Dr. Shannon Westin, Dr. Lakshmi Sandhya, and Dr. Prasanth Ganesan discuss the use of olanzapine to treat chemotherapy-related anorexia, as recently published in JCO.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. As always, I'm your host, Dr. Shannon Westin, GYN Oncologist and Social Media Editor for JCO. I'm very excited to be here today.

And please note that our participants do not have any conflict of interest.

So we are going to discuss a really exciting paper today entitled the "Randomized, Double-Blind, Placebo-Controlled Study of Olanzapine for Chemotherapy-Related Anorexia in Patients with Locally Advanced or Metastatic Gastric, Hepatopancreaticobiliary, and Lung Cancer." And this was published in the JCO on March 28, 2023, and has gotten a lot of excitement.

And so I'm very thrilled to have two of the authors with me today. First is Dr. Lakshmi Sandhya. She's a Junior Consultant at the SVICCAR Hospital in Tirupati, India. Welcome, Dr. Sandhya.

Dr. Lakshmi Sandhya: Thank you so much for the opportunity to be here.

Dr. Shannon Westin: And I also have the senior author here today, Dr. Prasanth Ganesan. He is a Professor in the Department of Medical Oncology at JIPMER, which is the Jawaharlal Institute of Postgraduate Medical Education and Research in Puducherry, India. Welcome, sir.

Dr. Prasanth Ganesan: Thank you. Thank you very much, Dr. Westin. It's good to be here. Thank you very much.

Dr. Shannon Westin: Great to have you both. So we're going to get right to it. I think this is an excellent paper and certainly something we see across many of our patients who are diagnosed with cancer and who are receiving treatment for cancer. But first, I want to level set. What is the true definition of chemotherapy-related anorexia, and really approximately how many patients do you think it impacts?

Dr. Prasanth Ganesan: As you know, anorexia itself is very common in advanced cancers. Almost like maybe 80%, 90% of patients have some form of anorexia. But at diagnosis, it depends on the type of cancers. Very high in upper GI cancers, esophagus, stomach, pancreas, or lung cancer. But when we talk about chemotherapy-related anorexia, we specifically mean anorexia that is brought on or probably worsened by chemotherapy. So this depends a lot on the regimen that is used. So studies in lung cancer, upper GI cancer that have used something like platinum agents, maybe as high as 50% to 80%. Now, the challenge is how much of it is contributed by the underlying cancer itself and how much of it is worsened by the chemotherapy. It's tough to say, but I think we all have seen that chemotherapy does kind of really increase the anorexia in many of these patients. So I would say the problem is common. Depends on the type of cancer, the type of agent being used, and also sometimes on how intently we are looking for it.

Dr. Shannon Westin: You bring up a great point in really kind of making sure that we're screening our patients for it and understanding who's actually experiencing those things. And I do think putting it on our list of things that we, on a day-to-day basis, discuss with our patients is really relevant, although I will say sometimes we haven't done that because we don't have a good treatment. So that's what makes your paper so exciting. But before we get into the results of the paper, why don't we talk a little bit more about some of the factors that contribute to anorexia? Dr. Sandhya, I don't know if you want to elaborate a little bit on some of those.

Dr. Lakshmi Sandhya: Yeah. So most important would be the cancer type and the type of chemotherapy agent being used. So, as we mentioned, some cancer types have high anorexia incidence even at baseline. So the most important and prominent would be the upper gastric cancers and the pancreatic and lung cancer. Among the chemotherapy types, I think the platinum agents are known to cause anorexia more often and also associated with nausea or vomiting. So anorexia and weight loss is not very common in other cancers like breast, if you see, or ovarian cancer during the therapy. In fact, there has been weight gain in most of the patients with breast cancer, and most of the data which comes from breast cancer show that weight loss is experienced only by around 5% of the patients. So we would say the factors contributing most commonly would be the type of cancer and the chemotherapy that is being used.

Dr. Shannon Westin: Yeah, I think it's a great point. As a gynecologic oncologist, we do a lot of platinum, but we balance it, especially in upfront with paclitaxel or taxanes and we're giving steroids as premeds for them. And so we definitely see patients expecting to lose weight and instead actually getting hungry with the steroid use and eating to some degree.

