A multi‐institution experience comparing the clinical and physiologic differences between upper extremity and lower extremity melphalan‐based isolated limb infusion

Abstract

Background Although studies of melphalan-based isolated limb infusion (ILI) combine data from upper extremity (UE) treatments with those from lower extremity (LE) treatments, differences between the 2 may be clinically important. Methods Candidates for UE ILI (n = 51) and LE ILI (n = 192) were identified from prospective databases at 2 institutions. The response Evaluation Criteria in Solid Tumors and Wieberdink toxicity scale were used as appropriate. Results The following patients had indications for UE ILI: melanoma, 36 of 47 patients (77%); sarcoma, 5 of 47 patients (11%); Merkel cell sarcoma, 3 of 47 patients (6%), and squamous cell carcinoma, 3 of 47 patients (6%). The patients who underwent UE ILI, as expected, had lower limb volumes (mean, 2.5 L vs 8.6 L; P < .001) and lower mean melphalan doses (20.7 mg vs 49.5 mg; P < .001). On perfusate blood gas analysis, the mean base excess at 30 minutes (−13.9 vs −9.1; P < .001) and the mean pH at 30 minutes (7.06 vs 7.15; P < .001) were lower for UE procedures than for LE procedures, although the mean ischemic time was longer in LE procedures (67.2 minutes) than in UE procedures (61.6 minutes; P = .03). The rate of regional toxicity grade ≥3 for UE ILI was 7% compared with 24% (P = .005) for LE ILI. There was no difference in the complete response rate for melanoma UE procedures (28%; 95% confidence interval, 16%–44%) compared with LE ILI procedures (32%; 95% confidence interval, 25%–39%). Conclusions ILI for UE disease was associated with similar complete response rates but lower toxicity than ILI for LE disease and with different physiologic sequelae despite comparable methods. The UE appears relatively resistant to toxic effects of melphalan-based ILI as currently performed, which suggests a potential for further optimization of drug dosing for UE ILI.

Australian multi‐center experience outside of the Sydney Melanoma Unit of isolated limb infusion chemotherapy for melanoma

“…The significantly lower response rate following upper limb ILI was unexpected given the similar dosing schedule. Also, a recent report, incorporating a large number of upper limb ILI, showed no difference in response when compared to lower‐limb procedures . A possible explanation for our observation could be the fact that only a total of 14 upper ILI procedures were performed at the four institutions in our study, limiting the experience in upper ILI.…”

Regional therapy in metastatic melanoma: an update on minimally invasive intraarterial isolated limb infusion and percutaneous hepatic perfusion

“…Similar to the discussion above on the potential applications to enhance drug delivery in regional therapy via targeting the tumor microvasculature, results from an animal model demonstrated slow tumor growth when sorafenib was combined with ILI [34]. However, a Phase I trial of sorafenib and melphalan-based ILI combination in 20 patients resulted in increased toxicity without seeing an appreciable increase in clinical response [39]. Although patients treated with sorafenib have been reported to have reduced VEGFR2 expression, a factor reported to potentially correlate with clinical response, inhibition of the RAF-MEK-MAPK pathway has not been demonstrated in sorafenib-treated tumors [8].…”

Resection of Residual Disease after Isolated Limb Infusion (ILI) Is Equivalent to a Complete Response after ILI-Alone in Advanced Extremity Melanoma

“…Differences in methodology from those in Australia may contribute to the differences in outcome seen so far. In a recent multi-institutional United States experience, ILI was offered as a regional therapy for patients with in-transit melanoma, stage IIIB or IIIC; this is contrary to the MIA which reports on ILI inclusive of stage I and II disease as well as planned double or repeat ILI(14). Additionally, response at our institute and Duke University Medical Center is typically recorded at 3-month follow-up, based on both clinical exam and PET imaging, while MIA reports response by two clinical observations <4 weeks apart (15).…”

“…All ILIs were performed as previously described from both Duke University Medical Center and Moffitt Cancer Center (12, 14). Briefly, percutaneous catheters were placed by Interventional Radiology under fluoroscopic guidance to the affected limb.…”