Michelle Ghert, PARITY Investigators Receive 2023 Kappa Delta Ann Doner Vaughn Award

The 2023 Kappa Delta Ann Doner Vaughn Award has been given to Michelle Ghert, M.D., on behalf of the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) investigators for their research on preventing surgical site infections (SSIs) through antibiotic prophylaxis following oncologic reconstruction surgery for bone tumors. Their work resulted in the first-ever international, multi-center randomized controlled trial (RCT) in orthopaedic oncology as well as the largest collaborative effort in orthopedic surgery for the number of countries collaborating. 
 
“In the field of medicine, conducting a 600-patient randomized study isn’t out of the ordinary,” said Ghert, principal investigator and professor in the Department of Surgery at McMaster University in Hamilton, Ontario, Canada. “However, in orthopedic oncology, where we treat rare diseases, it was a shift in our research paradigm. While initially there wasn’t much optimism that this study would work, we believed it was time to move forward for our patients and the research question really resonated. I give a lot of credit to the first few clinical sites that joined the study as they took a leap of faith.”
 
Bone sarcomas—malignant tumors of long bones in the arms or legs—are treated through limb salvage surgery, which involves reconstructing the limb with implants.ⁱ While bone sarcomas are rare, comprising less than 1% of all cancers, these typically affect younger patients._ⁱⁱ SSIs rates are high following surgery, as it is a long and complex procedure, and the patient has a compromised immune system due to chemotherapy.^i,iii SSIs can be devastating to patients, requiring revision surgery and long-term intravenous antibiotic therapy. Even so, reinfection and eventual amputation are common,^iv greatly affecting patients’ quality of life and increasing the overall healthcare costs.^v
 
To reduce SSIs in orthopedic reconstruction surgery, antibiotics are used and typically discontinued after 24 hours as dictated by guidelines for other surgical procedures. However, with no studies examining the role of antibiotic regimens for surgical reconstruction of lower extremity bone tumors, there were no firm conclusions regarding antibiotic duration. The PARITY Steering Committee brought experts together from orthopedic oncology, infectious diseases, clinical epidemiology, biostatistics, and health research methodology to lead research on this issue.
 
PARITY Trial Findings
Prior to the PARITY trial, the team conducted several supportive studies that helped inform the study’s design, implementation and feasibility, including:

• a multinational survey of orthopedic oncologists to determine standard SSI prevention practices
• a systematic review to determine a baseline SSI rate
• a trial protocol publication
• a qualitative study to understand the barriers and facilitators to collaborative perspective research in orthopedic oncology
• a pilot randomized trial
• an assessment of blinded outcomes assessment for SSIs
• an a priori statistical analysis plan

The PARITY trial was conducted across 55 clinical centers in 12 countries as a parallel, blinded RCT from January 2013 to October 2019. Ghert led the study in collaboration with the trial lead in Europe, Roberto Velez, M.D., Ph.D. The trial followed 604 patients with primary bone or soft-tissue sarcoma or oligometastatic (a more treatable form of metastatic cancer) bone disease in the femur or tibia with an expected survival of one year who required surgical resection and implant reconstruction. Patients were randomized to a one- or five-day regimen (311 to one day and 293 to five day) of post-operative intravenous antibiotics (cefazolin or cefuroxime) within eight hours of skin closure and then administered every eight hours after that. Patients, caregivers and outcome assessors were blinded to treatment allocation.
 
The primary outcome focus was a SSI (superficial incisional, deep incisional or organ space) within one year and classified according to the Centers for Disease Control and Prevention (CDC) criteria. Additional secondary outcomes included antibiotic-related complications, unplanned reoperations, oncologic and functional outcomes and mortality. Patients were assessed at two and six weeks, three, six and nine months, and one year after surgery. The PARITY trial findings included:

• Fifteen percent of patients allocated to the five-day regimen and 16.7% on the one-day regimen had a SSI.
• The most common causes of SSIs were Staphylococcus aureus and coagulase-negative Staphylococci.
• There was a significant increase in antibiotic-related complications in the five-day regimen group, with the main complication reported to be antibiotic-associated diarrhea caused by Clostridioides difficile which can be severe and may lead to toxic megacolon, organ failure or even death.^vi
• Other secondary outcomes didn’t differ significantly between treatment groups. 

