385
Views
10
CrossRef citations to date
0
Altmetric
Research Article

The use of isolated limb infusion in limb threatening extremity sarcomas

, , , , , , , & show all
Pages 1-7 | Received 07 Aug 2012, Accepted 11 Oct 2012, Published online: 03 Dec 2012

Abstract

This paper reports a single-institution experience with the use of isolated limb infusion for limb salvage in locally advanced, unresectable, recurrent limb threatening soft tissue sarcomas.

Background: Locally advanced, limb threatening soft tissue sarcomas (STS) pose a significant treatment challenge. We report our experience using isolated limb infusion (ILI) in patients with unresectable extremity STS.

Methods: A total of 22 patients with extremity STS underwent 26 ILIs with melphalan and dactinomycin. Patient characteristics, intra-operative parameters and toxicity were recorded. Outcome measures included limb-salvage and in-field response rates.

Results: Of the 19 lower and 7 upper extremity ILIs, Wieberdink grade III toxicity or less was observed in all. Median followup was 11 months. A total of 17 patients were evaluable at 3 months post-ILI with an overall response rate of 42%. Four (24%) had complete response (CR), three (18%) partial response (PR), three (18%) stable disease (SD) and seven (41%) progressive disease (PD). Twelve of 17 (71%) underwent successful limb preservation at a median of 9 months post-ILI. Two (12%) were downstaged to resectable disease and remain showing no evidence of disease (NED) after surgery at 30 and 22 months post-ILI.

Conclusions: ILI is an attractive modality that provides regional disease control and limb preservation in patients with limb threatening sarcoma. Although short-term results appear encouraging, long-term follow-up is needed to fully assess the role of ILI in unresectable extremity STS.

Introduction

Locally advanced (unresectable without an amputation or functionally debilitating surgery) extremity soft tissue sarcomas (STS) were routinely treated with amputations until several studies showed a high risk of progressive disease and distant metastasis and a lack of survival benefit Citation[1–6]. Limb preservation for locally advanced sarcoma often requires radical resection and reconstruction which may result in significant morbidity, disfigurement, loss of function and compromised quality of life Citation[7–9]. Although several studies have shown response rates in the range of 62–91% with the use of hyperthermic isolated limb perfusions (HILP) for soft tissue sarcomas of the extremity, only a few small studies using isolated limb infusion (ILI) (a well-established treatment modality for recurrent melanoma on the extremities) have been described Citation[10–19]. In this study we report our institutional experience on response rates and limb salvage rates in patients who undergo ILI for locally advanced limb threatening sarcomas of the extremity.

Methods

Patient selection – ok?

Institutional Review Board approval was obtained at Moffitt Cancer Center prior to performing this retrospective analysis. Patients who underwent ILI for locally advanced soft tissue sarcoma of the extremity from January 2008 to March 2012 were identified using a prospectively collected ILI database. Locally advanced/unresectable sarcomas in this series pertained to patients who had failed surgery and were not candidates for or who had failed systemic chemotherapy and/or radiation. All patients who were deemed eligible for ILI had an informed discussion with the medical oncologist, radiation oncologist and surgical oncologist as well as being discussed in our sarcoma multidisciplinary tumour board regarding best treatment options for these patients. Most patients were heavily pretreated with extensive surgeries, systemic therapy and previous radiation with very few other options aside from amputation. In the current series the only other option for these patients at the time of discussion of ILI in the clinic was amputation, which was given as options to the patients when discussing risks, benefits and alternatives of the ILI. Repeat ILIs were offered to patients who had shown either a response to a melphalan-based ILI in the past and then progressed or completely responded and recurred. We did not offer repeat ILIs to patients who did not show a response to a melphalan-based ILI initially. No patient received more than 2 ILIs in this series.

