Saving Arms and Legs in Advanced Soft Tissue Sarcomas

Kristin Jenkins

February 22, 2017

In patients with soft tissue sarcomas facing amputation of an arm or leg, regional chemotherapy with isolated limb infusion (ILI) can provide prolonged limb salvage without compromising overall disease control, say researchers reporting on a 22-year retrospective analysis of the largest experience of the technique to date.

With a median follow-up of 20.6 months, the limb salvage rate was 78% in 77 patients with treatment-resistant, locally advanced soft tissue sarcomas of the extremity, reports a research team led by John E. Mullinax, MD, from the Sarcoma Department at the H Lee Moffitt Cancer Center and Research Institute in Tampa, Florida.

At 3 months, the overall response rate was 58% in patients who underwent ILI from 1994 to 2016 at four centers in the United States and one in Australia, say the researchers.

The findings are detailed in a report published online February 15 in the Journal of the American College of Surgeons.

"Isolated limb infusion is a safe and effective technique of treatment of patients with locally advanced soft tissue sarcoma who otherwise might require amputation," the researchers said in a statement. "For centers with experience in regional chemotherapy, our data suggests that expansion of this treatment to patients with sarcoma would result in a clinically relevant response for the majority of patients, allowing them to keep their limb with no detriment in overall survival," they write in their report.

Of the 23 patients who had a complete response, 13 were able to undergo a complete resection of disease. Six patients who had a partial response at 3 months underwent resection and had no evidence of disease.

The median overall survival for the entire cohort was 44 months, with patients who underwent ILI for lower-extremity disease having a median overall survival of 57 months compared with 28 months for those who received ILI for upper-extremity disease.

Interesting Results

The results of this retrospective review are interesting but not practice-changing, said George D. Demetri, MD, professor of medicine at Harvard Medical School and director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts, who was approached for comment.

"I actually do believe that in rare cases this [technique] could be helpful. However, it's a very retrospective look at a technology that different people do differently. In Europe, for instance, tumor necrosis factor is mixed into the perfusion. This makes it difficult to draw any conclusions," he told Medscape Medical News.

The technique, first developed to deliver chemotherapy without systemic toxicity to patients with melanoma, was initially performed using hyperthermic isolated limb perfusion (HILP) with open cannulation.

More recently, ILI has been used to circulate chemotherapy less invasively through arterial and venous catheters following complete tourniquet occlusion of the extremity. Retrospective comparison of ILI and HILP has demonstrated equivalent outcomes, although ILI can be repeated whereas HILP usually can't, the researchers note.

The analysis shows that while ILI did not prevent disease progression or amputation in all patients, those with a response 3 months after infusion had a longer median time to amputation than those with no response (P = .0001). In 17 patients who had disease progression, the median time to amputation was 4.5 months.

"Most patients would prefer to have more time with their leg rather than face an amputation," Dr Mullinax said in a statement issued by the American College of Surgeons.

Study results were presented at the Southern Surgical Association 128th Annual Meeting in Palm Beach, Florida (December 4-7, 2016).

"Our experience sets a benchmark for outcomes with a new treatment modality," Dr Mullinax told Medscape Medical News. "From a technical standpoint, expanding this technique to other cancer centers who may have the infrastructure but don't offer this could be arranged."

In the study, 84 ILI procedures were performed. These included 21 infusions for upper-extremity disease in 19 patients and 63 infusions for disease of the lower extremity in 58 patients.

The median age of the study cohort was 69 years, and 62% of patients were female. Almost half had undifferentiated pleomorphic sarcoma, followed by synovial sarcoma, leiomyosarcoma, and angiosarcoma in descending order of prevalence. All had "very few systemic treatment options," Dr Mullinax and colleagues say.

In the 90 days before receiving ILI, 21 patients received systemic cytotoxic chemotherapy and 39 received external-beam radiation therapy.

All patients received general anesthesia for a 30-minute perfusion to the limb of melphalan (Alkeran, ApoPharma) and dactinomycin (actinomycin D). This was followed by active washout to prevent systemic exposure. The median length of hospital stay was 7.1 days.

It is estimated that about half of all patients with intermediate- or high-grade soft tissue sarcomas develop metastatic disease and that the overall survival is approximately 50% at 5 years.

To address concerns that residual disease following ILI could lead to a more rapid distant metastatic progression or decreased overall survival, the researchers compared outcomes against those in an independent cohort of 72 patients who underwent amputation for locally advanced soft tissue sarcoma at the Moffitt Cancer Center in Tampa from 2006 to 2016.

While the comparative analysis revealed "no apparent impairment" in distant metastatic or overall survival, the study didn't randomly assign patients between ILI and amputation. As a result, the researchers say they could not use the data set to perform a head-to-head comparison of response to treatment and survival.

However, analysis of ILI perfusion outcomes shows that distant metastatic-free survival was longer for patients who responded to ILI than for those who didn't (P = .01), while the disease-specific survival was the same for both groups (P = .2).

At the time of the analysis, 21 patients who received ILI were alive with disease and 20 had no evidence of disease after ILI.

"Advocates for ILI in these patients would argue that, with similar long term survival data and meaningful overall response rates, patients would much prefer a treatment that preserves the affected extremity to one that does not," Dr Mullinax and colleagues say.

"The reality is that those patients who develop metastatic disease after amputation or ILI likely already have distant microscopic disease at the time of the procedure but the radiographic staging studies are not sensitive enough to detect it. In this sense, the treatment of the extremity disease is not the determinant of long term survival and therefore a limb salvage approach with ILI might be justified," they write.

The fact that so few centers are offering the technique indicates how difficult the procedure is to perform, Dr Demetri said, noting that because only one third of patients included in the analysis had received chemotherapy in the 3 months before entering the study, ILI "was the first line of attack for two thirds of patients. How do we know that regular chemo wouldn't have shrunk the tumor?"

Sarcomas are rare, he pointed out. There are approximately 16,000 cases of all types of sarcoma in the United States and "at most" 50,000 cases worldwide. This may explain why it took more than 20 years to accrue a study population consisting of "a mixed bag of tumors," he said.

Newer, easier limb-salvage technologies are being tested for the treatment of rare sarcomas, Dr Demetri pointed out. One study in Europe is injecting nanoparticles with a radiation-enhancing metal into the tumor before radiation therapy, he said, noting, "It's a smaller operation because it's just an injection."

Although unproven, the technique has now been tested in a phase 3 randomized trial in which half of patients received standard radiation and the other half received an injection of the nanoparticles before radiation, he said.

This work was supported by a grant to the H Lee Moffitt Comprehensive Cancer Center and Research Institute. The study authors and Dr Demetri have disclosed no relevant financial relationships.

J Am Coll Surgeons. Published online February 15, 2017. Abstract

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