Infection Risk Increases With Longer Surgical Duration in Lower Extremity Bone Tumors

Increased surgical duration was found to be an independent risk factor for surgical site infection in patients with lower extremity bone tumors undergoing endoprosthetic reconstruction after tumor resection, according to findings from a secondary analysis of data from the phase 3 PARITY trial (NCT01479283).¹

Findings published in the Journal of Bone & Joint Surgery showed that among the 604 patients enrolled on PARITY, patients who experienced a surgical site infection had a mean duration of surgery of 6.2 hours compared with 4.9 hours for patients who did not have a surgical site infection (P < .0001). Additionally, extended postoperative prophylactic antibiotic therapy was not linked with lower risk of surgical site infection, even in patients with prolonged surgical duration.

“Like all secondary analyses, this study was not powered to answer these questions, but these [findings] can shed some light on trends. Because we have all this data available to us, we should ask some meaningful questions,” co-study author R. Lor Randall, MD, said in an interview with OncLive.^®

The international, multicenter, randomized, controlled PARITY trial was designed to assess the rate of surgical site infections within 1 year of surgery for patients with lower extremity bone tumors requiring endoprosthesis who received a 5-day regimen of postoperative, prophylactic, intravenous antibiotics vs those given a 1-day regimen. Data showed that the 5-day regimen was not superior to the 1-day regimen in preventing surgical site infections.²

Fifteen percent of patients treated with the 5-day regimen (n = 293) experienced surgical site infections compared with 16.7% for those treated with a 1-day regimen (n = 311; HR, 0.93; 95% CI, 0.62-1.40). Additionally, antibiotic-related complications were reported in 5.1% of patients in the 5-day regimen arm vs 1.6% of patients in the 1-day regimen arm (HR, 3.24; 95% CI, 1.17-8.98; P = .02).

In the interview, Randall discussed the primary results of the PARITY study and their implications for the use of antibiotics for patients with lower extremity bone tumors undergoing surgery and highlighted the findings from the secondary analysis of the study on the effect of surgical duration on risk of infection. Randall is the David Linn Endowed Chair for Orthopedic Surgery, chair of the Department of Orthopedic Surgery, and a professor at University of California (UC) Davis Comprehensive Cancer Center in Sacramento.

OncLive: Could you expand on the key findings for the PARITY study?

Randall: PARITY stands for “prophylactic antibiotic regimens in tumor surgery.” This [study] was the first of its kind. It was a global study that looked at 1 day vs 5 days of perioperative antibiotics for limb salvage surgery in patients with bone cancer, [particularly] bone sarcomas. We required a conglomeration of investigators from around the world to enroll [611] patients.

The study was published in JAMA Oncology, and it showed that there was no difference in infection rates for antibiotic regimen durations of 1 day vs 5 days for patients undergoing these massive limb salvage procedures. Infection is a known complication for these limb salvage procedures. Accordingly, people have used longer durations of antibiotics, which then puts the patient at risk for Clostridioides difficile and other secondary infections. This was a fundamental question that the Musculoskeletal Tumor Society and other international sarcoma organizations put forward for our first cooperative trial.

What was the rationale for conducting secondary analyses based on data gathered from PARITY?

The lead primary investigator of PARITY, who has really been our champion, is Michelle Gert, MD, FRCSC, [of McMaster University in Hamilton, Ontario, Canada]. She's the current president of the Musculoskeletal Tumor Society, and she challenged [fellow] investigators to potentially do some secondary analyses. She distributed out the datasets and we leapt at the opportunity. Our group [at UC Davis] looked specifically at surgical duration and its effect on increased risk of surgical site infection relative to the [duration of] antibiotics. Specifically, we looked at whether longer surgeries were a risk factor.

Could you highlight the key findings from the secondary analysis conducted at UC Davis on the effect of surgical duration on risk of infection?

Our team at UC Davis looked at the data set, and with my co-authors Lauren Zeitlinger, DO, Machelle Wilson, PhD, and Steven Thorpe, MD, we looked at the duration of surgery to see if it had any influence [on infection risk]. What we found was that longer surgeries, not surprisingly, did lead to increased risk of infection. It broke out at approximately 5 to 6 hours.