Calculation of limb volume

Limb volume was calculated by taking circumferential limb measurements starting from the distal portion (hand or foot) of the extremity at 2-cm intervals. The most proximal measurement was taken at the level of the inferior edge of the tourniquet where such would be applied during the actual procedure. Final limb volume was calculated by entering these measurements into an Excel software program (Microsoft, Redmond, WA, USA) that was developed by Anthony Perez-Tamayo to calculate the volume of the limb.

Dosing of chemotherapeutic agents

The dose of melphalan used was 7.5 mg/L limb volume for lower extremity and 10 mg/L limb volume for upper extremity, with a maximum total dose of 100 mg for lower extremity and 50 mg for upper extremity. A corrected melphalan dose based on ideal body weight (cIBW) was used in all but 1 patient (96%). Dactinomycin was used at 100 µg/L limb volume for both upper and lower extremities. These doses were based on original descriptions of ILI by the Sydney Melanoma Unit Citation[12], Citation[20], Citation[21]. Chemotherapy consisting of appropriately dosed melphalan and dactinomycin admixed with 400 mL heparinised normal saline.

Technique of isolated limb infusion

The ILI procedures were performed as described previously Citation[20], Citation[21]. Briefly, high-flow 5 F to 6 F arterial and venous catheters were inserted under fluoroscopic guidance via a femoral artery and vein approach in the contralateral extremity and positioned with their tips in the involved extremity at a previously marked site distal to the tourniquet. The extremity was prewarmed with liquid warming blankets (Kimberly Clark®, Roswell, GA, USA). Full systemic heparinisation was used to achieve a target activated clotting time of 400 s or more. A pneumatic or Esmarch tourniquet was placed on the proximal aspect of the limb to isolate the limb and to avoid leakage of the chemotherapy into systemic circulation. Two subcutaneous temperature probes were placed in the proximal and distal aspects of the involved extremity. Once temperatures of 37°C or greater were achieved, the tourniquet was inflated to 250 mmHg (upper extremity (UE)) or 350 mmHg (lower extremity (LE)), and 60 mg of papaverine hydrochloride was injected into the arterial catheter. The catheters were then connected to form a closed circuit and blood was circulated with either one-way valves or three-way stopcocks for unidirectional flow. The chemotherapy was rapidly infused in 5 min through the arterial side of the circuit and then manually circulated for 30 min using a 20-mL syringe. Perfusate blood gases were drawn at 25 and 30 min after the start of the infusion to document the degree of hypoxia and acidosis in the circuit. After 30 min of infusion, the limb was manually flushed with 750 to 1000 mL of isotonic crystalloid solution until the effluent was clear. The flush/effluent was manually extracted from the venous catheter and discarded. Heparinisation was reversed with protamine. Catheters were removed when the activated clotting time was at or near baseline.

Post-operative care and toxicity

Post-operatively, patients were monitored in the intensive care unit for 24 h for serial neurovascular checks, after which they were transferred to the surgical ward. The serum creatinine phosphokinase (CPK) level was measured twice daily while patients were in the hospital. Patients were discharged once CPK levels peaked (usually post-operative day 4 for lower extremity and 2 for upper extremity) and started to decline. Patients who developed grade IV CTCAE serologic toxicity (CPK levels >1000 IU/L) were treated with intravenous hydration using normal saline to maintain a urine output greater than 0.5 mL/kg/h and corticosteroids (4 mg of dexamethasone every 6 h) until their CPK levels decreased to less than 1000 IU/L Citation[22]. Limb toxicity was determined by close physical examination throughout the hospitalisation and assessed again at visits 2, 6, and 12 weeks post-operatively using the scale shown in proposed by Wieberdink et al. Citation[23]. Severe acute limb toxicity was defined as Wieberdink grade IV or higher.

Table I.  Wieberdink Toxicity Scale.

Outcome measures

Response rates were measured using the modified Response Evaluation Criteria in Solid Tumors (RECIST) on cross-sectional imaging at 3 months post-operatively and every 3 months thereafter Citation[24]. For cutaneous lesions, modified RECIST and serial caliper measurements were used to evaluate response to treatment.

