abnormalities. - Infusion reaction. - Ocular toxicity. - Quality-of-life impact. Clinical notes: - Consider prophylactic skin care according to local practice. - Avoid anti-EGFR therapy if a RAS mutation is present. - HER2 amplification may indicate reduced anti-EGFR sensitivity and supports later HER2-directed planning. - Bevacizumab-based therapy remains an alternative when anti-EGFR is unsuitable or not preferred.
                                      • Response assessment
                                        Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                        • Progressive disease or intolerable toxicity
                                          Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                          • Open: Progression and next-line sequencing pathway
                                            Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                        • Disease control / no progressive disease
                                          De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                          • Open: Maintenance and de-escalation pathway
                                            Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                        • Conversion to resectability
                                          Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                          • Open: Metastasis-directed therapy pathway
                                            Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
                                    • Right-sided RAS/BRAF wild-type therapy
                                      Use doublet chemotherapy + bevacizumab as the usual first-line direction. Preferred direction: - FOLFOX, CAPOX, or FOLFIRI + bevacizumab. Selected fit patients: - Consider FOLFOXIRI + bevacizumab when high burden, symptomatic disease, or conversion is a major goal. Clinical notes: - Anti-EGFR therapy is generally not preferred in first-line right-sided disease. - An anti-EGFR-based strategy may be discussed only in highly selected cases when maximal shrinkage is required and alternative options are unsuitable. - Confirm that the tumor is RAS and BRAF wild-type. - Monitor bevacizumab-related hypertension, bleeding, thrombosis, proteinuria, impaired wound healing, and gastrointestinal perforation risk.
                                      • Response assessment
                                        Assess response, toxicity, symptoms, CEA, and conversion potential approximately every 2–3 months. Assess: - CT or MRI using consistent baseline and follow-up imaging. - Clinical symptoms and functional status. - CEA trend when informative. - Treatment tolerance and cumulative toxicity. - Neuropathy, diarrhea, marrow suppression, dermatologic toxicity, fatigue, hypertension, and organ dysfunction. - Adherence and treatment interruptions. - Potential for surgery, ablation, or SBRT. - Oligoprogression that may be suitable for local treatment. - Patient goals and quality of life. Outgoing pathways: 1. Conversion to resectability. 2. Disease control / no progressive disease. 3. Progressive disease or intolerable toxicity. Return potentially convertible patients to MDT promptly rather than waiting for maximum chemotherapy duration.
                                        • Progressive disease or intolerable toxicity
                                          Confirm progression, reassess molecular and clinical context, and proceed to biomarker-directed second-line therapy. Before changing therapy: - Confirm radiographic or clinical progression. - Distinguish generalized progression from oligoprogression. - Review adherence, dose intensity, treatment interruptions, and toxicity. - Reassess ECOG performance status and goals. - Review prior chemotherapy, biologics, targeted therapy, and immunotherapy. - Repeat tissue or plasma molecular testing when resistance biology may affect selection. - Consider local therapy for isolated progression while continuing otherwise effective systemic therapy. - Integrate supportive and palliative care.
                                          • Open: Progression and next-line sequencing pathway
                                            Proceed to a dedicated pathway incorporating prior treatment exposure, chemotherapy backbone switching, actionable biomarkers, refractory-line therapies, clinical trials, and supportive care. This terminal node redirects the user to a dedicated progression and next-line sequencing pathway. The linked pathway should address: - Confirmation of progression and distinction from oligoprogression. - Switching the chemotherapy backbone according to prior exposure. - Continued or alternative anti-angiogenic therapy when appropriate. - Anti-EGFR therapy for eligible RAS/BRAF wild-type, anti-EGFR-naïve disease. - Encorafenib + cetuximab for BRAF V600E disease when not previously used. - Immunotherapy for MSI-H / dMMR disease when immunotherapy-naïve. - HER2-directed therapy for eligible HER2-positive disease. - KRAS G12C-directed therapy in the approved, previously treated setting. - NTRK or other rare actionable alteration-directed therapy. - Trifluridine/tipiracil + bevacizumab, fruquintinib, or regorafenib in refractory disease. - Clinical trials. - Supportive and palliative care. Repeat tissue or plasma molecular testing may be considered when acquired resistance could alter treatment selection.
                                        • Disease control / no progressive disease
                                          De-escalate to maintenance or treatment break according to induction regimen, toxicity, disease burden, and patient preference. After disease control: Following oxaliplatin + bevacizumab: - De-escalate to fluoropyrimidine + bevacizumab when appropriate. Following oxaliplatin + anti-EGFR: - Consider fluoropyrimidine + anti-EGFR maintenance. - Avoid anti-EGFR monotherapy when a fluoropyrimidine-containing maintenance regimen is tolerated and appropriate. Following FOLFIRI: - Continued FOLFIRI or treatment de-intensification may be considered because irinotecan lacks cumulative neurotoxicity comparable with oxaliplatin. Other options: - Treatment break in selected patients after informed shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. Monitor: - Symptoms, CEA, imaging, toxicity, quality of life, and treatment goals.
                                          • Open: Maintenance and de-escalation pathway
                                            Select maintenance, treatment de-intensification, or a treatment break according to induction regimen, toxicity, disease burden, and patient preference. Dedicated maintenance and de-escalation pathway. The linked pathway should address: - Fluoropyrimidine + bevacizumab after oxaliplatin-based induction with bevacizumab. - Fluoropyrimidine + anti-EGFR after appropriate anti-EGFR-based induction. - Continuation or de-intensification after irinotecan-based therapy. - Oxaliplatin discontinuation when cumulative neuropathy becomes clinically relevant. - Treatment break in selected patients after shared decision-making. - Reintroduction of an effective induction regimen at progression when appropriate. - Monitoring with symptoms, imaging, CEA, toxicity assessment, and quality-of-life review. Maintenance should preserve disease control while reducing cumulative treatment burden.
                                        • Conversion to resectability
                                          Return to MDT and proceed to definitive local therapy when complete local disease control becomes feasible. - Confirm resectability or local-treatment eligibility. - Re-stage all known disease. - Define timing of surgery, ablation, or SBRT. - Plan biologic washout before surgery. - Review cumulative treatment toxicity. - Aim for complete treatment of all active sites. - Reassess postoperative systemic therapy and surveillance.
                                          • Open: Metastasis-directed therapy pathway
                                            Proceed to surgery, ablation, SBRT, or another MDT-selected local-treatment strategy. This terminal node redirects the user to a dedicated metastasis-directed therapy pathway. The linked pathway should address: - Confirmation of technical resectability. - Complete treatment of all active metastatic sites. - Sequencing of systemic therapy and local treatment. - Surgery, thermal ablation, SBRT, or combined local strategies. - Management of the primary tumor when relevant. - Timing after bevacizumab or other systemic therapy. - Assessment of cumulative chemotherapy toxicity. - Post-treatment systemic therapy and surveillance planning. Final treatment selection should be made through multidisciplinary review.
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