Randall Issues Call for Multidisciplinary Management in Giant Cell Tumor of Bone

R. Lor Randall, MD, FACS

Multidisciplinary management is needed in to provide the best care possible to patients with giant cell tumor of bone (GCTB), according to R. Lor Randall, MD, FACS, who added that tumor boards offer the opportunity to collectively weigh the efficacy with the toxicity of agents such as denosumab (Xgeva).

In 2013, the FDA approved denosumab for the treatment of adults and skeletally mature adolescents with GCTB that is considered unresectable or where surgical resection is thought to likely result in severe morbidity. The decision was based on data from 2 open-label trials in which the overall objective response rate was 25% in 187 evaluable patients with a median time to response of 3 months. Although the RANK ligand inhibitor has demonstrated efficacy in the treatment of locally advanced GCTB, there are some concerns with regard to toxicities associated with the agent, according to Randall.

“Denosumab has its own set of issues with regard to morbidities, and [so, many] don't like to use prolonged courses of treatment. As such, [this decision] really requires a discussion, like at a [multidisciplinary] tumor board for sarcoma, where you have your medical oncologist and/or your pediatric oncologist weigh in on the pros and cons of [this agent],” said Randall. “In the current era, with a second good tool in the treatment of [patients with] GCTB, the medical oncologist and pediatric oncologist should be working with the orthopedic oncologist to manage these patients.”

In an interview with OncLive, Randall, professor and The David Linn Endowed Chair for Orthopaedic Surgery, as well as professor and chair of the Department of Orthopaedic Surgery at the University of California, Davis Health, discussed the need for multidisciplinary collaboration in GCTB, challenges faced in the space, and directions for future research efforts.

OncLive: Could you start off by providing some background on GCTB? What does the current treatment landscape look like?

Randall: GCTB is technically considered to be a benign condition. Small numbers of cases, approximately 5% or so, are reported in which patients will develop non-contiguous disease in the lungs. I hesitate to use the term “metastasis” because is it truly going through the dogmatic process of metastasis or is it potentially just an embolic phenomenon? We don't know. However, patients infrequently will develop lung disease from the primary.

Some of those conditions will be indolent, meaning that lesion won't necessarily grow or that one will grow, but it can be managed either surgically or in a variety of other ways. For those who develop more fulminant aggressive disease, [the lesion can take] over the lung and [become] a threat to the patient's life. It’s a spectrum of disease, but we still call it a benign condition of bone primary. It's important also to distinguish this from tenosynovial GCT, which is a soft tissue tumor that has giant cells within it, but it is a class of tumors that is a distinct entity from GCTB.

The issue with GCTB is that it's a locally aggressive tumor that eats up the bone. Oftentimes, recurrences occur if it's treated by just scraping it out, or curettage as we call it. Surgeons have also learned to use certain types of adjuvants, such as liquid nitrogen, an argon beam coagulator, or even just simple garden variety hydrogen peroxide, to try and extend the local control of the tumor. Despite these efforts, approximately 15% of patients will develop a local recurrence. We sometimes fill them with a bone substitute or bone graft, and we sometimes fill the defect with cement; however, it can be a local control problem. It's not a radiosensitive tumor; it’s generally treated historically with surgery.

Now, the reason I bring it up as a multimodality therapy is that there is a RANK ligand inhibitor called denosumab that has been shown to be very effective in treating non-contiguous disease of GCTB or locally advanced GCTB. The literature is replete with relative success stories of managing a nefarious condition with adjuvant denosumab. Just like with the CSF1R inhibitors with tenosynovial GCT, again a different entity, but a benign condition where we now have a therapy. In GCTB, we also have therapy for conceptually benign disease and in having this new tool in our armamentarium it introduces a whole new cadre of questions. For example, for this tumor that has high local recurrences, should we consider pretreatment or a neoadjuvant course of denosumab, then local control, and then maybe more [treatment]? Or should we consider just taking it out and then if we are worried about the recurrence, just treating [patients] in an adjuvant setting? Many questions are being asked around this.