Statistical analysis

Statistical analysis was performed using Stata version 9 (StatCorp, College Station, TX, USA). Associations were tested with the Fisher exact test, the χ2 test, and the Wilcoxon rank sum test, as appropriate. A 2-tailed P value less than 0.05 was considered statistically significant. Multivariate models were not used, given the small sample size in our study.

Results

Demographic characteristics

As shown in , 22 patients who underwent a total of 26 ILIs for soft tissue sarcomas of the extremity from January 2008 to March 2012 were identified using the ILI database at Moffitt Cancer Center. The median age was 71 years (range, 19–93 years); 14 (64%) were women. Of the 22 patients, four (18%) underwent repeat infusions. Seven (30%) of the 26 infusions were in the UE. ILI was aborted in one patient due to occlusion of the brachial artery secondary to compression resulting from the tumour. demonstrates the ten different histologic subtypes that were encountered in the 22 patients: nine (41%) patients had undifferentiated pleomorphic sarcoma, four (18%) had high grade myxofibrosarcoma, two (9%) had Kaposi's sarcoma, and synovial sarcoma whereas one (4.5%) had epithelioid sarcoma, leiomyosarcoma, angiosarcoma, alveolar rhabdomyosarcoma and fibrohistiocytic sarcoma.

Table II.  Demographic characteristics of patients undergoing isolated limb infusion.

Table III.  Histological subtypes of sarcoma in patients undergoing isolated limb infusion.

Intraoperative parameters

As depicted in , limb volume, melphalan and dactinomycin doses are significantly higher in patients undergoing lower extremity ILI. Melphalan dose was corrected for ideal body weight in all but one patient who had his ILI prior to the implementation of cIBW in all ILI patients at our institution. Although a significantly greater degree of hypoxia is achieved in the LE (median PaO2 at 30 min, 9 mmHg in LE versus 17 mmHg in UE, p = 0.02), UE ILIs were noted to have significantly higher acidosis and base deficit (median pH at 30 min, 7.08 in UE versus 7.2 in LE, p = 0.03, base excess −15.3 mEq in UE versus −7.1 mEq in LE, p = 0.006). Papaverine was used in all patients. Median ischaemia time was 51 min (range, 46–73). The median limb temperature at 30 min (39.5°C) was 1°C higher than the median initial limb temperature (38.5°C).

Table IV.  Intraoperative and post-operative parameters for patients undergoing isolated limb infusions.

Post-operative parameters and toxicity

Median peak CPK values for LE ILIs were higher than those of UE ILIs; however, the difference was not statistically significant. CPK was noted to peak earlier in the post-operative period in patients with UE ILIs; however, the length of stay did not differ significantly in the two groups (median post-operative day to CPK peak, 2 days versus 4.5 days, p = 0.02 median LOS, 5.5 days versus 6 days, p = NS) (). Toxicity as measured using the Wieberdink scale described in was similar in both groups. The majority of the patients had grade I or II toxicity with only 23% of the patients exhibiting grade III toxicity. No grade III toxicity was seen in any of the upper limb infusions. More importantly no grade IV or V limb toxicity was seen after any of the 26 infusions.

Three patients were noted to have deep venous thrombosis during their post-operative follow-up, requiring systemic anticoagulation. Two of these were in the UE, one associated with placement of a percutaneously inserted central catheter and one in the arm that was infused. The patient with the lower limb DVT was also noted to have a pulmonary embolus discovered on routine imaging studies 3 months after ILI.

