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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 3  |  Page : 87-92

Hyperthermic isolated limb perfusion: Does it still have a role?


1 Discipline of Surgery, The University of Adelaide, The Queen Elizabeth Hospital, Adelaide, South Australia
2 Department of Plastic Surgery, The Royal Adelaide Hospital, Adelaide, South Australia
3 Department of Cardiothoracic Surgery, The Royal Adelaide Hospital, Adelaide, South Australia
4 Discipline of Surgery, The University of Adelaide, The Queen Elizabeth Hospital; Cardiothoracic Surgery, The Royal Adelaide Hospital, Adelaide, South Australia
5 Translational Oncology Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology; Cancer Clinical Trials Unit, Royal Adelaide Hospital; Discipline of Medicine, The University of Adelaide, Adelaide, South Australia

Date of Web Publication30-Apr-2019

Correspondence Address:
Jessica Reid
Discipline of Surgery, University of Adelaide, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, 5011
South Australia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/VIT.VIT_18_18

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  Abstract 

BACKGROUND: Hyperthermic-isolated limb perfusion (ILP) with melphalan is an established modality for the treatment of irresectable malignancy of an extremity, including melanoma. ILP isolates the affected limb from the systemic circulation, using an extracorporeal bypass circuit, and administering high-dose intra-arterial chemotherapy. While this technique remains the “gold standard” and is practiced at high-volume surgical oncology centers worldwide, as new systemic treatments have become available, it is timely to review the current place of regional chemotherapy.
PATIENTS AND METHODS: Twenty-six ILPs were performed between 2006 and 2013 at a single center. Patient's parameters, clinical outcomes, and survival were evaluated. Twenty procedures were for melanoma, five for sarcoma, and one for extensive basal cell carcinoma (BCC).
RESULTS: ILP was well tolerated with few intraoperative or postoperative complications. Within the melanoma group, limb toxicities were low with one Grade III and no severe (Wieberdink IV+) toxicities. Limb salvage was achieved in 2/5 sarcoma patients. At 6 weeks' postprocedure, 13 melanomas, two sarcomas, and the BCC patient reported a complete response (16/26). However, 5 years after the last procedure, and a median follow-up of 23 months, the majority of melanoma and all sarcoma patients went on to develop local recurrence or metastatic disease.
CONCLUSIONS: ILP is a useful technique to provide high-dose chemotherapy to refractory limb malignancy to provide effective palliation, delay progression, or even obtain cure. However, as new effective systemic therapies emerge, the role of isolated regional chemotherapy (ILP and isolated limb infusion) needs to be reevaluated.

Keywords: Melphalan, metastatic melanoma, perfusion, sarcoma, targeted therapy


How to cite this article:
Reid J, Rooke M, Hawksmith C, Jurisevic C, Brown MP, Neuhaus SJ. Hyperthermic isolated limb perfusion: Does it still have a role?. Vasc Invest Ther 2018;1:87-92

How to cite this URL:
Reid J, Rooke M, Hawksmith C, Jurisevic C, Brown MP, Neuhaus SJ. Hyperthermic isolated limb perfusion: Does it still have a role?. Vasc Invest Ther [serial online] 2018 [cited 2019 Jul 20];1:87-92. Available from: http://www.vitonline.org/text.asp?2018/1/3/87/257415


  Introduction Top


Isolated limb perfusion (ILP) was first described by Creech et al. in 1958[1] and has been used for both treatment and palliation of patients with extensive irresectable malignancy of the limbs, particularly and in-transit melanoma, and extremity soft-tissue sarcoma. In Australia, ILP has predominantly been used for the management of in-transit metastases; a phenomenon which affects up to 8% of melanoma patients.[2] In the management of sarcoma, some European centers use ILP preoperatively to downstage extremity soft-tissue sarcoma either because of proximity to neurovascular structures or likely functional deficit after resection.[3] ILP is also used in a palliative setting as an alternative to amputation.

