Managing Diarrhea and Optimizing Dose Reductions With NALIRIFOX

Diarrhea remains a primary distinguishing toxicity associated with NALIRIFOX (liposomal irinotecan [Onivyde], oxaliplatin, fluorouracil, and leucovorin) relative to other frontline regimens for metastatic pancreatic cancer. Managing it effectively can determine whether a patient stays on treatment long enough to derive benefit. In the phase 3 NAPOLI-3 trial (NCT04083235), more than half of patients receiving liposomal irinotecan required some type of dose reduction.

Following a Frontline Forum program, Timmy Nguyen, MD, and Raji Shameem, MD, spoke about the proactive strategies they use to manage diarrhea and guide dose reduction decisions on NALIRIFOX. Nguyen described diarrhea as a manageable toxicity when addressed with preventive antidiarrheal medication and access to hydration support, noting that this approach has not created adherence issues in his practice. Shameem expanded on that framework, detailing how he counsels patients upfront about the likelihood of diarrhea, incorporates dietary changes and proper loperamide (Imodium) use, and evaluates severity relative to each patient's individual baseline stool frequency rather than applying a uniform grading standard.

Shameem is a hematologist and medical oncologist at Orlando Health Cancer Institute, and Nguyen is a hematologist and medical oncologist at Cleveland Clinic Florida.

Transcript:

CancerNetwork®: NALIRIFOX's safety profile differs somewhat from the other approved frontline regimens. How do you approach managing that toxicity in practice?

Nguyen: Those 3 regimens [of NALIRIFOX, FOLFIRINOX, and gemcitabine/nab-paclitaxel (Abraxane)] are effective overall, but they have some different toxicity. What's good about the [NALIRIFOX] regimen is that the main [toxicity] is diarrhea compared to the other 2, and that, for me, is manageable. Cytopenia is there but manageable in terms of optimizing preventive antidiarrheals and being able to get patients in for hydration if they need it, to give them extra supportive care to prevent dehydration, so they can stay on and get the next treatment. I don't find such an adherence issue in using NALIRIFOX; that's the only difference in terms of toxicity.

Shameem: I would definitely agree. When I have a patient and I recommend a regimen like NALIRIFOX, I counsel them about diarrhea because if they don't know about it, they're not going to be happy. As you mentioned, that's my experience; diarrhea can occur, but [you can use] proactive management. I like how you include hydration, dietary changes to try to ameliorate the severity of diarrhea, and just making sure patients use [loperamide] correctly. We tell them to use it, but do they really know how to use it? When making a decision about treatment interruption and considering dose reduction, when that diarrhea improves, it's always important to know the severity. I feel like a lot of our patients with metastatic pancreatic cancer have baseline increased stool frequency from malabsorption. As we look at the grading of something, what is truly grade 3 is 7 or more episodes compared to baseline; but what is their baseline?

I incorporate the same proactive management, and I feel it's really helped in the clinic to identify diarrhea, control it, prevent worsening toxicity, and make sure patients are actually able to tolerate the regimen for the long run. But a lot of times, when the decision is to make a dose reduction, I comment on the trial—for [liposomal irinotecan] specifically, approximately 50% of patients did require some type of dose reduction, and that gives me confidence that if the trial did that and we still saw survival benefit, I can do the same in my practice.

Reference

Hussein MA, Khan G, Chandana SR, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): updated overall survival analysis with 29-month follow-up of NAPOLI 3. J Clin Oncol. 2024;42(suppl 16):4136. doi:10.1200/JCO.2024.42.16_suppl.4136