Episode 104: Colorectal Cancer Series, Pt. 6 - Colorectal Cancer Pharmacology
We have another guest joining us this week! Dr. Allison Schepers, PharmD, BCOP is a Clinical Pharmacist Specialist at the Rogel Cancer Center at the University of Michigan where she focuses on GI, GU, and Thoracic malignancies! In this episode, Allison discusses the high yield points we need to know about important drugs we use in the colorectal cancer treatment space and how she approaches counseling her patients. Another great episode from our pharmacy colleagues you do NOT want to miss!
5-fluorouracil (5-FU)
One of the backbones of treatment for colorectal cancer is 5-fluorouracil or 5-FU or it’s oral pro-drug version, capecitabine.
Why was there a push to move from 5-FU from bolus formulations to infusional 5-FU?
The original protocols used bolus formulations (15 minutes to 2 hours; performed in 1980s-1990s), which were hard for patients to tolerate; side effects that limited the ability for patients to complete therapy:
Myelosuppression (more so than infusional)
Diarrhea
Mucositis
Transition to infusional 5-FU in the 1990 to 2000s:
This is a continuous infusion of 5-FU via a pump for about 46 hours
Much better tolerated, with better side effect profile
Side effects are less common than bolus with exception of coronary vasospasm
Can be seen rarely with bolus and capecitabine
Undergo same workup as typical acute coronary syndrome (ACS)
In patients who develop coronary vasospasm, do you ever recommend rechallenging?
Important to make a case-by-case decision. Some attempts to mitigate coronary vasospasm include premedication:
Nitrate: Isosorbide
Calcium Channel Blocker: Diltiazem (consider 24 - 48 hours prior to 5-FU and continued 48 hours after infusion completed
Thought to be due to exposure to 5-FU over time, there switching to capecitabine is not an effective option
Can consider inpatient admissions for observation for the re-challenge
Capecitabine
Capecitabine is the oral prodrug of 5-FU. How does the side effect profile compare?
Less hematologic side effects, however other side effects can be more severe:
Hand-foot syndrome
Onset typically one week after initiation
Prophylaxis
Administering moisturizing lotion 2x daily when in cycle
Consider use of urea-based lotions
Avoid heat (hot showers) and friction (wearing gloves and socks)
Treatment
Topical corticosteroids
Need to make a case-by-case decision about holding the drug vs. dose reduction for severe toxicity
Diarrhea
Mucositis
Nausea
How would you recommend capecitabine dosing changed in the event of severe symptoms?
Once the side effects have resolved, consider dose reduction strategies
% Reduction Based on Severity of Symptoms
Example: 4 x 500mg tablets BID → 3 x 500mg Tablets BID
What is uridine triacetate and when should we use it?
Competes with fluorouridine triphosphate, a fluorouracil metabolite, for incorporation into RNA of hematopoietic progenitor cells and gastrointestinal mucosal cells to reduce fluorouracil toxicity
Use only in cases when there is catastrophic overdose (even if there are no symptoms) severe toxicity from 5-FU or capecitabine WITHIN 96 hours
Indications: Catastrophic overdose or severe early symptoms
Catastrophic Overdose:
Pump Malfunction
Dosing error
Self harm attempts
Symptoms that should make you suspect the need for uridine triacetate:
Early-onset severe or life-threatening cardiac or central nervous system toxicity
Early-onset unusually severe adverse reactions (eg, severe mucositis or diarrhea despite it being first administration and/or neutropenia)
This may be secondary to undiagnosed dihydropyrimidine dehydrogenase (DPD) deficiency
Severe early toxicity
START WITHIN 96 HOURS ADMINISTRATION: If unable to deliver within 96 hours of administration unlikely to be efficacious
Indication for Hospitalization
Most require additional support, often in a critical care setting with mechanical ventilation in early keynote studies
Oxaliplatin
One of the most notorious side effects of oxaliplatin is neurotoxicity. How does this present and what can we do about it?