Outcome measures

Response rates

All patients included in the outcome analysis had at least a follow-up of 3 months or more. Among the 17 evaluable patients who underwent a total of 21 infusions the median duration of follow-up was 11 months (range, 3–33 months), whereas the median follow-up after each ILI was 9 months (range, 3–33 months). This difference in follow-up exists because the patients who underwent repeat ILIs had their follow-up separated for each infusion. We chose 3 months post-ILI as the first time point to evaluate for response using RECIST criteria, which is consistent with previous reports on the use of ILI and determining response. At 3 months the overall response rate as shown in was 42% (18% complete response (CR), 24% partial response (PR)) per infusion and 42% per patient (24% CR, 18% PR). Three patients (18%) had stable disease (SD) while seven (41%) had progressive disease (PD). When evaluating responses stratified by extremity as shown in , the overall response rate was 45% in the lower limb infusions and 33% in the upper extremity, with no statistical difference between the two. In addition, no correlation was observed between histological subtype of the sarcoma and response rates. Of the four patients undergoing repeat ILI there was one (25%) with a CR, PR, SD and PD.

Table V.  Response rates for patients undergoing isolated limb infusions.

Table VI.  Response rates for patients undergoing isolated limb infusions stratified by extremity.*

Limb salvage rates and conversion to resectability

Of the 17 patients with a minimum of 3 months follow-up, 12 (71%) had successful limb preservation with a median limb preservation time of 9 months (range, 3–28 months). Six patients (33%) in the intention-to-treat population (those who had one ILI or more, or who had an attempt at an ILI) eventually required amputations. Five patients required amputations for progressive disease after their ILIs, and one patient required an amputation after an aborted infusion secondary to occlusion of the brachial artery from compression by the tumour. Three patients had amputation below the knee, 1 had amputation above the knee, 1 had hip disarticulation, and 1 had above the elbow amputation with a median time to amputation of 5 months (range, 3–8 months). Two patients (12%) underwent resection of the sarcoma in the lower extremity after ILI down-staged their disease to resectable, resulting in no evidence of disease. Both of these patients remain NED to date at 30 and 22 months post-ILI.

Discussion

Treatment of patients with locally advanced extremity STS presents a unique challenge to the oncologist. Surgeons are often faced with situations whereby they have to strike a balance between optimal oncological outcomes and limb function Citation[25]. Although an amputation is sometimes the only way to achieve a margin-negative resection, we know that even with an amputation and good local control, ultimately there is no significant survival benefit Citation[7], Citation[26]. Regional therapy with ILI is an attractive and acceptable alternative therapy for disease control and limb preservation in patients with unresectable locally advanced or recurrent soft tissue sarcomas of the extremity that are otherwise facing an amputation due to no other therapeutic options available Citation[27]. All of the patients in this study were facing amputation, most were heavily treated with radiation and/or systemic chemotherapy with progression of their local/regional disease, or were not candidates for systemic chemotherapy due to comorbidities that preclude use of systemic chemotherapy prior to referral to the surgical oncologist. Their cases were discussed at our sarcoma multidisciplinary tumour board and were offered ILI since no other therapeutic options were available, including chemotherapy, radiation or aggressive surgical resections. The purpose of the current study was to report on a single institution series of the use of ILI for unresectable sarcomas of the extremities as a limb preserving option.

There have been three previously published studies reporting the use of ILI for STS of the extremity with encouraging results Citation[12–14]. While this study contains some of the patients reported in the multicenter experience by Turaga et al., the current study is a single-institution experience that has a longer follow-up and more patients with the diagnosis of limb threatening sarcomas Citation[13]. In comparing our outcomes to the published studies, we find our overall response and limb preservation rates to be somewhat lower. Moncrieff et al. reported their experience with ILI for STS at the Sydney Melanoma Unit on 21 patients with an overall response rate of 90% (CR 57%, PR 33%) Citation[12]. In contrast we have a response rate of 42% with a 24% CR and 18% PR. There are several possible reasons to explain these observed differences. Firstly, 67% of the patients in the Moncrieff study underwent preoperative ILI, whereas 82% of our patients undergoing ILI had previous attempts at resection and most were treated with other modalities Citation[12]. In addition, over 80% of our patient population had recurrent tumours compared to only 33% in the Moncrieff study Citation[12]. The difference in outcomes may be related to differences in the patient population being treated, with the majority of our patients being heavily pretreated with multimodality therapy. Secondly, we used melphalan dose-corrected for ideal body weight. We know that this dose correction leads to lower toxicity in melanoma patients with equivalent CR and slightly lower PR; however, the impact of this correction on response rates for sarcoma is unknown Citation[28–30]. The multicentre study by Turaga et al. showed a 75% response rate (CR 17%, PR 58%) for STS Citation[13]. The high response rate in the Turaga et al. study may be related to a small number of patients in the soft tissue sarcoma group, but more importantly a short follow-up duration overestimating the true treatment effect, with the current study having longer median follow-up than the Turaga study Citation[13].