Surgeries that lasted over 6 hours were significantly more at risk for infection [P < .0001] compared to surgeries that were less than 5 hours. Again, the study wasn't designed to answer this question, so this [analysis] raises questions just as much as it provides information. However, it does emphasize the fact that expeditious surgery can help take care of these patients.

It is also important to point out [data for] antibiotic duration. Those patients who had long surgery and 5 days of antibiotics were not at less risk than those patients who had a longer surgery and only 1 day of antibiotics. The antibiotics were not preventative for those infections in longer [surgeries].

What are the potential implications of this secondary analysis?

What we take from this from a clinical standpoint is: move quickly, move efficiently, be well prepared for your surgery, and have contingency plans when things go awry. It doesn't mean you should do a shorter surgery just to decrease the infection risk if a longer surgery is indicated. Certainly, plastic surgery procedures to cover defects will add length to the procedure and should still be done. It is paradoxical in the fact that if you're [working with] a big flap, by covering the defect, you’re trying to decrease the risk [of infection], but because the surgery is longer, you're at increased risk for infection. We don't want to send out any message that surgeons should change their behaviors in terms of longer operations, but they should move quickly and expeditiously.

Could you expand on the findings regarding antibiotic use for 1 vs 5 days following surgery?

I'm not an infectious disease expert, so take this with a grain of salt, but the idea is that you want to ensure that you get the antibiotics right in that immediate phase when the wound is colonized. No matter how sterile we try to make our environment, there are little bits of dust particles and microbes that get into the wound. If you have the antibiotics in there while those bugs are setting up shop, you're probably doing an adequate job. The antibiotics have probably done what they needed to do within those first 24 hours.

In terms of moving expeditiously, efficiently, and having contingency plans, could you elaborate on what that looks like?

For any well-trained surgical or orthopedic oncologist, they take this for granted, but this just means making sure that you have all the right teams involved. Sometimes the team is the resection and the reconstruction team. Sometimes, those individuals are the same. You also have the plastic surgeons and other people who are doing coverage, and you want to ensure that those people are coming in and doing their part quickly so there is not an idle time while surgical teams are transitioning. You want to have all the backup implants available if necessary. If, for example, a frozen section comes back positive and you need to take more tissue, you want to be able to adapt to that situation quickly.

This just means being very compulsive about things. I joke with my trainees that only the paranoid survive; you just want to be equipped to not have delays in the surgery. As I tell my trainees often, when we do have to idle for whatever reason—it’s usually beyond our control but perhaps not—that's when I get most frustrated. Sometimes a surgery will take up 6, 7, or 8 hours, and that's necessary. However, when an operation that can be done in a shorter period and ends up taking a few extra hours, this study tells us that this puts patients at [increased] risk [for infection]. Therefore, make sure your teams are on top of their game.

For medical oncologists, what is the most important takeaway for this research?

As always, it's important that medical oncologists understand the paradigm for surgeons. In this particular case, surgeons definitely need adequate time to prepare and orchestrate these complex operations. In many of these cases, patients are getting neoadjuvant chemotherapy, [then] local control, then post-operative chemotherapy. It's in that neoadjuvant window where [surgeons] have do all our planning.

Frequent communication between the surgical and medical oncology teams is important. For example, say a patient doesn't make their counts, so they're not going to be admitted for [neoadjuvant] chemotherapy. The local control window is then pushed back. Sometimes that involves multiple doctors other than the primary doctor, and they have to re-coordinate and reschedule. Getting that information up-front is important so that the team can be fully prepared come the day of the surgery.

References

1. Zeitlinger L, Wilson M, Randall RL, Thorpe S. Surgical duration is independently associated with an increased risk of surgical site infection and may not be mitigated by prolonged antibiotics: a secondary analysis of the PARITY trial of infection after lower-extremity endoprosthetic reconstruction for bone tumors. J Bone Joint Surg Am. 2023;105(suppl 1):79-86. doi:10.2106/JBJS.23.00056
2. Ghert M, Schneider P, Guyatt G, at al. Comparison of prophylactic intravenous antibiotic regimens after endoprosthetic reconstruction for lower extremity bone tumors. JAMA Oncol. 2022;8(3):345-353. doi:10.1001/jamaoncol.2021.6628