Treatment of Metastatic Carcinoma and Myeloma of the Femur: Joint MSTS/ASTRO/ASCO Guideline

An interview with Dr. Felasfa Wodajo from Virginia Cancer Specialists on "The Treatment of Metastatic Carcinoma and Myeloma of the Femur: Joint MSTS/ASTRO/ASCO Guideline." This guideline covers medical oncology, radiation oncology, and surgical recommendations regarding the management of patients with metastatic or myelomatous lesions of the femur. Read the full guideline at www.asco.org/supportive-care-guidelines.

Transcript

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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's cancer care. You can find all the shows, including this one, at podcast.asco.org

My name is Brittany Harvey and today I'm interviewing Dr. Felasfa Wodajo from Virginia Cancer Specialists in Fairfax, Virginia, co-chair on the treatment of metastatic carcinoma and myeloma of the femur, joint Musculoskeletal Tumor Society, American Society for Radiation Oncology, and American Society of Clinical Oncology Guideline. Thank you for being here Dr. Wodajo.

Dr. Felasfa Wodajo: Thank you so much Brittany, I really appreciate the opportunity to talk about our joint guideline that is being published as we speak. It's a great opportunity to share the information with your members as well as hopefully patients and members of other societies.

Brittany Harvey: Great. Then first I'd like to note that ASCO takes care in the development of its guidelines in ensuring that the conflicts of interest are managed for each guideline. This guideline expert panel was assembled in accordance with the American Association of Orthopedic Surgeons conflict of interest policy implementation for clinical practice guidelines. And the full conflict of interest information for this guideline panel is available online in the full text of the joint guideline on the MSTS website.

Dr. Wodajo, do you have any relevant disclosures that are related to this guideline topic?

Dr. Felasfa Wodajo: There's one relevant, but not directly conflicting. I'm a consultant for ONKOS Surgical. That's a maker of implants, but mostly for patients who need sarcoma surgery, and they don't make implants for the types of conditions that are in the guideline.

Brittany Harvey: OK, well thanks for letting us know. First, can you give us a general overview of what this guideline covers?

Dr. Felasfa Wodajo: Sure. The guideline is focused on the effects of metastatic carcinoma or myeloma on the femur. And, as all medical oncologists are aware, metastatic disease to the bone and myeloma are often associated with skeletal pain and sometimes skeletal fractures. Those fractures can occur in any part of the body, spine, of course long bones, and ribs, and so on.

But in our world of orthopedic surgery-- I'm a representative from the Musculoskeletal Tumor Society-- the bones and then added complication are not all equal, and some areas have greater morbidity and effect on patient's outcome than others, the femur being a very important one. And we wanted to focus our efforts on discussing the causes and potential treatments of metastatic disease to the femur.

Brittany Harvey: And then what are the key recommendations of this guideline?

Dr. Felasfa Wodajo: Sure, I'm looking forward to discussing those. I do want to, of course, take a second to acknowledge the hard work that was done by my co-chairs, Dr. Patrick Getty, also from the MSTS, Dr. John Charlson, who was an ASCO co-chair, and Dr. Josh Petit, who is the ASTRO co-chair. And also this gives me a chance to say that this guideline was a joint effort between those three organizations which you already mentioned.

The initiative was led by our organization-- the Musculoskeletal Tumor Society, MSTS-- which is a mostly North American, but also international, society of musculoskeletal tumor surgeons, also known as orthopedic oncologists. And therefore, in almost every place that members of our group work, they're working in close association with medical oncologists and radiation oncologists.

So we wanted to make sure that the guideline reflects the input of all three specialties since all three specialists are often treating the same patients. And in developing the PICO questions-- which are the underlying questions in developing a guideline-- we made sure that we had co-chairs-- one from each of the societies-- agree on which PICO questions to include in the final literature search.

And then finally, the guideline as written, roughly breaks the recommendations down by specialty. It starts off with medical oncology topics, then radiation oncology topics, and then surgical topics. So that's a little bit of background that might be helpful.

I also wanted to mention that one of the meta level findings was the paucity or the dirth of literature that directly addressed the question at hand which is, what kinds of treatments can prevent femur fractures, and then which therapies are best for patients with disease in the femur that may or may not lead to fractures. And we started off with a fairly broad net. But as we focused down on the questions, our initial literature search-- which resulted in over 4,000 journal articles-- was winnowed down to a total of 23 papers which had the high enough level of evidence to be included in our guideline production. And therefore, that inevitably a good number of our questions-- not having strong enough evidence to make a strong evidence based recommendation-- and therefore more than half of our recommendations in the end had to be consensus or expert opinion.