With multiple studies showing that hyperthermic isolated limb perfusion (HILP) has a response rate of 62–91%, it seems logical to compare outcomes and toxicity of the two different techniques Citation[10], Citation[11], Citation[15]. While ILI is a minimally invasive technique of delivering regional chemotherapy with minimal morbidity, HILP is an invasive, complex, labour intensive technique requiring cannulation and clamping of the main artery and vein of the diseased extremity with infusion of chemotherapy using an oxygenated extracorporeal circuit Citation[31]. In our study we did not observe grade IV or V limb toxicity, while studies using HILP describe a significant limb toxicity rate of 10–50% based on the chemotherapeutic agent used Citation[10], Citation[11], Citation[15]. In addition, systemic toxicity is rare in patients undergoing ILI in contrast to HILP Citation[27]. Moreover, the technical/operative ease of repeating an ILI in a patient who has manifested a good partial response is far superior to that of a repeat HILP, making ILI a more attractive option for repeat regional therapy. Clearly comparing HILP and ILI in a randomised fashion would allow us to answer which technique is superior; however, such a clinical trial would be quite difficult to perform given the rarity of this disease, the various different histological subtypes with different disease biology and the complexity of fair randomisation based on disease burden.

ILI has been used in the neoadjuvant setting. Hegazy and colleagues reported the use of ILI in the neoadjuvant setting whereby patients underwent preoperative ILI with doxorubicin followed by external beam radiation 3 to 7 days after ILI. A total of 85% of the patients had some response to treatment, rendering them resectable Citation[14]. With a median follow-up of 15 months, there were four (13%) local recurrences; two were managed with reoperation, one with amputation and one with chemotherapy Citation[14]. Although our study was not specifically looking at the use of ILI in the neoadjuvant setting, it is important to mention that two patients with lower extremity sarcomas who may have otherwise been treated with an amputation were down-staged to resectable disease. Both were rendered disease-free after undergoing resection and remain so at 30 and 22 months post-ILI. These results certainly point towards exploring an expanding role of ILI to include neoadjuvant therapy.

HILP with melphalan and tumour necrosis factor (TNF) has been used with good success in European countries. TNF is not available for use in the USA and therefore was not included as a drug in the ILI regimen. A randomised study of HILP with TNF and melphalan was published by Bonvalot et al. using four different doses of TNF in the effluent Citation[32]. In that study there was no difference in response rates but regional toxicity was significantly lower in the lower TNF dose (1 mg).

It should be noted that there may be some degree of systemic toxicity in patients who undergo HILP. Some of this in the literature can be related to the dose of TNF used (only available for use in European centres) as well as some melphalan leak, and that regional toxicity might be abrogated with the use of milder hyperthermia. However, systemic toxicity of ILI is almost never seen due to no leak being detected from the total pneumatic tourniquet occlusion of the extremity. Regional toxicities have been shown to be greater on an individual study-by-study basis for HILP than for ILI in extremity sarcomas. These results have been detailed very nicely in a recent review of ILI and HILP for sarcomas and melanomas by Moller et al. in 2008 Citation[29].

There are several limitations to our study. This is a retrospective review with a small number of patients and a short follow-up interval. Although the results are encouraging, longer follow-up will help determine the durability of these responses. However, these results certainly warrant further investigation into the use of this low morbidity procedure for the treatment of locally advanced soft tissue sarcomas. With the advent of novel chemotherapeutic agents and pathway-specific targeted agents, it is possible that in the near future this procedure could be optimised to achieve even better outcomes with minimal morbidity Citation[33].

