Appropriate Systemic Therapy Dosing for Obese Adult Patients with Cancer Guideline Update

An interview with Dr. Jennifer Griggs from University of Michigan and Dr. Gary Lyman from Fred Hutchinson Cancer Research Center & University of Washington, co-chairs on "Appropriate Systemic Therapy Dosing for Obese Adult Patients with Cancer: ASCO Guideline Update." This guideline updates recommendations on appropriate dosing of systemic antineoplastic agents – including cytotoxic chemotherapy, checkpoint inhibitors, and targeted therapies – for obese adults with cancer. Read the full guideline at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

[MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at podcasts.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Jennifer Griggs from the University of Michigan and Dr. Gary Lyman from Fred Hutchinson Cancer Research Center and University of Washington, co-chairs on appropriate systemic therapy dosing for obese adult patients with cancer ASCO guideline update. Thank you for being here, Dr. Griggs and Dr. Lyman.

DR. GARY LYMAN: Thank you, Brittany.

DR. JENNIFER GRIGGS: Thanks for having us.

BRITTANY HARVEY: First, 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 full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Griggs, do you have any relevant disclosures that are directly related to this guideline topic?

DR. JENNIFER GRIGGS: No, I don't.

BRITTANY HARVEY: And Dr. Lyman, do you have any relevant disclosures related to this guideline?

DR. GARY LYMAN: I have no relevant disclosures to this guideline.

BRITTANY HARVEY: Great. Thank you, both. Then let's get into the substance of this guideline update.

So Dr. Lyman, can you explain what prompted an update to this guideline on appropriate dosing for obese adult patients with cancer last published in 2012, and what is the scope of this update?

DR. GARY LYMAN: Thank you, Brittany. Yes, this is an update of a previous guideline, several years old, that was prompted by evidence that there was wide variation in how chemotherapies at that time were being dosed, particularly in the overweight and obese population. Some were capping the dose, some were giving the full weight-based dosing, and all sorts of permutations in between. So that guideline was greeted, I think quite favorably, and, in fact, led to changes in clinical practice in many institutions and I believe also in the cooperative group research networks.

Since that time, however, a whole array of new therapies have come along. These, we'll talk about briefly in this podcast, include the novel targeted therapies based on molecular targets, as well as the new checkpoint inhibitors, and other monoclonal antibody therapies, where the dosing issues, in general, are different for many of these agents. And specifically for patients who are overweight and obese, we thought it was important that we update this guideline, review the evidence in total appropriate to the dosing of these new agents in overweight and obese patients, and make updated recommendations that would be more relevant to that practice of oncology in 2021.

BRITTANY HARVEY: Great. Thank you for explaining the previous version of the guideline and for explaining the expanded scope. So given that, I'd like to review those key recommendations made in this guideline. So Dr. Griggs, what are the recommendations regarding dosing of cytotoxic chemotherapy in obese adults with cancer?

DR. JENNIFER GRIGGS: With rare exception, we recommend, and the evidence supports, using actual body weight when we calculate doses. So whether it's just per kilogram, milligrams per kilogram for example, or per meter squared, using body surface area, we recommend that the actual body weight of the patient be used with no compromise or capping, no maximizing the dose as if it were calculated using 2 meter squared for example. There's no evidence that that's necessary to avoid side effects, and, in fact, there's increasing evidence that doing so, that limiting the doses in patients, is associated with decreased benefit of the treatment.

Since the original guideline came out, there's been no convincing evidence that has made us change our recommendation. So again, in brief, we recommend that actual body weight be used in calculating the target dose for cytotoxic chemotherapy.

BRITTANY HARVEY: Great. Thank you. That's very clear for clinicians. So Dr. Lyman, you mentioned this in your introduction to the scope of this guideline, what are the recommendations for dosing of checkpoint inhibitors and targeted therapy in obese adults with cancer?

DR. GARY LYMAN: Well, Brittany, these are the new agents that I referred to in the introduction that have appeared in broad usage in oncology and other disciplines since our 2012 guideline recommendation. Many of these are monoclonal antibodies, and they just generally have a wider therapeutic index and distribute an extracellular fluid and plasma with less correlation with body size descriptors, such as weight or body surface area. They may be, in fact, in some cases are amenable to fixed dosing schedules.

So this has all led to a whole array of new agents approved by the FDA for cancer therapies that are being dosed on a wide variety of means, some based on dosing like we have done for classical chemotherapy that Dr. Griggs discussed using body surface area, in some cases body weight, and then some being dosed base on fixed dosing-- fixed size regardless of the body size that the patient represents. So it gets a little complicated, because currently the monoclonal antibodies and many of these therapies are dosed in different ways, versus fixed dosing is recommended for some of the immunotherapies, alemtuzumab, afatinib, as well as targeted therapies like pertuzumab, which are relatively recent.

And then weight-based dosing, milligram per kilogram, is used for other checkpoint inhibitors, like ipilumumab, as well as other monoclonals like bevacizumab and trastuzumab among others. And then again some were still dosing based on body surface area, such as rituximab and cetuximab. So the bottom line is these agents will be dosed and the approved dosing by the FDA will generally be based on the schedule and dosing that was used in the pivotal clinical trials. And different companies in different disease areas have chosen different ways of dosing these.

