Surgical Complications Unrelated to Timing of Neoadjuvant Chemotherapy in Lower-Extremity Sarcomas

R. Lor Randall, MD, FACS

The amount of time between neoadjuvant chemotherapy and local control surgery did not influence the rate of surgical complications for patients with lower-extremity sarcomas, according to a subset analysis of the phase 3 PARITY trial (NCT01479283).¹

These findings, said R. Lor Randall, MD, FACS, underscore the need to minimize the time between neoadjuvant and adjuvant chemotherapy to improve patient outcomes.

The PARITY study initially evaluated a 24-hour course of antibiotics vs a 5-day course of antibiotics in patients with sarcomas who were preparing to undergo surgical resection and endoprosthetic reconstruction. Results showed that 24 hours of antibiotics was not inferior to a 5-day course in terms of preventing infections. Furthermore, the shorter course was associated with fewer antibiotic-associated adverse effects.²

The subset analysis examined patients who received surgery within 3 weeks of neoadjuvant chemotherapy, between 3 and 6 weeks following neoadjuvant chemotherapy, and more than 6 weeks after neoadjuvant chemotherapy. Rates of surgical site infections and reoperations were not affected by the timing of neoadjuvant chemotherapy.

“The real contextual message is don’t wait to do the surgery,” Randall explained. “Proceed with local control because in the time after the surgery, that talk clock is ticking, and we want to get these patients back on chemotherapy.”

In an interview with OncLive^®, Randall, the David Linn Endowed chair for Orthopedic Surgery, the chair for the Department of Orthopedic Surgery, and a professor in the Department of Orthopedic Surgery at University of California Davis Health, discussed the findings from the subset analysis on the timing of neoadjuvant chemotherapy. He also detailed how chemotherapy could affect complication rates associated with limb salvage surgery and explained the multidisciplinary approach needed between medical and surgical oncologists for patients with sarcomas undergoing limb salvage surgery.

OncLive^®: What did the PARITY results show about the relationship between surgical complications and the timing of neoadjuvant chemotherapy and surgery for patients with lower-extremity sarcomas?

Randall: The PARITY study, a world conglomeration orthopedic oncology study by Michelle Ghert, MD, FRCSC, et al, published in JAMA Oncology, is a recent study that randomly assigned patients undergoing big bone sarcoma resections to 1 vs 5 days of antibiotics. This study looked at infection rates as an outcome.³

[Investigators] are now conducting a subset analysis. This project is being led by a group of investigators who wanted to specifically look at patients undergoing limb salvage procedures who received neoadjuvant chemotherapy [to evaluate the influence of] the timing of that chemotherapy relative to the surgical procedure itself.

Investigators [classified] patients into those who got surgery within 3 weeks of their chemotherapy, surgery within 3 to 6 weeks of chemotherapy, and surgery more than 6 weeks after chemotherapy. Investigators found no difference in complication rates between the 3 cohorts, and patients had similar outcomes.

[However, investigators] did not stratify for the patients who were randomly assigned to 1 vs 5 days of antibiotics. This was a subset analysis, so it has its own inherent flaws, as any subset analysis will have. That was the 1 limit of the study.

The important takeaway from this [subset analysis] is if a patient is going to get chemotherapy [prior to limb salvage surgery] for osteosarcoma, Ewing’s sarcoma, and potentially a few other bone sarcomas, it doesn't matter if they fall within the 3-week window [following chemotherapy, since this will not affect the] complication rate from the surgery.

The big exclamation point for consideration is that [the timing of the] resumption of chemotherapy [following surgery is important]. The way it works in bone sarcomas, we call it the ‘local control sandwich,’ where a patient receives up-front chemotherapy, local control surgery, and then more chemotherapy. The surgery is sandwiched in between neoadjuvant and adjuvant chemotherapy. This study nicely demonstrated that for neoadjuvant chemotherapy, whether surgery is given within 3 weeks, within 6 weeks, or after 6 weeks, complication rates from the surgery [aren’t affected].

Another study [by Hamayun Imran, MD, MSC, et al] highlighted that patients who didn't begin adjuvant chemotherapy within 3 weeks of surgery had higher risk of poor oncologic outcomes.⁴ [If it takes 3 weeks after surgery to resume chemotherapy, and you waited more than 3 weeks [between neoadjuvant chemotherapy and surgery], it has been too long to get the chemotherapy going again.

What are the complications of limb salvage? How can complications differ based on when chemotherapy is administered?

The big things we worry about in limb salvage surgery are infections and wound complications. There are a variety of other complications that can happen, such as local recurrence and other things of that sort, but infections and wound complications are the [primary] problem. Some surgeons have an understandable angst about ensuring that patients have their immune system back in shape and their counts have recovered from neoadjuvant chemotherapy. [We want to see that] patients have an absolute neutrophil count of at least [1000 cells/µL]. Patients must have an intact immune system to be able to limit infection. We are putting metallic endoprostheses in these patients, which have high infection rates.