Acknowledgments

Angela Reagan, CIM and Susan Sharpe, MALS provided invaluable support in the drafting and preparation of the manuscript.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References

  • Brennan MF. Soft tissue sarcoma: Advances in understanding and management. Surgeon 2005; 3: 216–223
  • Rooser B, Gustafson P, Rydholm A. Is there no influence of local control on the rate of metastases in high-grade soft tissue sarcoma?. Cancer 1990; 65: 1727–1729
  • Williard WC, Hajdu SI, Casper ES, Brennan MF. Comparison of amputation with limb-sparing operations for adult soft tissue sarcoma of the extremity. Ann Surg 1992; 215: 269–275
  • Stotter A. Comparison of amputation with limb-sparing operations for adult soft tissue sarcoma of the extremity. Ann Surg 1992; 216: 615–616
  • Gustafson P, Rooser B, Rydholm A. Is local recurrence of minor importance for metastases in soft tissue sarcoma?. Cancer 1991; 67: 2083–2086
  • Rosenberg SA, Tepper J, Glatstein E, Costa J, Baker A, Brennan M, et al. The treatment of soft-tissue sarcomas of the extremities: Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982; 196: 305–315
  • Paredes T, Pereira M, Moreira H, Simões MR, Canavarro MC. Quality of life of sarcoma patients from diagnosis to treatments: Predictors and longitudinal trajectories. Eur J Oncol Nurs 2011; 15: 492–499
  • Ferrone ML, Raut CP. Modern surgical therapy: Limb salvage and the role of amputation for extremity soft-tissue sarcomas. Surg Oncol Clin N Am 2012; 21: 201–213
  • Davidge KM, Wunder J, Tomlinson G, Wong R, Lipa J, Davis AM. Function and health status outcomes following soft tissue reconstruction for limb preservation in extremity soft tissue sarcoma. Ann Surg Oncol 2010; 17: 1052–1062
  • Deroose JP, Eggermont AM, van Geel AN, Burger JW, den Bakker MA, de Wilt JH, et al. Long-term results of tumor necrosis factor alpha- and melphalan-based isolated limb perfusion in locally advanced extremity soft tissue sarcomas. J Clin Oncol 2011; 29: 4036–4044
  • Grunhagen DJ, de Wilt JH, Graveland WJ, Verhoef C, van Geel AN, Eggermont AM. Outcome and prognostic factor analysis of 217 consecutive isolated limb perfusions with tumor necrosis factor-alpha and melphalan for limb-threatening soft tissue sarcoma. Cancer 2006; 106: 1776–1784
  • Moncrieff MD, Kroon HM, Kam PC, Stalley PD, Scolyer RA, Thompson JF. Isolated limb infusion for advanced soft tissue sarcoma of the extremity. Ann Surg Oncol 2008; 15: 2749–2756
  • Turaga KK, Beasley GM, Kane JM III, Delman KA, Grobmyer SR, Gonzalez RJ, et al. Limb preservation with isolated limb infusion for locally advanced nonmelanoma cutaneous and soft-tissue malignant neoplasms. Arch Surg 2011; 146: 870–875
  • Hegazy MA, Kotb SZ, Sakr H, et al. Preoperative isolated limb infusion of Doxorubicin and external irradiation for limb-threatening soft tissue sarcomas. Ann Surg Oncol 2007; 14: 568–576
  • Wray CJ, Benjamin RS, Hunt KK, Cormier JN, Ross MI, Feig BW. Isolated limb perfusion for unresectable extremity sarcoma: Results of 2 single-institution phase 2 trials. Cancer 2011; 117: 3235–3241
  • Bonvalot S, Rimareix F, Causeret S, Le Péchoux C, Boulet B, Terrier P, et al. Hyperthermic isolated limb perfusion in locally advanced soft tissue sarcoma and progressive desmoid-type fibromatosis with TNF 1 mg and melphalan (T1-M HILP) is safe and efficient. Ann Surg Oncol 2009; 16: 3350–3357
