Following endoprosthetic limb reconstruction to treat tumors, the rate of surgical site infections (SSIs) ranges from 10 percent to 15 percent—quite high compared with a rate of less than 1 percent in total joint replacement. Also, unlike joint replacement, no evidence-based clinical guideline has been developed for prophylactic antibiotic treatment to prevent such infections.
The difficulty of conducting prospective clinical treatment trials for rare diseases is just one reason that standards haven’t been developed yet. Michelle Ghert, MD, FRCSC, associate professor of orthopaedic surgery at McMaster University in Hamilton, Ontario, explained, “Because we deal with rare cases in orthopaedic oncology, it’s very difficult to compile evidence. Even large medical centers publish relatively small retrospective studies.”
To meet this need for a practice guideline, Dr. Ghert received a 2012 Orthopaedic Research and Education Foundation/Musculoskeletal Tumor Society (OREF/MSTS) Clinical Research Grant in Orthopaedic Oncology. Dr. Ghert and her colleagues conducted a pilot trial to assess the feasibility of a randomized, multicenter clinical trial of prophylactic antibiotic regimens in tumor surgery.
The OREF/MSTS Clinical Research Grant in Orthopaedic Oncology is a 2-year, $100,000 award that funds promising research—particularly randomized trials—that will yield clinical outcomes for oncology patients.
A need for clinical guidelines
Endoprosthetic limb reconstruction is a standard intervention for malignant or aggressive tumors of the long bones. The duration and complexity of the surgery, as well as preoperative chemotherapy, likely contribute to the high SSI rates. SSIs require additional surgery and long-term antibiotic use, diminish quality of life and functional abilities, and significantly increase the likelihood for eventual amputation.
In preliminary work on this subject, Dr. Ghert’s research team surveyed orthopaedic oncologists and found significant variation in choice of antibiotics, dosages, and duration of treatment. But most survey participants also welcomed better clinical evidence to guide prescribing practices.
In addition to informing best practices in treatment, clinical data would improve antibiotic stewardship. The overuse and misuse of antibiotics are primary factors contributing to antibiotic resistance. Therefore, determining the appropriate use of the drugs in orthopaedic oncology would contribute to a larger effort to ensure the effectiveness and longevity of antibiotics.
Designing the right trial
McMaster University’s Centre for Evidence-Based Orthopaedics provides faculty with expertise, infrastructure, and support for all aspects of clinical research, including project management, data management, statistical analysis, and report preparation. This resource is essential for Dr. Ghert’s work as well as an impetus for her investigation.
Dr. Ghert stated, “After several years of reading one case series after another on this matter, I thought, ‘We can do this. We have the resources to do trials in my specialty.’”
After consulting with an expert panel of six orthopaedic oncologists and three infectious disease specialists, Dr. Ghert’s team decided that the ideal study would be a trial comparing the efficacy of 2 grams of cefazolin (Ancef) given intravenously every 8 hours for either 24 hours or 5 days (or until discharge from acute care).
The trial was designed to test whether the short-term treatment is similar or better than the long-term use. The researchers reasoned that because the short-term use would be best with regard to antibiotic-related complications, then it would be the regimen of choice unless it proves to be inferior at preventing subsequent infection. The expert panelists recommended cefazolin, a first-generation cephalosporin, because it is effective against gram-positive bacteria, which account for most prosthetic infections, and it also exhibits appropriate gram-negative coverage.
Small question on a big scale
“The trial examined a very simple question. It’s 1 day versus 5 days of postoperative antibiotics. And that’s it,” stated Dr. Ghert. “It sounds very simple, but the logistics of running a multicenter, international trial can at times seem overwhelming.”
To conduct an adequately powered, full-scale study, they will eventually need to recruit at least 600 research participants at medical centers in several different countries. The primary purpose of the pilot trial, therefore, was to assess on a smaller scale their capacity to conduct this investigation. Could they meet recruitment goals, maintain data quality, adhere to follow-up schedules, and comply with study protocols? How could they accomplish this in the context of different institutions and different government regulations?
For the pilot, they recruited 60 patients with lower extremity bone sarcomas at 10 sites in Canada and the United States. Postoperative monitoring for infection was conducted at 2 weeks, 6 weeks, 3 months, 6 months, and 1 year. Secondary outcome measures included functional outcomes, quality of life, and oncologic outcomes. Complications of antibiotic treatment were recorded, and the causative organism of any SSI was documented.
Dr. Ghert and her research team completed the pilot study last fall and are now preparing a manuscript for the MSTS annual meeting in October. In addition, they used the data from the initial trial to apply for funding from the Canadian Institutes of Health Research and the Canadian Cancer Society. The researchers have received approximately $1.5 million Canadian ($1.2 million U.S.). This additional funding has allowed them to begin the full-scale study with open patient enrollment at 28 sites in four countries. Thirty more sites across the world are interested in participating.
Funding clinical trials
Clinical trials are expensive undertakings. The entire budget of the pilot study was about $500,000 Canadian. “The OREF/MSTS grant was enough to get us started and propel the project to the next grant application,” stated Dr. Ghert. “When we’ve applied to other agencies, the trust of OREF and MSTS in our project was validating.
“Our field is challenged by the size of the patient population,” she continued. “If we are able to collaborate internationally, and if we can develop clinical guidelines based on hard evidence, we are going to improve outcomes and improve patients’ lives.”
Jay D. Lenn is a contributing writer for OREF. He can be reached at firstname.lastname@example.org