Dr. Charles Loprinzi shares the latest update to the management of cancer cachexia guideline. Dr. Loprinzi discusses the evidence that prompted the rapid update to the guideline and reviews the new evidence-based recommendations, including the addition of low-dose olanzapine as a treatment option for patients with advanced cancer to improve weight gain and appetite. Dr. Loprinzi reviews the limitations of the update, and outstanding research questions in the domain of cancer-associated cachexia.

Read the latest update, "Cancer Cachexia: ASCO Guideline Rapid Recommendation Update" at www.asco.org/supportive-care-guidelines

TRANSCRIPT
This guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01280

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Charles Loprinzi from Mayo Clinic, Co-Chair on "Cancer Cachexia: ASCO Guideline Rapid Recommendation Update." Thank you for being here today, Dr. Loprinzi.

Dr. Charles Loprinzi: It's a pleasure to participate.

Brittany Harvey: Then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Loprinzi who has joined us here today, are available in line with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

Then, to get into the content of this rapid recommendation update, first, Dr. Loprinzi, what prompted this rapid update to the ASCO management of cancer cachexia guideline, which was previously published in 2020?

Dr. Charles Loprinzi: The impetus for the updated guideline was a recent JCO publication regarding the results of a randomized controlled trial looking at olanzapine. This prompted the expert panel to revisit this topic. The trial, conducted in India, involved 124 patients with stomach, hepatopancreatobiliary, or lung cancers as they initiated chemotherapy. Weight gain greater than 5% occurred in 60% of patients in the olanzapine arm versus 9% of the patients in the placebo arm with a p-value of 0.001 or less. Substantially improved appetite was seen in 43% versus 13%, with placebo also a p-value of less than 0.001. Grade 3 or greater chemotherapy toxicity was less common with olanzapine 12% versus 37%, with placebo with a p-value of 0.002. No substantial olanzapine-associated toxicity was apparent. There was one evidence of this with olanzapine versus two for placebo. So that was the reason for going ahead with this update.

Brittany Harvey: I appreciate that background information. So then, based on this updated study on olanzapine, what are the updated recommendations from the expert panel for treating cancer cachexia?

Dr. Charles Loprinzi: So, let me start to address this question by reviewing what the 2020 ASCO guidelines published said regarding the management of cancer cachexia in adults with advanced cancer. It concluded that evidence was insufficient to strongly endorse any pharmacologic agent for established anorexia/cachexia. Nonetheless, the guideline recommendation supported that clinicians could offer a short-term trial of a progesterone analog such as megestrol acetate or a corticosteroid such as dexamethasone to patients experiencing weight loss and/or appetite stimulation. These drugs stimulated appetite and caused weight gain, but they did not improve quality of life, they did not improve survival, and there was toxicity associated with these agents and therefore it was not strongly recommended.

The expert panel thoroughly discussed a potential role for olanzapine because of a couple of trials suggesting it was beneficial but concluded that the evidence was insufficient for a recommendation. Now, there was evidence from two randomized trials that supported olanzapine was an effective alternative for treating cancer-associated anorexia/cachexia. Thus, olanzapine was considered promising, but the data were not conclusive enough to support a guideline treatment recommendation. The new JCO publication was the impetus for making this guideline change.

Brittany Harvey: Understood. So then, based off this new change to the recommendations, what is the breadth of these recommendations and what do these options mean for patients with advanced cancer?

Dr. Charles Loprinzi: The updated guidelines recommended that for adults with advanced cancer, clinicians could offer low-dose olanzapine once daily to improve appetite and cause weight gain. It was noted that the majority of the evidence for this recommendation came from patients with lung or GI cancers, and the largest study enrolled patients who were receiving cytotoxic chemotherapy concurrently. Having said this, there's evidence from the other two randomized trials noted above that olanzapine is helpful in patients with a wide variety of cancers and regardless of whether patients were receiving concomitant chemotherapy.

Of note, extensive data support that olanzapine leads to significant appetite stimulation and weight gain in patients without cancer who were taking olanzapine for psychiatric reasons. This was known from a long time ago in patients in that situation, who don't necessarily want to gain weight, would gain 10-20-30-40 pounds, get prediabetes, and get diabetic sort of troubles. The guideline update continues to support that clinicians may offer a short-term trial of a progesterone analog or a corticosteroid to those experiencing weight loss and/or appetite when there's a good reason for not using olanzapine.

Brittany Harvey: Understood. I appreciate you reviewing those two updated recommendations from the guideline panel.

So then you've talked about this a little bit already in describing the study details, but what is exciting about olanzapine in this setting and what should clinicians know as they implement these updated recommendations?

Dr. Charles Loprinzi: It's exciting that olanzapine is now the best-studied established treatment available for patients suffering from cancer-associated anorexia/cachexia in different oncologic situations, for prevention and/or for treatment of cancer-associated or cancer treatment-associated nausea and/or vomiting, and for treatment of cancer-associated anorexia/cachexia. Varying daily doses of olanzapine have been used, ranging from 2.5 to 10 milligrams per day. Data support that it is quite appropriate to use the 2.5-milligram per day dose for the initial treatment of cancer-associated appetite and/or weight loss. For patients who do not appear to benefit and have no apparent olanzapine toxicity, it seems reasonable to me to try a higher dose. Another thing to note is that olanzapine is a generic drug which is relatively inexpensive. While this drug has been noted to cause sedation, such sedation is usually short-lived despite drug continuation.

Brittany Harvey: So then, it's great to hear that recent data have caused an update to these guidelines. But in your perspective, Dr. Loprinzi, what are the most pressing outstanding questions regarding the management of cancer cachexia?

Dr. Charles Loprinzi: My goodness, you're putting pressure on me. I've been involved with a large number of cancer anorexia/cachexia trials for the better part of four decades, which did not support as strong an ASCO guideline recommendation as we now have with olanzapine. Noting that I was involved with one of the trials that supported that olanzapine was helpful for treating cancer-associated anorexia/cachexia. This is one of the trials. It was a short trial. We were mainly looking at nausea and vomiting treatment for advanced cancer, but we saw a marked increase in appetite in over just a day or two of using olanzapine. Having said this, there's always room for improvement, and a number of drugs are under development for treatment of cancer-associated anorexia/cachexia.

Recent discussions regarding the topic of olanzapine for treating cancer-associated anorexia/cachexia noted that the primary endpoint of the current trial was weight gain and that this was felt to be a more objective endpoint than appetite would be. As noted in the earlier part of the discussion, substantial improvement was seen both in weight gain and appetite, both with p-values of less than 0.001. My own opinion is that appetite improvement is as important, if not more important than is weight gain in the study population. Given that the trial was double-blinded and placebo-controlled, appropriate questionnaires regarding appetite should be able to be considered as an objective evaluation of a subjective symptom in the same way that appropriate questionnaires regarding a patient's pain can be considered an objective evaluation of a subjective symptom. For some of these subjective symptoms, you just don't have other good ways we can figure these things out by a blood test or something like this. So it's what the patient says which is most important.

Brittany Harvey: Absolutely. Incorporating how the patient feels is key to achieving better outcomes for patients.

So I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Loprinzi.

Dr. Charles Loprinzi: You're welcome. Pleasure to participate.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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