Metastatic Colorectal cancer treatment

Pathologic confirmation of CRC is required before chemotherapy for  metastatic CRC (mCRC).

Typically colonoscopy guided biopsy confirms the primary cancer, and biopsy of the liver, lung or lymph nodes confirm metastases.

Diagnostic staging includes CT scans of the chest abdomen and pelvis. 

MRI and PET scans may help distinguish metastasis from benign lesions. 

Bone and central  nervous system metastases are rare and bone scans in brain imaging are unnecessary in asymptomatic patients. 

Serum levels of CEA and CA 19-9 can help monitor treatment response.

All metastatic MCRCs should uncergo molecular profiling.

See ((Molecular profiling in colorectal cancer)).

Standard of care for metastatic colorectal cancer combines cytotoxic chemotherapy with biologic agents.

The three major therapeutic classes of treatment include: cytotoxic agents, angiogenesis inhibitors, and anti-epidermal growth factor receptor antibodies.

All Colorectal tumors should be tested for mismatch repair deficiency via immunohistochemistry or microsatellite instability-high, via polymerase chain reaction to screen for ((Lynch syndrome)).

When metastatic CRC is limited to a few metastatic foci typically involving the liver or lung, revisions may be termed resectable when the primary tumor and all metastasis are amenable to complete surgical removal.

In general, metastatic colorectal cancer, patients are characterized into two groups: mismatch repair – proficient, or microsatellites stable (97%) , and those with disease that is mismatch repair deficient, or microsatellite unstable (3-4%).

Resection of metastatic colorectal cancer achieves long-term cure for less than 20% of metastatic CRC patients.

Systemic therapy is the primary treatment for metastatic CRC. 

Metastatic CRC  remains incurable for most patients. 

Five year survival for metastatic CRC is approximately 14%, but does not reflect recent advances.

Patients with metastatic CRC who  receive chemotherapy with intensive treatment with multiple agents can survive 2-3 years.

The most commonly used regimens for first-line therapy, are FOLFOX, FOLFIRI, and CAPOX:agents include leucovorin, 5FU,, oxaliplatin, Irinotecan, and capecitabine.

for patients with mismatch repair deficient disease program death receptor1 inhibitors are utilized.

Survival in metastatic CRC varies with molecular subtype.

Molecular subtypes can indicate which therapies are and  are not likely to be effective. 

For the 50% of patients with KRAS/NRAS;BRAF  wild-type metastatic CRC, median survival with treatment is approximately 30 months, with survival rates of 80% at one year, 40% at three years and 20% at five years after start a first line chemotherapy.

Median survival is about 19 months for right sided primary tumors and 34 months for left-sided primary tumors, which may be related to the distinct genomics patterns between right and left sided CRCs.

Right sided tumors are more than twice as likely to have MSI-H and more commonly have KRAS sequence variations and BRAF sequence variations compared with left-sided tumors.

Median survival is about 21 months for patients with KRAS sequence variations and 11.7 months for those with BRAF sequence variations.

Patients with MSI-H and MMR-D tumors have a better prognosis than patients with microsattelite stable or MMR-proficient tumors because they respond to immunotherapy agents.

Additional factors that influence metastatic CRC prognosis include previous surgery in chemotherapy, time between adjuvant therapy and development of metastases with shorter time being associated with worse prognosis, comorbid conditions, and frailty.

They are treatment survival for metastatic CRC is typically 6-12 months.

The vast majority of patients with metastatic colorectal cancer will die of their disease.

Patient with a life expectancy of less than six months rarely benefit from systemic chemotherapy. 

For frail patients who cannot tolerate intensive therapy, single agent fluorouracil  or capecitabine survival is 12-18 months with only modest toxicity. 

Multi agent chemotherapy is necessary to attain survival beyond 18 months.

Trails comparing FOLFOX regimen to see CAPOX have reported no associated differences in overall survival for metastatic CRC.

No survival differences were noted between the CAPIRI and FOLFIRI regimens, as well.

Patients should undergo restaging every 2 to 3 months with CT scans of the chest, abdomin, and pelvis.

Patients demonstrating tumor regression continue therapy, and those with disease progression are switched to next line therapies.

Studies have demonstrated that bevacizumab plus FOLFOX or FOLFIRI is associated with improved progression free survival, but not overall survival.

Bevacizumab should not be given to patients who have recently undergone surgery because it has associated the delayed wound healing and increased rates of bowel perforation, arterial thrombosis, and bleeding.

The EGFR inhibitors  cetuximab and panitumumab are only effective in patients with KRAS/NRAS wild type metastatic colorectal cancer.

They extend survival by less than two months when utilized alone. 

Typically they are combined with multiple chemotherapeutic agents, and they provide survival by approximately four months when wild type populations are confirmed.

Presently guidelines recommend first line EGFR inhibitors be used with chemotherapy only for KRAS/NRAS wild type, left-sided metastatic CRC.

Among patients with RAS wild type metastatic colorectal cancer, adding panitumumab compared with bevacizumab, to standard first line, chemotherapy significantly improved overall survival in those with left-sided tumors, and in the overall population.

Presently there are six different classes of agents to treat metastatic colorectal cancer: three classes of cytotoxic agents and three classes of biologic agents.

The three classes of cytotoxic agents include a fluoropyrmidines, that is 5-FU and the oral fluropyridine analog capecitabine, topoisomerase I inhibitors, irinotecan), and platinum containing compounds, oxaliplatin.

Tumor response is highest in the first line setting, ranging from approximately 30%-60% in certain groups, and then the second line setting tumor response decreases to 5-10%.

Combination regimens that consist of protracted infusions of 5-FU modulated by leucovorin and oxaliplatin or by leucovorin and irinotecan are the backbone of agents.