[The decision on whether to use the drug is] also complicated by the fact that there are emerging data that [show that] sometimes when you pretreat with denosumab, there's higher local recurrence than historical controls. That doesn't mean that there is a cause and effect directly observed with the drug; it just might be that it changes the nature [of the disease].

What happens is that the tumor becomes less aggressive. The giant cells go through a process by which they stop proliferating; it definitely can involute and there are cases where treating just with denosumab have shown durable local control with no surgery at all. However, when we've treated patients surgically after they have received denosumab, early data show that some of them are recurring. It might be the fact that the surgeon doesn't have the same sort of level of appreciation of the gross disease when they go in because some of the tumor may actually be more embedded in the bone to the point where the surgeon doesn't do as wide a curettage as they might have done otherwise.

Could you expand on some of the toxicities associated with long-term use of denosumab to be aware of?

It's somewhat extrapolatory because there haven't been enough patients on [denosumab] for too long, but they do worry about things like osteonecrosis of the jaw that you see with some of the bisphosphonates. There's also concern about overall bone health and bone turnover

because of the interference with the osteoclast pathway, so there could be incidents of atypical fractures, although it hasn't been shown yet because it hasn't been around long enough. Certainly, however, bone pain and other [events] like that [are expected].

Are multidisciplinary boards already being used in this space or is this not really being done currently?

For centers that have engaged sarcoma teams, this falls into that category. The orthopedic oncologist is hopefully bringing these cases to the tumor board to engage their medical oncologist and their pediatric oncologist; however, I can't say that it's uniformly happening.

What advice do you have for centers that don't have these core sarcoma teams? How can they loop in orthopedic oncologists during the management of these patients?

The most common pathway for a patient is, they come in with an area that is bothersome and they get an X-ray which shows a destructive lesion in the bone and they're then referred to an orthopedic oncologist because they're active with the musculoskeletal tumor societies or other international societies in other countries. [Orthopedic oncologists] know about denosumab and they would bring it to some sort of medical oncology panel, if not a full-blown tumor board.

The demographic around this [disease] is that it tends to happen in young adults, so [in patients who are] anywhere from 20 to 40 years of age, sometimes older. Every once in a while, it could come to the attention of a medical oncologist because the patient has a destructive lesion to the bone and they're around 40 and there’s concern regarding metastatic carcinoma to the bone or something of that sort. Medical oncologists will appropriately work it up but they need to know about this entity, too, in their differential diagnosis for treating metastatic carcinoma of the bone, is that in some patients, if it's really very aggressive, if it's in the epiphysis of the bone, that GCTB is in the differential. Therefore, they should sooner rather than later get their orthopedic oncologist involved.

Are there any exciting clinical trials being done in GCT that you wanted to highlight?

Certain individuals in the Musculoskeletal Tumor Society are really passionate about this topic. Unfortunately, getting surgeons to participate in clinical trials is like herding cats. That's not to be disparaging of my colleagues or myself because we are all certainly trying; it's more so that the nuances of decision making around whether or not a patient would benefit from surgery alone versus having an agent introduced in benign disease is a difficult one. We've talked about it and I would hope that if we're doing [clinical trials] in a couple of years, we would revisit this topic and we would be able to say, “Hey, there's a trial coming up about neoadjuvant versus no neoadjuvant denosumab in the setting of GCTB.”

Is there anything else that you would like to add?

There's a small but real number of patients [with GCTB] who develop lung disease. I hesitate to use the term “metastasis,” but they develop non-contiguous disease in the lung, [underscoring

the need for] lung imaging. Sometimes, orthopedic surgeons aren't thinking about the lungs; however, I would humbly posit that orthopedic oncologists certainly are. Regardless, it's very important that we consider getting at least chest radiographs, if not chest imaging, for patients with this condition.

Reference:

FDA approves Amgen’a Xgeva (denosumab) for the treatment of giant cell tumor of bone. News release. Amgen. June 13, 2013. Accessed June 29, 2020. bit.ly/3dFKiUt.