Two types of neuropathy:
Acute Cold Sensitivity
Virtually 100% of patients will experience this. They should be counseled on avoiding cold beverages, reaching into cold
Typically self-limited; typical onset is peaks 2-3 days after treatment and resolves in about 5 days
Treatment strategies:
Non-pharmacological interventions:
Gloves when handling cold items
Warm clothes in the winter
Avoid iced drinks
Chronic peripheral neuropathy
This is a cumulative effect that worsens with increased exposure; starts interfering with ADLs at around 800mg/m2
Once the drug is stopped, can PEAK 3 months post-therapy and then will steadily taper off over months to year
Prevention: no good data
Treatment
SNRI → Duloxetine
GABAergic medications → Gabapentin / Pregabalin
Irinotecan
What are typical side effects associated with irinotecan?
Diarrhea (“I ran to the can”)
There are TWO distinct types of diarrhea that can present:
Cholinergic-mediated
MOA: Acetylcholinesterase inhibition → Cholinergic excess syndrome (diarrhea, cramping, etc). These patients will get diarrhea and abdominal cramping WHILE they are still getting the infusion
Treatment
Atropine
PRN (usually enough)
Premedication with atropine prior to infusion
Secretory diarrhea
This occurs 7 - 10 days after infusion
Treatment
Imodium (Loperamide) → lomotil / tincture of opium
Refractory diarrhea:
Bacteria can convert metabolite back into active drug component
Treatment: Oral Cephalosporin / fluoroquinolone
Myelosuppression
Nausea /Vomiting
Similar rates of diarrhea with liposomal irinotecan versus traditional
VEGF Inhibitors (Bevacizumab; Ramucirumab; Regorafenib, Fruquitinib)
In patients with a history of MI, are VEGF inhibitors still safe to use?
If the MI had been in the past 6 -12 months, that is a moderate to strong contraindication
If it had been multiple years ago and the patient is medically optimized, then can consider
Other aspects of the medical history, such as prior VTE/PE and active anticoagulation use are NOT contraindications
In patients who have recent surgery, how long should we hold?
After a major surgery (such as primary colon resection), typically about 8 weeks post surgery, assuming no wound healing complications
For VEGF TKIs, wounds should be completely healed first
If patients are on these drugs, need to hold typically weeks to a couple months prior to upcoming due to prolonged half-life of medication!
EGFR Inhibitors (cetuximab and panitumumab)
What are important side effects to be aware of?
Diarrhea
Acneiform Rash
Prevention
Oral doxycycline entire cetuximab course, topical hydrocortisone daily, sun protection every time they went outside, topical moisturizer
Decreased rate from approximately 60% → 30%
Treatment
Doxycycline
Topical corticosteroids
Clobetasol shampoo (scalp involvement) ; HOLDING therapy
Magnesium wasting
This is because of blocking EGFR-dependent transporter in the renal tubule
Need aggressive magnesium repletion
Why are there regional differences for anaphylactic reactions to cetuximab?
Increased rates of anaphylaxis in the “Bible Belt” region / Deep South
Same Distribution as Rocky Mountain Spotted Fever and Lone Star Tick
Contains Alpha Gal → transmitted if bitten by lone star tick → IgE antibodies to cetuximab
We do NOT see with panitumumab
Lonsurf
What are the major side effects?
Myelosuppression:
If patients have had myelosuppression from prior treatment, reasonable to consider dose reduction
As patients are starting therapy, MUST have CBC on days 1 and 15
N/V
Diarrhea
In light of side effects, how should we uptitrate the dose?
The dosing schedule is days 1-5, 8-12 of a 28 day cycle, with target dose of 35mg/m2
Using CBC and side effects as your guide via regular check ins should be how doses are increased
HER2-directed therapies
Are there any specific side effects that are unique to colorectal cancer that are different than when used in breast cancer?
For trastuzumab/pertuzumab, still lots of diarrhea
Trastuzumab-deruxecan has more GI side effects (nausea, diarrhea)
About our Guest:
Dr. Allison Schepers, PharmD, BCOP is a Clinical Pharmacist Specialist at the Rogel Cancer Center at the University of Michigan where she focuses on GI, GU, and Thoracic malignancies. In addition, she is the Program Director for the pharmacy PGY2 Oncology Program and an Adjunct Clinical Assistant Professor at the College of Pharmacy. Dr. Schepers completed pharmacy school at University of Michigan, after which she completed her PGY1 and PGY2 residencies, the latter in oncology, at the University of North Carolina - Chapel Hill.
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Ronak Mistry, Zach Wills
Social media management: Ronak Mistry
We are proud to partner with HemOnc.org!
Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org
This episode was created in collaboration with our friends at Pharmacy Podcast Network!