Targeted biologic treatments for metastatic colorectal cancer fall into three groups: inhibitors of vascular endothelial growth factor, including bevacizumab and aflibercept, monoclonal antibodies against epidermal growth factor receptor on the surface of tumor cells, including cetuximab and panitumubab, , and a small molecule inhibitor of intracellular kinase involved in various signaling cascades, regorafenib.

Three anti-angiogenic compounds-Bevacizumab, afibercept, and ramucirumab

3% of people have an autosomal recessive inheritance a deficiency of dihydropyridine dehydrogenase, an enzyme required for catabolism of fluorouracil and capecitabine.

For MSI-high/MMR-D  metastatic CRC is responsive to immune checkpoint inhibitors.

Immunotherapy in patients with mismatch repair-deficient disease have a relatively high response rate which are often durable: Up to 10% of patients have a complete clinical response.

Most metastatic CRC Patients respond the first line therapy with FOLFOX or FOLFIRI  for several months but then have stable disease.

Continue chemotherapy in the above ages causes fatigue, chronic diarrhea, or adverse events in more than 80% of patients.

Maintenance therapy with fluorouracil plus leucovorin May be  continued with without biologics such as bevacizumab, cetuximab, amd panitumumab.

Alternatively,  treatment can be discontinued temporarily until tumor progression occurs.

With progressive disease the selection of a second line regimen requires consideration of prior chemotherapy agents, timing of progression after first line therapy, molecular testing results, tolerance of previous chemotherapy, and patient preference.

Patients with BRAF, MSI, KRAS/NRAS, EGFR lesions can be treated with targeted agents with or without chemotherapy.

HER2 positive targeted  therapies with trastuzumab,  pertuzumab, or trastuzumab Deruxetan trastuzumab can benefit such patients.

MSI-H/MMR metastatic colorectal tumors are generally less responsive to conventional cytotoxic chemotherapy.

Prior to immunotherapy the median overall survival for such lesions range from 10.1 to 17.3 months. 

Immunotherapy has improved outcomes for these patients resulting in DNA replication errors, frameshift mutations, production of abnormal proteins or neo antigens that are  immune system targets.

Agents approved for treatment of MSI-H/MMR-D metastatic colorectal cancer includes Pembrolizumab, Nivolumab, and ipilimumab.

For MSI-H/MM-D metastatic CRC, sustained responses of greater than one year can be achieved.

Alkylating agents

Oxaliplatin Eloxatin5mg/mL solution for IV infusion after dilution Day 1: 85mg/m² + leucovorin, followed by 5–FU.

Give by IV infusion every two weeks.


Capecitabine Xeloda 150mg, 500mg tabs 1250mg/m² twice daily for 2 weeks on and 1 week off, for a total of 8 cycles

Fluorouracil 50mg/mL soln for IV inj 12mg/kg once daily for 4 successive days; max 800mg/day.

Folic acid derivatives

Leucovorin 100mg, 350mg lyophilized pwd for IV or IM inj reconstitution, 200mg/m² by slow IV inj over a minimum of 3min followed by 5–fluorouracil (370mg/m²); or 20mg/m² IV followed by 5 fluorouracil (425mg/m²); both regimens: daily for 5 days, may be repeated at 4 week intervals for 2 courses and then repeated at 4–5 week intervals

Levoleucovorin Fusilev 50mg/vial lyophilized powder for IV inj after reconstitution 100mg/m² by slow IV inj over a minimum of 3min, followed by 5-FU at 370mg/m² by IV inj; or 10mg/m² by IV inj followed by 5-FU at 425mg/m² by IV inj.

Fusion Protein

Ziv-aflibercept Zaltrap 25mg/mL soln for IV infusion after dilution 4mg/kg as an IV infusion over 1 hour every 2 weeks; continue until disease progression or unacceptable toxicity

Monoclonal antibodies

Bevacizumab Avastin 100mg, 400mg soln for IV infusion after dilution 5mg/kg (with bolus–IFL) or 10mg/kg (with FOLFOX–4) once every 14 days until disease progression detected.

1st infusion over 90min, 2nd infusion over 60min, subsequent infusion over 30min.

Cetuximab Erbitux 100mg, 200mg soln for IV infusion Loading dose: 400mg/m² once over 2 hours; then 250mg/m² once weekly over 1 hour

Panitumumab Vectibix 20mg/mL soln for IV infusion after dilution 6mg/kg as IV inf over 60min once every 14 days until disease progression detected.

Dose >100mg over 90min.

Topoisomerase inhibitors

Irinotecan Camptosar 20mg/mL soln for IV infusion after dilution

Combination therapy (with 5-FU and leucovorin): 125mg/m² on days 1, 8, 15, 22; or, 180mg/m² on days 1, 15, 29; both: give every 6 weeks.

Monotherapy: 125mg/m² on days 1, 8, 15, 22, then 2–week rest; or, 350mg/m² once every 3 weeks.

The recommended dose for regorafenib is 160 mg daily, taken in four 40-mg tablets, for the first 21 days of each 28-day cycle.

Trifluridine, tipracil:15mg/6.14 taken within one hour of a.m. and p.m. meals: Initially 35 mg meter squared twice daily on days 1 through 5 and 8 through 12 of each 28 day cycle until disease progression or unacceptable toxicity.

Maximum dose 80 mg based on trifluridine component.

Immunotherapy has improved outcomes for patients with MSI-H/MMR-D metastatic CRC but has not been effective in microsatellite stable/MMR proficient tumors which comprise 95% of metastatic colorectal cancers.

ERBB2 (HER2) is involved in cell growth and differentiation and its amplification contributes to the growth of multiple cancer cell types.

Patients with ERBB 2 amplified metastatic colon rectal cancers should be considered for targeted therapy.

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