So let me continue with your original question which is, what are the key recommendations. Well, questions that we were interested in were number one, to what extent can non-surgical treatments of metastatic disease to the femur, or myeloma in the femur, will reduce the risk of fracture.

So almost everybody listening to this podcast will know well that bone targeted agents such as the bisphosphonates and denosumab have a strong effect validated in multiple high level randomized and prospective studies in reducing Skeletal Related Events, SREs. As you know, as the listeners also know, Skeletal Related Events is a fairly broad umbrella term, and it includes fracture of any bone as well as hypercalcemia and need for surgery.

But like I said earlier on, a compression fracture of a vertebral body which causes back pain but is treated conservatively, and a fracture of the rib, which also causes pain, treated conservatively or nonoperatively, is a very different matter from a femur fracture which always requires surgery in order to allow the patient to ambulate and regain function.

Having said that, we were disappointed to find that in much of the literature around bone targeted agents-- of which there is plenty-- there's really very little of it that you can find where they stratify, or at least retort, which bones were fractured. So even though there is a strong literature base supporting reduction skeletal events, we can't really say for sure that the risk of a fracture of a femoral lesion is diminished by both targeted agents.

That came out as a consensus statement because this seems to reduce fractures overall, so we left this as a consensus and agreed that BMAs may assist in reducing the incidence of femur fractures.

The next item, number three, in our final report recommended that clinicians consider decreasing the frequency of zoledronic acid dosing to 12 weeks instead of the usual, and most common, four week interval.

There's actually a fair amount of literature supporting quarterly injections as equally efficacious. That's mostly focused on zoledronic acid. It may be true for [INAUDIBLE]. It may also even be true for denosumab, but the literature didn't support that as yet.

But we did make this strong recommendation on our part that clinicians consider reducing the frequency of dosing. If nothing else, because in addition to reducing costs to the patient and time of the patient, we think there may be-- and we put this in our rationale-- there's some chance that some of the unintended side effects of long-term treatment with these bisphosphonate and bismuth therapies such as aseptic necrosis of the jaw and atypical fractures, or brittle bone fractures, of the femur may be reduced with decreased frequency.

Extrapolating from the finding that the longer patients are treated, the higher the incidence of these conditions are, especially atypical fractures. So it could be that less frequent dosing is analogous to less length of treatment. So that was an evidence based and strong recommendation.

We also then looked at the effect of radiation on bone lesions and whether or not it does reduce risk of fracture. We found, not surprisingly, that the radiation oncology literature really focuses on pain. And it's been proven many times and in multiple studies across many decades that radiation therapy does reduce pain at 80% to 90%. And even re-treatment will reduce pain in up to 50% to 70% of patients. But surprisingly, there's actually very little data out there whether it reduces the risk of fracture.

Now we would presume that fracture risk is correlated to bone loss, and that would be radiolucency or loss of calcification on the X-ray. And there are some studies out there which attempt to measure density of bone before and after radiation therapy. And there seems to be some validation, or at least some measurement out there that radiodensity does increase with radiation therapy, and again, we went from that and extrapolated that fracture risk would best be reduced.

But that ended up being a consensus statement. And it's actually a fairly important topic. And hope that more studies would be forthcoming on this, because it would be very helpful for us to predict ahead of time whether this patient can avoid a fracture with radiation alone or do they need to go to surgery.

Next we talked about how effective or beneficial is radiation after somebody's had surgery. So whether or not they've had a fracture, is there a further benefit to radiation. And here the amount of data was even more disappointing.

There's really only two studies that attempt to address this question-- is there a benefit to additional radiation following surgery-- neither one of which was well controlled. They're way out of date and the criteria themselves used in measuring the benefit were not validated.

Now we felt, as a work group-- again consisting of medical oncologists, radiation oncologists, and surgical oncologists, in this case orthopedic oncologists-- that the additional morbidity from radiation after surgery is fairly low. So we left that recommendation as that it has some benefit, but that was the consensus only.