Dr. Prasanth Ganesan: So I just want to add that even targeted agents, when you use something like sunitinib or everolimus, some of these agents, even they have got anorexia, probably 20% to 30%. So we did not include them in our study, but I'm just saying that even with targeted agents, we do get anorexia, at least some of them. So it's a problem across them.

Dr. Shannon Westin: Yeah, we've been using PARP inhibitors and definitely can see that nausea, vomiting, and anorexia in that population. So I appreciate you making a point that that wasn't included but could be potentially extrapolated here. And then I guess the other question that I have is how does anorexia impact cancer-related outcomes? Does it have an impact in that way?

Dr. Prasanth Ganesan: I believe it does, but it's probably not in a direct sort of way. So anorexia is strongly associated with weight loss and some amount of cachexia, and weight loss per se has been associated with poor outcomes across the board. There's a lot of data, especially in lung, upper GI cancers, and even head and neck cancer where weight loss before or during therapy has been associated with poor survival impact. So, again—in pancreatic cancer, it's associated with poor survival. So it's difficult to pin the weight loss only on anorexia here because weight loss is often multifactorial, but yeah, anorexia is probably a significant factor which is also adding to that. So I would say indirectly, yes, anorexia has an impact on cancer-related outcomes. Yes.

Dr. Shannon Westin: And I guess just getting into kind of what we can do before we get into the novel findings in your study, I know we've tried to talk about some dietary-related interventions that we can utilize to combat anorexia. Anything that you all have found to be most helpful from a diet standpoint?

Dr. Lakshmi Sandhya: So, from the diet standpoint, I would say dietary counseling is generally recommended for all the patients. To be very frank, we don't usually have a dietitian to spare at our outpatient clinic to counsel all the patients. So this is not something we are able to practice in the clinic. But in this trial, of course, we had a dietitian who counseled all the patients, and she gave them a diet chart to follow and gentle advice on what item to use and which is good, specifically emphasizing on high-calorie and high-protein diet. So we did not find that any particular dietary intervention is impactful. If you've seen various studies on dietary intervention, they have shown mixed results on improvement of anorexia or weight gain. So we're not sure whether dietary counseling particularly has impacted the results.

Dr. Prasanth Ganesan: Yes.

Dr. Shannon Westin: Okay. And then I imagine that would be one of the reasons that led to your exploration of this agent of olanzapine to treat chemotherapy-related anorexia. And can you just walk us through any data that existed kind of prior to your study to support this work?

Dr. Prasanth Ganesan: Yeah, definitely. I think olanzapine has been in the news for the last decade or so because we've been using it consistently for vomiting and nausea in patients getting emetogenic therapies. So there are at least three studies which we found for olanzapine in cancer anorexia. I think one was from Dr. Navari, and he had done a randomized trial comparing megestrol with megestrol plus olanzapine. And this was done in patients with advanced cancers, and they found about 35% of the patients in the olanzapine group had additional weight gain. So it was useful. And this was not a very recent study. It's almost done about 10 years back.

Dr. Shannon Westin: Oh, wow.

Dr. Prasanth Ganesan: Then, after that, there was an interesting phase I study by Dr. Naing, and that was from MD Anderson, and that looked at various doses of olanzapine also. And that was interesting for us because that's where we got our starting dose of 2.5 mg because even at this dose, there was an effect on anorexia. So that was a very useful study because we were also trying to figure out what is the best dose to use in our trial. So that's why we went with the 2.5 mg.

Dr. Shannon Westin: That's great. I know everyone's excited to hear about the results. So, Dr. Sandhya, do you want to walk us through the design of the study and maybe how you chose your patient population? I think you've already kind of hinted at it, taking people that at baseline have high levels of anorexia.

Dr. Lakshmi Sandhya: Yes, sure. So this was designed as a phase III randomized blinded trial. So we used olanzapine in one arm and the matched placebo in another. So we gave olanzapine at a dose of 2.5 mg once a day for 12 weeks. And similarly, a placebo which looked similar was given to the other group. So we assessed for weight gain as an objective measure and improvement in appetite as one of the endpoints, which is more of a subjective measure. And we wanted to focus on population where the problem of anorexia was maximum. So we focused on upper GI, lung and pancreas, and biliary tract cancers to make it more uniform when it comes to anorexia.