[Additionally], patients must be nutritionally and constitutionally healthy enough so they can heal these large wounds. Those are the 2 things we worry about most as surgeons. Some surgeons understandably wait longer following [neoadjuvant] chemotherapy to optimize all of the considerations around infection and wound complication. However, you also have this other clock that you are influencing [by waiting longer for surgery following neoadjuvant chemotherapy].

Is there a scenario where amputation is preferable to limb salvage therapy?

Amputation is always on the table. Fortunately, we do more limb salvage than we do amputations. Amputation in some cases is the better functional outcome compared with limb salvage, [though it is a complex debate].

[Results from the PARITY] study do not influence that discussion around whether amputation is necessary. Usually, that decision can be made up front if the tumor has compromised neurovascular structures to the point that there is no way to salvage the limb, or if there is a bad pathologic fracture. However, that is not addressed in the work from PARITY.

What can be done to prevent post-operative infections following limb salvage therapy?

We've nicely answered this question with the antibiotic regimen, as more antibiotics won’t necessarily change the infection rate. There was a slight decrease in the rate of infection, but only minimally so, in the cohort of patients who received 5 days of antibiotics vs the cohort of patients given 1 day of antibiotics. However, it came at the cost of increased complications such as Clostridioides difficile and other things that are associated with prolonged antibiotics.

More antibiotics are not necessarily the right answer. As a surgeon, it is important to be expeditious in your surgery and to do all your homework up front, as all good surgeons know. When you’re in and conducting surgery, you’ll be prepared to get the patient’s operation done as quickly as possible. No matter how sterile the environment is, the longer the patient's limb is open, the more likely they are going to get at least 1 microbe in there.

How have adjuvant chemotherapy, appellation techniques, and computer navigation affected the traditional treatment paradigm within limb salvage?

The technologies that employ 3D printed cutting jigs and implants have decreased the operative times dramatically. Although there is a cost to the implants and cutting jigs, the amount of operative time has dramatically decreased by using this technology, [though no one has done a value analysis of the cost of the jigs and implants vs time saved in surgery]. In many cases, [jigs and implants] obviate the need for any navigation technologies.

Ablation technologies are certainly coming online. I have an ablation case coming up where we are using ablations to control a tumor locally. Obviously, we don’t like to ablate [solid tumors], primarily because we prefer oncologic resection, [aside from] Ewing sarcoma. However, we are doing more ablation technologies for metastatic cases and some benign conditions.

From a surgeon’s perspective, based on recent developments and the current treatment landscape, how can medical oncologists optimize patient outcomes when limb salvage is on the table?

The sarcoma medical oncology community has a finger on the pulse. Like all of oncology, with basket studies looking at pathways and disease-specific treatments, targeted therapy is where we need to go.

For advanced cancers, we’re all realizing that it’s more about controlling cancers than curing people of their cancers. We can make [cancers] chronic diseases, similar to diabetes or other conditions, where we may not totally eradicate the disease, but we can treat for a period of time, controlling the disease progression.

Like every living organism, cancer evolves in its course and picks up a new pathway or a new mutation to evade targeted therapy. Then the oncologist picks up on it, switches a patient to another agent, and keeps the tumor at bay. The goal is that patients live long and productive lives with their cancer and meet their end with their cancer as opposed to from their cancer.

What would you impart to colleagues about this and future trials?

These conglomerate orthopedic oncology trials are exciting, and it is important to shout out to Michelle Gert, MD, FRCSC, and Patricia Schneider, BSc, at McMaster University. They have shown us how we can do these global studies in orthopedic oncology and beyond in sarcoma.

There’s another trial looking at randomly assigning patients to imaging surveillance of chest radiographs vs chest CTs. This trial hopes to address whether chest CTs are always necessary. This is a very exciting time in orthopedic oncology, with much more level 1 data coming out in the near future.

References

1. Gazendam AM, Schneider P, Spiguel A, Ghert M. Neoadjuvant chemotherapy and endoprosthetic reconstruction for lower extremity sarcomas: does timing impact complication rates? Ann Surg Oncol. Published online July 21, 2022. doi:10.1245/s10434-022-12258-w
2. Zeitlinger L, Randall RL. Assessment of the PARITY Sub-Analysis ‘‘Neoadjuvant Chemotherapy and Endoprosthetic Reconstruction for Lower Extremity Sarcomas: Does Timing Impact Complication Rates?’’ Ann Surg Oncol. Published online July 30, 2022. doi:10.1245/s10434-022-12307-4
3. Ghert M, Schneider P, Guyatt G, et al. Comparison of prophylactic intravenous antibiotic regimens after endoprosthetic reconstruction for lower extremity bone tumors: a randomized clinical trial. JAMA Oncol. 2022;8(3):345-353. doi:10.1001/jamaoncol.2021.6628
4. Imran H, Enders F, Krailo M, et al. Effect of time to resumption of chemotherapy after definitive surgery on prognosis for non-metastatic osteosarcoma. J Bone Joint Surg Am. 2009;91(3):604-12. doi:10.2106/JBJS.H.00449