John E. Mullinax, M.D., discusses a chemotherapy strategy that may be able to save the limbs of some patients with sarcoma.
There was a 58 percent overall response rate (ORR) with isolated limb infusion (ILI) in patients with extremity soft tissue sarcoma. The method also prolonged limb salvage for nearly 80 percent of patients in the study, which was recently published in the Journal of the American College of Surgeons.
Treatment-resistant, locally advanced soft tissue sarcomas frequently require amputation. In an attempt to achieve limb salvage, ILI selectively delivers high-dose chemotherapy to the extremity.
From 1994 to 2016, 77 patients underwent ILIs in a retrospective study across five institutions. For 30 minutes, melphalan and actinomycin D were circulated after complete tourniquet occlusion of the limb, then actively washed out to prevent systemic exposure.
Of the 77 patients, the procedure was performed on 19 with upper extremity sarcoma and 58 with lower extremity sarcoma. The 58 percent ORR for the overall population comprised ORRs of 37 percent and 66 percent in the upper and lower extremity cohorts, respectively.
Across the entire study population, the median overall survival was 44.3 months. With a median follow-up of 20.6 months, the overall limb salvage rate was 77.9 percent.
For those patients who underwent amputation for progression of disease, the median time to amputation was 4.5 months. The distant metastatic-free survival was longer for responders than nonresponders, though the disease-specific survival was not different for the same groups.
Can you start by discussing the rationale behind conducting this study?
In an interview with CURE, lead study author John E. Mullinax, M.D., surgical oncologist, Sarcoma Department, Moffitt Cancer Center, discussed ILI as a limb salvage strategy for locally advanced extremity sarcoma.ILI is a form of regional chemotherapy, meaning chemotherapy that is delivered just to one area of the body rather than systemic chemotherapy. The other forms would be isolated limb perfusion (ILP) instead of ILI. ILP involves a procedure where you essentially cut and identify the artery and vein and through a surgical procedure, you openly cannulate it, whereas ILI is done percutaneously, meaning it is less invasive than ILP.
Additionally, with ILI the drugs are used a little differently. Typically, in Europe, the ILP procedure is done with the addition of some other drugs that we don't use here in the States.
What were the most significant findings?
The reason that we put this study together was because centers do the ILI primarily for melanoma patients when patients have melanoma in extremity that's unresectable. There are a handful of centers that have done it for sarcoma, but no one has ever reported on it.During the course of the study, the number of patients that retained their extremity was 77 percent, which was higher than we anticipated. You would imagine that if someone does not respond to the procedure, then they would progress to an amputation, but the number that progressed to an amputation was low.
Were there any significant adverse events?
Secondly, there was around 23 percent of patients, that ultimately had the procedure and then were able to be resected without an amputation. The efficacy when you look across these institutions certainly shows a nice response for these patients. I believe around 56 percent had either a complete or a partial response. During the procedure, a tourniquet is placed on that extremity to prevent the chemotherapy from going systemically. For 30 minutes that extremity is isolated, causing patients to have redness and swelling for a couple of days, which is normal and was expected.
Are there any next steps following this research?
The most feared complication would, of course, be limb loss. If you cut the circulation off to an extremity, you would be worried that the patients would lose that limb. There were no patients that required an amputation, which would be the highest grade 5 toxicity but there were patients that did have redness and swelling. We put four other centers together that did this procedure. I think the message and reason that we wanted to publish this was to show our data for sarcoma patients since there may be a center that’s already doing this procedure for melanoma and they already have the infrastructure and a team available. This may be something that doctors will want to try for their sarcoma patients as well. That is really the next step, to expand the use of this at other centers.
What has been learned over the 20 years of this retrospective data that could have been potentially beneficial toward the beginning of the study?
In terms of what we learned, I think techniques certainly change and the processes become more streamlined. Certainly now, with our interventional radiology colleagues that I described doing this percutaneously, the catheters are placed just like you would place an IV. I think that's really the big advancement.
Are there any ongoing trials in sarcoma that you are particularly excited to see the results of?
Of course, the other advancement would be the circulatory machines, the chemotherapy during that 30 minutes has circulated through the extremity. But from a practical standpoint, there really hasn't been much change. I am a surgical oncologist at Moffitt and my lab effort is with immunotherapy. I study the immune system as it relates to cancer and I think there has been tremendous advancements to immunotherapy, specifically with lung cancer and melanoma. However, it hasn't really panned out or been studied quite as much in other diseases.
Is there anything else you would like to highlight?
In my opinion, sarcoma represents a particularly interesting disease process in that the mutational burden of the tumors is much more like melanoma instead of some of the other GI cancers. Now, there has been early data with anti—PD-1 therapy for sarcoma and with some cellular therapy, using gene-modified T cells to treat patients with metastatic disease. Those are things that I think are really at the forefront. The idea that there are other treatment options to consider is the main message, but referral to an appropriate center is also something that primary oncologists should also certainly consider.