Dr. Prasanth Ganesan: Just to add a point that, even though we had included three or four types of cancer, almost 60% of our patients were actually gastric cancer patients because that probably reflects the profile of patients that we see at our center. It's a very common cancer in our place, and the next common was the lung cancer. We had only about 15% of patients who had pancreaticobiliary cancer.

Dr. Shannon Westin: That makes sense. Obviously, wherever we're enrolling is what we're going to see, but I think hopefully these data can be extrapolated across all cancer types. So you mentioned that your primary endpoint was weight loss as well as the improved appetite. Can you walk us through, Dr. Sandhya, what you found? What were your results?

Dr. Lakshmi Sandhya: So we had two primary endpoints. One was weight gain, and the other was improvement in appetite. So we wanted to use weight gain, as I said, since we felt that it is more of an objective measure than measuring anorexia. And olanzapine in our trial improved weight more than 5% from baseline in 60% of the patients in the olanzapine group and 9% in the placebo. Correspondingly, we have also measured improvement in appetite by using various questionnaires, which are validated. So one was visual analog scale, and the other was FAACT AC subscale, which we used during this trial. So yes, olanzapine worked well. We had hoped to show improvement in weight in about 30%, but surprisingly, we found that the weight gain was about 60% in the olanzapine group.

Dr. Shannon Westin: That's so great. It's always nice when you outperform your wildest dreams. So congratulations. Were there other secondary endpoints you observed that were impacted by the olanzapine?

Dr. Prasanth Ganesan: Yeah. So we did have a bunch of secondary endpoints because, again, we were worried when we started off because this is a subjective endpoint and we're not really sure how it's going to pan out. So we looked at some endpoints like quality of life, obviously, and we also had some nutritional assessment with the SDA and consistently, all of these showed improvement with the olanzapine. And what is most interesting for us was the grade III/IV side effects of the chemotherapy regimens, and these were reduced in the olanzapine. So this was something which we were looking for because consistently—we had also done some earlier studies in elderly populations where we found that the nutrition was an important factor in determining the toxicities of therapy. So that's why we wanted that as an endpoint.

And in fact, we found that patients who started at lower doses in cycle one due to poor performance status and nutrition, many of them could actually increase their dose in their subsequent cycles and this was more commonly seen in the olanzapine arm. So this was something which was very pleasant and which was something which we found was very interesting. So we could deliver more better chemotherapy intensity in these patients, thanks to their better nutrition.

Dr. Shannon Westin: That's so exciting. Such a nice concrete thing for patients as well. I mean, obviously being able to gain weight is something that they could see and having that appetite, but knowing that they had less side effects from their chemo as well is such an important impact. I guess, on the converse side, were there any negative impacts to the olanzapine?

Dr. Lakshmi Sandhya: Not really. We specifically asked patients about olanzapine-induced side-effects like drowsiness. At this dose of 2.5 mg per day, we found very little side-effects which would be attributed to olanzapine. As we mentioned, overall side-effects were also lowered in olanzapine arm. So with short duration of three months and at this dose, we believe that olanzapine is fairly safe.

Dr. Shannon Westin: And that's great. And I'd be remiss—especially here in the States, this is high discussion around financial toxicity. As I recall, it's a pretty inexpensive agent. Is there any kind of negative financial impact for the use of this drug?

Dr. Prasanth Ganesan: Yeah, this is the best part. In India, for three months, olanzapine costs about 300 rupees. That would be like $4 or something for three months of therapy. I think that's pretty easily affordable across the board. Most patients here can easily buy this. And I'm not sure about the cost in the US, but I'm guessing it would not be too high. It's been around for some time. It should be out of patent and things like that. So I think it's a very inexpensive drug.

Dr. Shannon Westin: Yeah, we like that, like reuse of an old drug to do something good. The other question I had for you all is just any thoughts about how these results might compare to other things that we use, like glucocorticoids or progestational agents? I know we didn't have that as a comparator, but just your thoughts on that.