One item that we elevated from consensus to a moderate strength was the benefit of using multifraction radiotherapy to reduce the risk. There is some data-- again, it may be biased-- that patients who undergo single dose radiotherapy as opposed to multifraction radiotherapy for metastatic lesions have an increased risk of fracture. And it may be associated and it may be that those patients getting single dose radiation were at higher risk or had more rapidly progressing disease. But there may be some signal in that noise, and after evaluating the papers and with the help of our experts in radiation oncology, we elevated that to a moderate strength of recommendation.

Then there was a series of questions we tried to address, various surgical techniques and the management of pathology of fractures in the femur and prevention of, and those questions are really more about surgical technique. And these were addressed to our surgical colleagues in large part. I don't know, and I would suspect that the audience of this podcast probably won't be as interested in these questions as the ones we just discussed, so I'll leave those for another time. But I will say a large number of these ended up being also consensus driven evidence.

Brittany Harvey: Got it. Well, thank you so much for reviewing those highlights from the multidisciplinary group and the supporting level of evidence. That's very helpful. So in your view, why is this guideline so important and how will it impact clinical practice?

Dr. Felasfa Wodajo: So, thank you for the question. I'll answer that in two ways. I think the two items that might be of immediate clinical relevance, and therefore of help to patients and their physicians, is number one, further promulgation of the idea of less frequent dosing of bone targeted agents is equally efficacious.

We felt that, if based on our common experiences in our various practices and institutions, that still was not widespread practice. In other words, most patients were still receiving monthly injections of these medications. So we do believe that there is some net patient benefit available to us if those are reduced to quarterly injections for the reasons I mentioned above. So that's one potential immediate release and early improvement that we can expect for patients.

I think the other one, to some extent, may be that what I discussed a little while ago about and multifraction versus single fraction therapy. Again, we don't have nationwide survey data to tell us how often those techniques are used. Again, based on this sort of experience of the workup we thought that that may not be widely understood. So those are two immediate clinical benefits that may be there for patients.

The other way I would look at is at a meta level. Number one was that this is a cooperative venture in which the design and implementation of the guideline was across three organizations. And many times guidelines do incorporate the viewpoints of people of multiple specialties, and sometimes even patient representatives. But it's also, I think, further valuable to have multiple organizations involved because there's some cross-fertilization opportunities there, other products may arise from that, and then also you get what we hope is promulgation of that information to people of different specialties. In other words, these recommendations don't stay inside the ecosphere of one association.

Now when you have multiple organizations working on one project, necessarily it gets more complicated. And there is certainly a heavier administrative burden in getting this project initiated and completed. But hopefully the benefits of that will accrue.

The other thing which I'd like to mention is that I think the paucity of high level evidence for the questions we ask-- which we believe are important questions for physicians and patients-- I think hopefully should stimulate the researchers in these fields to accrue more data so that future researchers and clinicians have access to these information.

For example, I suspect that in future prospective studies of bone targeted agents-- those studies are ongoing-- new agents will be coming out. Pharma will be looking at how those work for their patients in the future. And we would like to ask that those future researchers include, at a minimum, anatomic data for fractures. In other words, they should unbundle Skeletal Related Events and tabulate fractures as occurring in which part of the bone, and if that resulted in surgery.

Those data are there in the records, but if they don't collate them as they go forward, they will not be available to us, and so therefore won't be as efficacious in helping our patients in the future.

Brittany Harvey: Definitely. Those are some important points and I like that you touched on the collaboration of the societies. We find that very important at ASCO to one, reduce the duplication of efforts, and then also to improve the clarity of the recommendations. So, I guess then, finally-- and you've addressed this a bit in terms of dosing of bone modifying agents-- what do these guideline recommendations mean for patients?

Dr. Felasfa Wodajo: Well, for the bone targeting agents, as I said, that might mean fewer doctors visits and maybe less expense, hopefully fewer side effects. For the hyperfractionated radiation, it may not be immediately apparent. I mean a lot of times when a patient's getting single fraction radiation they are fairly advanced in their cancer. But of course they'll get more fractions which means more time in the machine. But hopefully maybe some benefit If they survive longer, which of course, patients are now doing. So those are two potential patient benefits.

Brittany Harvey: Great. Well thank you for your work on these guidelines and for joining me on the podcast today Dr. Wodajo.

Dr. Felasfa Wodajo: I very much appreciate your invitation, and thank you.

Brittany Harvey: 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 in iTunes or the Google Play store.

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