  • Kroon HM, Moncrieff M, Kam PC, Thompson JF. Outcomes following isolated limb infusion for melanoma. A 14-year experience. Ann Surg Oncol 2008; 15: 3003–3013
  • Beasley GM, Ross MI, Tyler DS. Future directions in regional treatment strategies for melanoma and sarcoma. Int J Hyperthermia 2008; 24: 301–309
  • Beasley GM, Caudle A, Petersen RP, McMahon NS, Padussis J, Mosca PJ, et al. A multi-institutional experience of isolated limb infusion: Defining response and toxicity in the US. J Am Coll Surg 2009; 208: 706–715, discussion: 715–707
  • Thompson JF, Kam PC, Waugh RC, Harman CR. Isolated limb infusion with cytotoxic agents: A simple alternative to isolated limb perfusion. Semin Surg Oncol 1998; 14: 238–247
  • Thompson JF, Kam PC. Isolated limb infusion for melanoma: A simple but effective alternative to isolated limb perfusion. J Surg Oncol 2004; 88: 1–3
  • National Cancer Institute. Cancer Therapy Evaluation P: Common terminology criteria for adverse events. (CTCAE). v. 4.0. Bethesda, MD: National Institute of Health, 2009.
  • Wieberdink J, Benckhuysen C, Braat RP, van Slooten EA, Olthuis GA. Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur J Cancer Clin Oncol 1982; 18: 905–910
  • van Persijn van Meerten EL, Gelderblom H, Bloem JL. RECIST revised: Implications for the radiologist. A review article on the modified RECIST guideline. Eur Radiol 2010; 20: 1456–1467
  • Demetri GD, Antonia S, Benjamin RS, Bui MM, Casper ES, Conrad EU 3rd, et al. Soft tissue sarcoma. J Natl Compr Cancer Network 2010; 8: 630–674
  • Dagan R, Indelicato DJ, McGee L, Morris CG, Kirwan JM, Knapik J, et al. The significance of a marginal excision after preoperative radiation therapy for soft tissue sarcoma of the extremity. Cancer 2012; 118: 3199–3207
  • Deneve JL, Zager JS. Isolated regional therapy for advanced extremity soft tissue sarcomas. Surg Oncol Clin N Am 2012; 21: 287–299
  • Kam PC, Thompson JF. Isolated limb infusion with melphalan and actinomycin D in melanoma patients: Factors predictive of acute regional toxicity. Expert Opin Drug Metab Toxicol 2010; 6: 1039–1045
  • Moller MG, Lewis JM, Dessureault S, Zager JS. Toxicities associated with hyperthermic isolated limb perfusion and isolated limb infusion in the treatment of melanoma and sarcoma. IntJ Hyperthermia 2008; 24: 275–289
  • Santillan AA, Delman KA, Beasley GM, Mosca PJ, Hochwald SN, Grobmyer SR, et al. Predictive factors of regional toxicity and serum creatine phosphokinase levels after isolated limb infusion for melanoma: A multi-institutional analysis. Ann Surg Oncol 2009; 16: 2570–2578
  • Schraffordt Koops H, Oldhoff J, Oosterhuis JW, Beekhuis H. Isolated regional perfusion in malignant melanoma of the extremities. World J Surg 1987; 11: 527–533
  • Bonvalot S, Laplanche A, Lejeune F, Stoeckle E, Le Péchoux C, Vanel D, et al. Limb salvage with isolated perfusion for soft tissue sarcoma: Could less TNF-alpha be better?. Ann Oncol 2005; 16: 1061–1068
  • Riedel RF. Targeted agents for sarcoma: Is individualized therapy possible in such a diverse tumor type?. Semin Oncol 2011; 38S3: S30–42

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.