So for us, with this guideline, and this is true of overweight and obese patients in particular, we recommend dosing these agents based on the FDA approved dose and schedule for that agent. But be aware, as I indicated, that it will vary from agent to agent and category of agent from one to the other. Because of the convenience and perhaps some safety issues related to fixed dosing, additional data has been submitted to the FDA for some agents, nivolumab, for instance, and pembrolizumab, to suggest that a different dosing schema, fixed dose schema can be used, and that has led to a modification in those dosing recommendations.

So even if you think you know, if you're not using these agents day in and day out, you really should check and make sure you're using the currently recommended dosing. And final point is, in the overweight and obese patient, any dose modification because of adverse events or scheduling changes should be applied independent of the patient's obesity or overweight status. In other words, any dose modification that you would apply a healthy weight patient is the same type of dose modification you should apply in the overweight and obese patient and not modify solely based on the patient's weight or obesity status.

BRITTANY HARVEY: Definitely. Great. That was actually going to be my next question. So Dr. Griggs, do you have anything to add about for obese adult patients with cancer who experience high grade toxicity-- should clinicians modify dosing and schedules differently than they would for non obese patients?

DR. JENNIFER GRIGGS: Well, as Dr. Lyman says, the same with checkpoint inhibitors and targeted therapies, we don't recommend and the evidence doesn't support making changes in a different way. That is, there's no interaction between obesity status and the recommendation through dose modification. So in a patient who has severe toxicity related to chemotherapy as well as the targeted agents and checkpoint inhibitors, we recommend that standard dose modifications be made, and moreover that if the patient does better that one consider dose escalation again, if there were for example another concurrent illness that might have contributed in part to the toxicity. So if that other factor resolves, let the dose be increased again to try to maintain that relative intensity dose over time that we consider ideal.

BRITTANY HARVEY: Great. Thank you for reviewing that for the cytotoxic agents in addition to the immune checkpoint inhibitors and targeted therapies. So then, Dr. Lyman, the last clinical question of this guideline-- how should body surface area be calculated?

DR. GARY LYMAN: Well, this is the issue alluding to when I mentioned that there could be safety concerns with these complex calculations. And we tried to make it simple in the guidelines. There are multiple BSA-- Body Surface Area-- calculators out there. You can search them on the web, you can go to textbooks, and there's a whole range of them.

And we actually looked at this. This goes back to the original guideline, and it holds true today, that if you compare that the dose calculated by these different calculators, it's very close to one another. So our bottom line recommendation-- if you're going to use body surface area for calculating the dose of conventional cytotoxic therapy or any of these other agents where that dosing approach is recommended, any of these calculators are going to give you a safe and hopefully effective dose of the therapy. And we don't prefer or recommend one over the other.

Again, there are many on the web. Many institutions have their preferred and may even have embedded the calculator within the EMR or computer order entry system. Many prefer the Mosteller, the Du Bois, the Boyd, there's a whole variety of these, but all of them will generally yield very similar calculations. We haven't mentioned, and just to point out, as most oncologist know certainly, is one drug group, a specific agent, carboplatin is dosed differently. And for carboplatin, we calculate the dose based on a target area under the curve and GFR, so that the Calvert formula calculates the dose differently for carboplatin. And that's for historical as well as pharmacologic reasons.

So again, as Dr. Griggs mentioned, for classical chemotherapy, body surface area is the most common one. But any of the approved calculators or available calculators will give you essentially the same dosing recommendation. And I would follow what's recommended by your institution.

BRITTANY HARVEY: OK. Well, thank you both for reviewing the key recommendations in this guideline update. So finally, Dr. Griggs, in your view, why is this guideline update important, and how will it impact both clinicians and patients with cancer?

DR. JENNIFER GRIGGS: Dr. Lyman and I have viewed this as a really important guideline and guideline update. Because, as we know, the prevalence of obesity is increasing and obesity is associated with an increase in the risk of cancer-- many cancers, not all. And moreover, people who are obese tend to have worse outcomes. And so to try to level out and keep people from systematically what we consider underdosing people who are obese with chemotherapy is very likely to improve outcomes for an important group of our patients.

In addition, the update, because it's been updated now since 2012, we have more evidence that what we're recommending, what the evidence has supported thus far historically and in trials, is actually safe. There's been no signals, in other words, that the original guideline needed to be altered for certain patients or drugs. And now, with this update, we're pretty confident, based on what we know from the FDA and clinical trials, that using actual body weight is not just appropriate, but it's also recommended. So it's an important issue for the population and for our patients, and it's important for clinicians to have the confidence to use actual body weight when calculating anticancer drug doses.

BRITTANY HARVEY: Great. Thank you, both, for all the work you did to update this evidence-based guideline and thank you for taking the time today to speak with me on the podcast, Dr. Griggs and Dr. Lyman.

DR. GARY LYMAN: Thank you, Brittany.

DR. JENNIFER GRIGGS: Thanks, Brittany. We want to thank our co-authors on the guidelines, as well as the ASCO staff for their tremendous work.

DR. GARY LYMAN: Yes, we couldn't do it without all of them, and it's a tremendous team effort.

BRITTANY HARVEY: Definitely. We thank them all as well. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. 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 on iTunes 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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