“The risk for SSI was not significantly different for five days or one day, so when surgeons write post-operative orders, they have that information to work with,” Ghert said. “However, one of the secondary outcomes demonstrated you could actually hurt the patient by causing severe antibiotic-related complications that can be life altering. When you have a patient who is already going through a very difficult time, chemotherapy and morbid surgery, surgeons need to weigh the risk before prescribing prolonged antibiotics as they can cause added gastrointestinal issues that can be chronic.”
 
The PARITY investigators work resulted in 13 manuscripts published in peer-reviewed journals, including The Journal of the American Medical Association (Oncology).
 
Future Use of PARITY Data
The PARITY database represents the highest quality of information on a massive scale on the treatment and outcomes of patients undergoing oncologic reconstruction surgery for bone tumors. PARITY investigators and their research team submitted research questions that could be answered through a secondary analysis of the database and a further 13 manuscripts were developed for a special supplement edition of the Journal of Bone and Joint Surgery. These studies look at such issues as patient and treatment risk factors for SSI and reoperation and the incidence and risk factors for thromboembolic events in lower extremity reconstruction. Additionally, the PARITY Writing Committee worked with the editors of JAMA Oncology to release the PARITY data to the public on Jan. 6, 2023, to further study data dissemination.
 
The Kappa Delta Sorority established the Kappa Delta Research Fellowship in Orthopaedics in 1947. The first annual award, a single stipend of $1,000, was made available to the AAOS in 1949 and presented at the AAOS meeting in 1950. The Kappa Delta Awards have been presented by the AAOS to persons who have performed research in orthopedic surgery that is of high significance and impact. The sorority has since added two more awards and increased the award amounts to $20,000 each. Two awards are named for the sorority national past presidents who were instrumental in the creation of the awards: Elizabeth Winston Lanier, and Ann Doner Vaughn. The third is known as the Young Investigator Award. 

With more than 39,000 members, the American Academy of Orthopaedic Surgeons is the world’s largest medical association of musculoskeletal specialists. The AAOS provides comprehensive education to help orthopedic surgeons and allied health professionals at every career level to best treat patients. The AAOS is the source for information on bone and joint conditions, treatments and related musculoskeletal healthcare issues, and it leads the healthcare discussion on advancing quality.

The PARITY Project was funded by the Canadian Institutes of Health Research, the Orthopaedic Research and Education Foundation in partnership with the Musculoskeletal Tumor Society, the Canadian Cancer Society Research Institute, Physicians Services Incorporated, the Canadian Orthopaedic Foundation, the Silverhearts Foundation, and the Hamilton Health Sciences New Investigator Fund.

References 
ⁱ Jeys L, Grimer R. 2009. The Long-Term Risks of Infection and Amputation with Limb Salvage Surgery Using Endoprostheses. In: Tunn P-U, editor. Treatment of Bone and Soft Tissue Sarcomas. Berlin, Heidelberg: Springer. p 75–84. Available from: https://doi.org/10.1007/978-3-540-77960-5_7.
ⁱⁱ Mayo Clinic. Bone Cancer. Accessed 1/5/2023. URL: https://www.mayoclinic.org/diseases-conditions/bone-cancer/symptoms-causes/syc-20350217
ⁱⁱⁱ Morii T, Yabe H, Morioka H, et al. 2010. Postoperative deep infection in tumor endoprosthesis reconstruction around the knee. J Orthop Sci 15(3):331–339.
^iv Jeys LM, Grimer RJ, Carter SR, Tillman RM. 2003. Risk of amputation following limb salvage surgery with endoprosthetic replacement, in a consecutive series of 1261 patients. Int Orthop 27(3):160–163.
^v Akahane T, Shimizu T, Isobe K, et al. 2007. Evaluation of postoperative general quality of life for patients with osteosarcoma around the knee joint. J Pediatr Orthop B 16(4):269–272.
^vi Mullish BH, Williams HR. 2018. Clostridium difficile infection and antibiotic-associated diarrhea. Clin Med (Lond) 18(3):237–241.