Intriguing Research Brings Hope to Orthopedic Oncology

R. Lor Randall, MD, FACS, the David Linn endowed chair for Orthopedic Surgery, professor and chair for the Department of Orthopedic Surgery at University of California Davis Health, and president of the Musculoskeletal Tumor Society

R. Lor Randall, MD, FACS

The orthopedic oncology community has not seen many treatment advances due to the rarity of bone cancers, but emerging research could serve as a turning point for the specialized paradigm, explained R. Lor Randall, MD, FACS.

“Orthopedic oncology is a relatively niche discipline. We treat a lot of different conditions, most of which are cancers that are relatively rare,” said Randall. “These cancers make up about 1% of adult cancers and make up about 15% of childhood cancers.”

One promising study is the PARITY trial (NCT01479283), which is the first multicenter, international, prospective, randomized trial in the field of orthopedic oncology, is comparing the rates of deep infection in endoprosthetic reconstruction of the lower limb between 1 day versus 5 days of antibiotics in 600 patients.

Another study, the SAFETY trial (NCT03944798), will look at the effectiveness of chest computerized tomography (CT) versus chest radiograph in patients with primary extremity sarcoma that has metastasized to the lungs.

In an interview with OncLive, Randall, the David Linn endowed chair for Orthopedic Surgery and professor and chair for the Department of Orthopedic Surgery at University of California Davis Health, as well as president of the Musculoskeletal Tumor Society, discussed ongoing studies and treatment options in the orthopedic oncology landscape.

OncLive: What are some interesting ongoing trials in this field?

Randall: The PARITY trial is looking at the duration of antibiotic use in patients who had a tumor prosthesis put in for removal of a bone cancer, typically something like osteosarcoma or Ewing sarcoma. These big implants have a higher risk of infection than regular knee or hip replacements and we don't know what the best dose of antibiotics is. The simple thought of "more antibiotics is better" isn't necessarily true, because a longer duration of antibiotics can have some adverse events.

Michelle Ghert, MD, FRCSC, from McMaster University, and her team have tenaciously put together this global trial to look at 1 day versus 5 days of antibiotics in patients who undergo this procedure. While the procedure is rare in the grand scheme of the world, in orthopedic oncology, it's one of the most common [surgical procedures]. This will be pivotal in answering a relatively fundamental question of, "Should we be giving a shorter dose of antibiotics or should we be giving 5 days of antibiotics?" This study has brought together the world of orthopedic oncology to do other therapeutic prospective, randomized, controlled trials.

Why is international collaboration in clinical trial efforts important?

There has never been a trial of this magnitude. Any given institution cannot accrue the experience to answer the study questions because we need people as data points and that requires collaboration. In our institutions, we have our own internal pressures, agendas, and programs, making it very challenging [to work together]. This first trial has trained us so that we can answer more questions.

There is another trial, also spearheaded by Dr. Ghert and her team, that is not an interventional trial, per se, but is [examining] the way we look for metastases of these cancers. In patients who have soft tissue sarcoma, for example, their cancer can metastasize to the lungs and, currently, we do surveillance via chest imaging. We either get a chest radiograph or a chest CT scan to look for lung disease that has metastasized from the primary tumor. However, we don't know if we should be doing [chest imaging] every 3 months or every 6 months and whether we should use a chest radiograph or CT scan.

There are pros and cons to both of these interventions. A chest radiograph is quicker with slower radiation, whereas a chest CT scan has a bit more radiation but is more detailed. In one sense, if you get a chest radiograph, you're exposing the patient to less risk of radiation, albeit very small. The chest CT also has a small dose of radiation, but it's more than [a chest radiograph]. We would like to minimize radiation and want to know if we need a chest CT. Can we get by with answering the question of whether these patients have significant spread of their tumor with just a chest radiograph? That has been on the coattails of the PARITY study, which will be opening soon.

Moving on to tenosynovial giant cell tumor (TGCT), could you discuss some recent advances in treatment?

It's a very exciting time in this arena. The ENLIVEN trial is an incredible study with a lot of collaborators showing that pexidartinib (Turalio), a CSF1 inhibitor, can target patients with this disease. In TGCT, we have 2 sub classes: giant cell tumor of the tendon sheath and pigmented villonodular synovitis. These are benign conditions, for the most part, but they grow very aggressively, particularly around the knee and other areas that can be debilitating for patients.

Up until recently, the standard of care has been surgical removal. However, you can execute a great operation, clean it all out, but then it grows back over a period of time. This new drug [pexidartinib] has shown really remarkable results through this trial. It does not get rid of the tumor entirely, but it shrinks it and reduces some of the symptoms that these patients suffer. Now, we have a pill that a patient can take for a bad condition and improve their quality of life.

What other agents in the pipeline look promising?

Specific to TGCT, there are other drugs that have some promise. Imatinib (Gleevec), which has been on the market, has some benefit in some patients. There's also tumor necrosis factor (TNF)-alpha inhibition that can also help, but there are a lot of adverse events. There are other drugs in the pipeline, making it so that if a patient develops progression after a period of time on one drug, we might be able to go to another.

Beyond TGCT, there are all kinds of exciting stuff that is coming out. There are drugs that we use in situations where we have metastatic carcinoma to the bone. While we take care of primary bone cancers, we also take care of patients when they have another type of cancer, such as breast cancer or prostate cancer, that spreads from those sites to the bone. To treat these diseases, there are bisphosphonates and rank ligand inhibitors that have been shown to slow down this process and improve the quality of life for patients.

Are there any precision medicine efforts in this field?

In the primary bone sarcomas and primary soft tissue sarcomas, we are involved in doing some very deep sequencing of the tumor to look for mutations that can be targeted with the cadre of targeting agents. Patients with these tumors who receive chemotherapy will receive conventional chemotherapy. If they fail that, then they will go on to some of these other agents. At the University of California Davis Health, we try to take some of the original tumor when we diagnose it on biopsy and store that for [precision medicine treatments].