Metastatic colorectal cancer
Sites of metastases:
Presentation: asymptomatic, obstructive symptoms, bleeding, perforation
Sidedness of primary:
Mucinous subtype: Yes/No: 22%–40% of cases of Lynch syndrome-related CRC were mucinous colorectal adenocarcinoma, suggesting a close relationship between Lynch syndrome and the mucinous occurrence in CRC
Mismatch repair status:
Family history:
Genetic testing: meeting NCCN criteria, tested
NGS results:
a. RAS: KRAS and NRAS for all
b. BRAF: for all patients
c. HER 2 ( by IHC)
d. MSI-status: all patients. The absence of staining on IHC for the 4 MMR proteins is abnormal. Next step IHC for MLH mutation and BRAF V600E. If the latter positive, likely somatic. However, if strong family hx, proceed with genetics referral.
e. CPS score/PDL1:
f. TMB:
g. NTRK mutation status:
h. Other:
Interactive tool
Decision making:
Diagnosis: Stage 4 adenocarcinoma of the colon with hepatic and * mets
Performance status:
Age-appropriate considerations: Geriatric evaluation/ fertility considerations
Comorbid conditions:
- Hypertension: anti VEGF bevacizumab, ramucirumab, and ziv-aflibercept can cause hypertension
- DM
- CAD
- VTE
- On anticoagulants or antiplatelets: bleeding in those with liver disease, and VEGF agents periop if used less than 6-8 weeks before or after surgery. grade 3 or 4 hypertension ranged from 5% to 18%
- Pre-existing neuropathy
- Thyroid disease
- prior autoimmune conditions, prior cancer
- Organ transplant?
- Organ function assessment: Liver and kidney function based on labs, prior disease
irinotecan should be used with caution and at a decreased dosage in patients with elevated serum bilirubin levels (> 2 mg/dL)
Additional testing recommended:
1. Imaging
2. Mutational testing
3. NGS panel
4. Labs including CEA/ct DNA
Treatment recommendations:
1. MSI high disease: 5% of patients have this at presentation.
The 2 Rx approved are: ipi low dose with nivo, and Keytruda single agent
Single agent pembrolizumab:
The FDA’s approval for this indication was based on the results of one multicenter, international, open-label, active-controlled, randomized trial that compared Keytruda with chemotherapy treatment in 307 patients with MSI-H or dMMR metastatic colorectal cancer. Median PFS was 16.5 months in the Keytruda group and 8.2 months in the standard of care group. A longer-term analysis is needed to assess for an effect on survival.
phase III KEYNOTE-177 trial showed, for the first time, that upfront treatment with immunotherapy (pembrolizumab) could improve progression-free survival vs chemotherapy as a first-line treatment of microsatellite instability–high.
Second choice" nivo 3 mg plus low dose ipi 1 mg/kg q 2 weeks. Based on CheckMate 142. Phase 2 trial. Important to note that the FDA approval for this combo was in 2nd line. 75% percent of patients at 2 yr PFS. Approval based on ORR and DOR. CR rates were low.
2. Oligometastatic disease: Addition of Avastin to FOLFIRI: if the goal is to covert to resectable disease, Avastin improves resectability with IRI not oxali. Evaluate resectability every 2 months and resect as soon as the patient is operable. Periop chemo improves DFS HR 0.70 but not OS. Category 2B NCCN for total of 6 months perioperative chemo.
3. Synchronous widely metastatic MSI-stable disease, RAS, BRAF WT: FOLFOX or FOLFIRI with a biologic agent. Cetuximab with FOLFIRI only if left sided and WT RAS/RAF.
4. BRAF mutant: MSI stable. FOLFOXIRI can be considered in good PS, R sided disease or BRAF mutant disease, high tumor burden followed by Capecitabine with Avastin maintenance or 5FU Avastin maintenance.
Second-line treatment:
1. BRAF mutated: got FOLFOX front line and then maintenance, consider encorafenib with cetuximab.
2. NTRK fusion: Fusion is different from mutation. 2 drugs approved. Larotrectinib and entrectinib. Based on basket study looking at small number of patients with NTRK fusion positive disease. Incidence in colon ca is < 1%.
In CRC, NTRK fusions are associated with female gender, elderly age, right sidedness, lymph node metastatic spread, MSI-H, and RAS and BRAF wild-type status as well as dismal prognosis with median overall survival (OS) of around 15 months in the metastatic setting [27]. Beyond bearing a well-defined prognostic role NTRK fusions are likely to account for primary resistance to EGFR targeted agents
3. HER 2 mutated disease: Use anti HER 2 agents second line ( herceptin with lapatinib or pertuzumab i.e doublet). Use in front line if HER2 amplified and patient is not a candidate for intensive treatment.
