Effective RX for CINV and MBO: Do we really need so many drugs?

I’m using this month’s newsletter to highlight two GI problems, chemotherapy-induced nausea or vomiting (CINV) and partial or complete malignant bowel obstruction (MBO), because they’re the ones I’m most often asked to address during my palliative care inpatient consultations.  When I offer my recommendations, clinicians ask, “Do we really need so many drugs?” The short answer is YES! We really do need polypharmacy if patients receiving highly or moderately emetogenic chemotherapy are to avoid experiencing CINV; patients with MBOs also need a number of drugs to minimize their symptoms and maximize the odds that the obstruction will resolve. 

I’ll discuss CINV first then move on to MBOs. Ongoing post-chemotherapy nausea and/or vomiting can be caused by ondansetron-related constipation. But it often occurs because the complex antiemetic regimens for highly or moderately emetogenic chemotherapy either weren’t prescribed or weren’t taken. If you want more details. you can find PDFs of the ASCO 2020 guideline and the 2023 update on my website, www.janetabrahm.com, in the Pain and Symptom Management Resource, in the Subsection “GI issues”. 

It’s not that simpler regimens haven’t been studied.  They were. Dexamethasone is the most problematic agent for patients to tolerate—not just diabetics, but everyone.  The “high” can be pleasant, but the anxiety and the depressed mood are not.  Data, in fact, indicate that dexamethasone prophylaxis for days 2-4 after chemotherapy is the most frequent agent omitted by oncologists and patients in their antiemetic regimens. 

Unfortunately, studies have clearly shown that 5HT3 inhibitors like ondansetron give inferior CINV protection when used alone; even adding an NK-1 inhibitor like aprepitant is not enough. The dexamethasone adds significantly to the prevention of CINV.  

Luckily for all patients needing highly emetogenic chemotherapy, including women needing adjuvant therapy for breast cancer, most recent national guidelines substitute olanzapine for the dexamethasone days 2-4.  To tolerate these regimens, patients still need multiple drugs the night before therapy and the day of, including dexamethasone, a 5HT3 inhibitor, an NK-1 inhibitor, along with a benzodiazepine usually. Instead of the dexamethasone day 2-4, however, olanzapine, 5-10 mg daily, is now recommended.

Why all these drugs? Because they act in separate brain areas to minimize CINV. 

The lorazepam many patients find helpful the night before and during the first few days after chemo decreases the anxiety that exacerbates CINV. But it turns out that, also, all benzodiazepines are amnestic to one degree or another—they prevent the creation of proteins that encode memory of events.  Midazolam is the best of these, as anyone who has received it for an endoscopy procedure can attest. You have no memory of it, literally.  Lorazepam is less powerful in producing amnesia, but it also helps patients not remember whatever side effects they get from the chemotherapy and so can help prevent anticipatory nausea and vomiting.  Unfortunately, we have no idea how dexamethasone works.

The 5HT-3 and the NK-1 receptors each bind to a separate receptor in the brain, in the area that causes patients who get highly emetogenic chemotherapy to have nausea or vomit. If those receptors are blocked before the patient is treated, both acute and delayed vomiting and most of the nausea is prevented.  Patients receive the intravenous drug combo that blocks the 5HT3 receptor (e.g., ondansetron or palonosetron) which is most effective blocking acute symptoms, and the NK-1 receptor (e.g., aprepitant or fosaprepitant) that blocks delayed CINV. 

There is another receptor that might be of use if we could block it: the endocannabinoid receptor.  Patients know the beneficial effects of cannabinoids, but many cannot tolerate the CNS effects that accompany the “munchies”.  Since as many as 25% of patients still vomit after chemotherapy, and nausea is even more prevalent, identifying a derivative of marijuana that specifically blocks the endocannabinoid receptor would be a great advance. 

Malignant Bowel Obstruction (MBO)

Managing patients with MBOs with or without an NG or venting G tube also requires drugs with specific targets working together to minimize patient symptoms without worsening the obstruction.  The chart below reviews these drugs and their actions.

A few caveats

Dexamethasone really does help patients with MBO. I prescribe it unless the bowel is very distended and the dexamethasone might cause a perforation, the patient has brittle diabetes, or the patient has bad memories of dexamethasone’s side effects.  I use metoclopramide for patients with partial bowel obstructions to counter the slowing of the gut induced by the opioid or anticholinergic medications I use for abdominal pain from distention.  

I don’t start octreotide (IV or SQ) until day 5 of therapy, because it can convert a partial SBO to a complete one.  In many cases, when the patient is NPO, taking standing dexamethasone and metoclopramide, and PRN pain medication, the obstruction will resolve.  Octreotide limits the stomach’s fluid production and can decrease it to the 500-750 cc the stomach can tolerate, eliminating the need for an NG tube. 

But octreotide is not helpful for patients with NG or venting G tubes who continue to drink.  Taking fluids PO increases gut secretions and dehydrates patients faster. Patients with chronic MBO who can tolerate remaining NPO and receive monthly LAR octreotide shots as outpatients can avoid the NG tube or keep their venting G tube clamped.  

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RESOURCES

GI Issues: Articles

Hesketh PJ, Kris MG, Basch E, et al
Antiemetics: ASCO Guideline Update
J Clin Oncol 2020; 38:2782-2797

Roeland EJ, Bohlke K, Baracos VE, et al.
Cancer cachexia: ASCO guideline rapid recommendation update.
The ASCO panel confirmed that there are NO FDA-approved medications to treat cancer cachexia, including olanzapine and mirtazapine.

GI Issues: Slide Presentation

GI Disorders which includes a discussion of MBO and CINV