Lec 6: Colon Cancer Flashcards

Question

Metastatic Colon Cancer: Goal and treatment

Answer 1

NOTE: - mFOLFOX6 : 5FU, Leucovorin, oxaliplatin - FOLFIRI: 5FU, Leucovorin, Irinotecan - FOLFOXIRI: 5FU, Leucovorin, oxaliplatin, Irinotecan

Answer 2

The most commonly used drugs: 5-FU (+leucovorin), oxaliplatin, and irinotecan. . bevacizumab (VEGF inhibitor) can be added . cetuximab or panitumumab are Anti EGFR (only used if patients have WT! NO MUTATION of KRAS, BRAS, NRAS and left-sided tumors only!!!! . Pembrolizumab (dMMR/MSI-H only!) use if MSI is HIGH!

Answer 3

- MOA: prodrug of 5-FU. It undergoes hydrolysis in the liver and tissues to form fluorouracil (fluorinated pyrimidine form fluorouracil antimetabolite). Inhibits thymidylate synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a lesser degree, RNA synthesis - SE: Diarrhea, myelosuppression, n/v, handfoot syndrome, mouth sores

Answer 4

1.) Acute: transient, rapid onset hours to days after infusion - Oxalate metabolite of oxaliplatin chelates calcium and magnesium and interferes with voltage-gated sodium channels and electrical current - Prolonged opening of the sodium channels in sensory nerves that results in a hyperexcitable state - Prevention by prolonging infusion 2 – 6 hrs or dose reductions . 2.) Chronic: Onset >14 days after infusion, persistent between treatment - Thought to be related to interference with microtubule-based axonal transport, oxidative stress or drug accumulation in dorsal root ganglinon and sensory nerves - Prevention: Stop-and-Go approach, discontinuing oxaliplatin after 6 cycles followed by 5-FU maintenance may be considered

Answer 5

- Occurs during or immediately after infusion - Cholinergic symptoms! :Cramping, diohoresis (sweating), flushing, salivation, visual disturbances, and lacrimation, Direct inhibition of acetylcholinesterase . - Treatment: Atropine --> Suppresses cholinergic effect, Start at 0.25 mg IV (max dose 1.2 mg) . -Monitor blood pressure and heart rate -Can consider to give as secondary prophylaxis

Answer 6

- Occurs >24 hr after infusion. Reported 2 – 12 days after... Thought to be do to SN-38 reactivation . -Treatment: Loperamide 4 mg at first sign of diarrhea, then 2 mg every 2 hrs until 12 hrs following last bowel movement, then PRN up to 24 mg/day (higher that the 16 mg/day max)..go over max to 24mgQD is recommended!!!! . -Supportive care: Fluids and electrolyte replacement, Nutrition

Answer 7

MOA: Bind to VEGF preventing its association with endothelial receptors... VEGF binding initiates angiogenesis so inhibiting it = The inhibition of microvascular growth is believed to retard the growth of all tissues - Not indicated as single agents!!!!!! . SE: hypertension, proteinuria, wound dehiscence, bleeding, thrombotic events

Answer 8

- MOA: binds specifically to EGFR and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands - SE: Skin rash, hypersensitivity reactions, hypomagnesemia . NOTE: - Only for KRAS/NRAS wild-type tumors! NO MUTATION - Mutation in RAS predicts lack of response to EGFR inhibitors!!! - Recommended for left-sided primary tumors for front-line - If used in initial treatment, no evidence to use them in subsequent treatments (no need to continue using them if they are not working)

Answer 9

- Acneiform Rash characterized by papules and pustules coupled with itching and pain: Develops on face and scalp...THIS IS NOT acne (but looks like it) using acne products make it worst! - Positive correlation between rash severity and tumor response - Pre-emptive management: Hydrocortisone 1% + moisturized, sunscreen, and doxycycline 100 mg BID (For at least the 1st 6 weeks) . Treatment (based on CTCAE grade)  Grade 1: continue same dose, topical hydrocortisone, and clindamycin  Grade 2: continue same dose, topical hydrocortisone, and oral doxycycline or minocycline  Grade 3/4: dose reduce, topical hydrocortisone, and oral doxycycline or minocycline, oral prednisone

Answer 10

- MOA: inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on Tcells to block PD-1 ligands from binding....The negative PD-1 receptor signaling that regulates T-cell activation and proliferation is therefore disrupted....This releases PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response . - Only used in patients with dMMR/MSI-H . - If progression on one agent no use to switching to the other agents . - SE: Immune-mediated toxicities (pneumonitis, colitis, hepatitis, nephritis, and thyroid dysfunction)

Answer 11

- MOA: multikinase inhibitor; it targets kinases involved with tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment which results in inhibition of tumor growth - SE: hypertension, fatigue, diarrhea, mucositis, n/v, hand-foot syndrome, myelosuppression, proteinuria, liver toxicity

Answer 12

- MOA: Trifluridine, is a thymidine-based nucleic acid analogue which is incorporated into DNA and interferes with DNA synthesis and inhibits cell proliferation.... Tipiracil is a potent thymidine phosphorylase inhibitor which prevents the rapid degradation of trifluridine, allowing for increased trifluridine exposure . - SE: diarrhea, n/v, decrease appetite, fatigue, myelosuppression

Answer 13

- MOA: Inhibits tropomyosin receptor kinase (TRK) TRKA, TRKB, and TRKC proteins encoded by neurotrophic receptor tyrosine kinase (NTRK) genes, NTRK1, NTRK2, and NTRK3. -Anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression - SE: fatigue, n/v, anemia, neutropenia, liver toxicity, neurotoxicity (dizziness), cough, constipation, diarrhea

Answer 14

- MOA: Inhibits tropomyosin receptor kinase (TRK) TRKA, TRKB, and TRKC proteins encoded by neurotrophic receptor tyrosine kinase (NTRK) genes, NTRK1, NTRK2, and NTRK3. -Inhibits cancer cell lines derived from multiple tumor types harboring NTRK, ROS1, and ALK fusion genes thus inhibiting tumorigenic potential through hyperactivation of downstream signaling pathways and uncontrolled cell proliferation caused by fusion proteins - SE: edema, weight increase, constipation, diarrhea, n/v, taste changes, arthralgia, myalgia, fatigue, cough, shortness of breath, fever, neurotoxicity

Answer 15

- Can go for cure in 20-25% of patient - Resection of primary tumor and liver or lung metastases - Followed by FOLFOX or CapeOx (preferred) . Neoadjuvant chemotherapy - 2 – 3 months to increase curative resection and convert from unresectable to resectable ---- mFOLFOX6, CapeOx (preferred)