Dr. Prasanth Ganesan: So, in terms of efficacy in reducing anorexia, it's difficult to compare because, if you see the studies of steroids and megestrol, most of them have been done by patients with more advanced cancers, not necessarily patients who are getting chemotherapy in the front line. But we think the side-effect profile is what gives an advantage to olanzapine because three months of steroids, even if you say lower doses of dex at 4mg or something, which I would want to use in a newly diagnosed cancer patient. Megestrol also seems to have problems like DVT and is actually much more expensive, at least in our context. I mean, if you compare with these aspects, I would definitely put olanzapine ahead, but as you said, this is not a direct comparison between those so-called existing agents.

Dr. Shannon Westin: Yeah, I think that's a very thoughtful answer, but I think something we just needed to cover, even though we know that it wasn't a randomized trial between those two. Any limitations, Dr. Sandhya, on these results? Anything that you wish you had done a little differently?

Dr. Lakshmi Sandhya: Yeah. As such, it is applicable only in the context of upper GI and lung cancers, as we have mostly included upper GI and lung cancers, and most of the patients, almost two-thirds of the patients included in our study, were gastric cancers. So also the duration that we used was only for 12 weeks. So we don't know whether longer duration will benefit more or harm. And the sustainability of weight beyond 12 weeks, we have not actually looked into. So, yeah, maybe these are few limitations that we can think about.

Dr. Shannon Westin: That's very true. And I think that—I mean, obviously, when we design trials, we have to have a limit. Do you have plans—are you able to follow these patients out a little further? Do you know if clinically they're continuing it off-trial?

Dr. Prasanth Ganesan: So we have done that. So we have been following them for their survival data, and we just completed the analysis. So I think we have to really publish that next. So it is looking interesting. So some interesting data there. So that's something which we found it very exciting.

Dr. Shannon Westin: Okay, good.

Dr. Prasanth Ganesan: So that is something which is out there. And we also looked at some data on improvement of their muscle mass and on their CAT scans, we looked at that. So that's also something which we are trying to analyze and see whether we can have more concrete or objective endpoints in terms of improvement of the muscle mass and adipose tissue and things like that.

Dr. Shannon Westin: Okay, good. Well, we'll look forward to that in a future version of the JCO, I hope. I guess the last thing is where do we go from here? You kind of hinted at this a little bit. I'm kind of bummed because I was ready to start implementing this in my clinic tomorrow.

Dr. Prasanth Ganesan: So it's just safe, it's effective, and it's cheap. So I don't see any reason we should not start implementing something like this straightaway. I use it quite commonly, definitely for patients who are part of the trial population. And even for any patients with advanced cancer on or off chemotherapy with anorexia or weight loss, I'm comfortable to use olanzapine at least for a short term. And many patients at least they come back and say that it does help them. And I've not seen any side-effects at this dose of olanzapine. So it seems very safe to use. I'm comfortable to put it in the clinic right away.

Dr. Shannon Westin: Dr. Sandhya, what do you think?

Dr. Lakshmi Sandhya: I feel, in this trial, we came across the safety part of it and also the affordability part of it, and definitely it has been very encouraging results, so yeah. So, day-to-day practice, it can be used.

Dr. Shannon Westin: Well, great. I think this is super-educational, and I hope everyone else is just as convinced as I am how important this work was and how potentially impactful it will be for our patients. I just want to again thank these wonderful physicians and researchers. Dr. Sandhya, Dr. Ganesan, thank you so much for your time and a little bit of a late time for this taping across the globe. So thanks again for being here.

Dr. Prasanth Ganesan: Thanks, Dr. Westin, for giving us this chance.

Dr. Lakshmi Sandhya: Thank you so much.

Dr. Shannon Westin: So, again, y'all, this has been JCO After Hours discussing the important paper, "Randomized Double-Blind Placebo-Controlled Study of Olanzapine for Chemotherapy-Related Anorexia in Patients With Locally Advanced or Metastatic Gastric, Hepatopancreaticobiliary, and Lung Cancer," published March 28^th, '23. We are just so grateful that you joined us and hope you'll check out the other podcast offerings on the website. Take care.

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Olanzapine for Chemotherapy-Related Anorexia

Journal of Clinical Oncology (JCO) Podcast

Olanzapine for Chemotherapy-Related Anorexia