The most commonly utilized cytotoxic agent used in ILP is melphalan, which can be delivered into the circulation of the limb at doses of up to ten-fold higher than the systemic mean tolerated dose with minimal systemic toxicity.[3] A variety of other chemotherapeutic agents have been used, including doxorubicin, tumor necrosis factor alpha (TNF-α), and interferon gamma. However, no Phase III trial has established the efficacy of combination therapy over melphalan alone. In addition, TNF-α requires close monitoring to avoid systemic toxicity.[4]

Overall response rates in published literature following ILP for melanoma vary widely and range from 71% to 82% with complete response (CR) rates of 12%–100%.[3],[4],[5],[6] This variation reflects patient selection and heterogeneity of histopathology and disease burden. Response rates for advanced soft-tissue sarcoma are generally lower than those for melanoma.[3],[6]

Internationally, ILP continues to be utilized in a number of centers. In European centers, TNF-α is commonly added to the perfusate. The toxicity profile of TNF-α requires secure vascular control and leakage monitoring, which is most safely achieved through a closed, monitored circuit such as that used in ILP.[4]

In Australia, over the last two decades, the use of ILP in melanoma has largely been replaced by isolated limb infusion (ILI); ILI was developed at the Sydney Melanoma Unit (now Melanoma Institute Australia) as a simplified alternative to ILP with percutaneously inserted catheters replacing open cannulation. The procedure is well tolerated, and clinical response rates for melanoma are comparable to ILP.[7] In addition, ILI can be administered without general anesthesia and is readily repeatable.[5]

Recent developments in melanoma chemotherapeutics have led to a paradigm shift in treatment and palliative approaches to recurrent and metastatic melanoma. Novel systemic therapies, such as targeted therapies and immunomodulators (e.g., BRAF inhibitors and CTLA-4 inhibitors), have demonstrated good outcomes in the management of metastatic melanoma and represent viable alternatives to regional chemotherapy.[8] Given this changing landscape, it is appropriate to review the underlying efficacy, safety, and use of ILP in a modern tertiary center and consider the ongoing relevance of the procedure.


  Patients and Methods Top


A retrospective case-note review of all patients who underwent ILP at the Royal Adelaide Hospital between January 2006 and December 2013 was performed. This was approved by the Royal Adelaide Hospital Human Research Ethics Committee. Survival for patients known to be alive was calculated to July 21, 2018. Follow-up was calculated from the date of procedure to July 21, 2018, or date of death.

Patients were considered suitable for ILP if the extent or anatomical position of the disease precluded treatment by surgical resection or, for melanoma, the use of an alternative therapeutic modality such as laser ablation or intralesional therapy. Some patients with low-volume melanoma or significant comorbidity were excluded from this series and referred for ILI, which was also performed at the Royal Adelaide Hospital during the study period. The presence of distant metastatic disease was considered a relative, but not absolute contraindication to ILP. In particular, for sarcoma patients with unresectable disease, ILP was offered as a palliative, salvage therapy in place of immediate amputation.

Operative approach

All perfusions were performed under general anesthesia, and patients were prewarmed using hot-air blankets (Bair Hugger®) for approximately 30 min. Limb isolation was achieved by a pneumatic upper thigh tourniquet for femoral perfusions or an Esmarch bandage secured into either the anterior superior iliac spine or humeral head for femoral or brachial perfusions, respectively. In lower limb perfusions, the foot was excluded when possible to avoid postoperative neuropathy. In patients undergoing synchronous groin dissection, en bloc lymphadenectomy was performed before cannulation of the vessels and perfusion.

The perfusion circuit comprised arterial and venous lines, a Capiox baby-RX™, (Terumo Corporation) Oxygenator and a double action Jostra roller and console, Jostra HL-20 TM, and (Marquet Company) blood pump. For the first perfusion, the circuit was primed with packed red cells. In all subsequent cases, autologous blood was drawn off after initial vascular cannulation, drained into the oxygenator, and translocated into the perfusate. This process enabled an optimal hematocrit in the extracorporeal circuit to be achieved without requiring the addition of banked erythrocytes.

Perfusion volumes were adjusted according to body surface area (BSA), with lower limb considered 18% of the total BSA and the upper limb as 9%; this protocol was an adaptation of that used in The Royal Marsden which has been well described previously.[6] BSA is used, rather than limb volume as the position of the tourniquet can alter relative percentage. The circuit was primed with 250 ml Albumex, 250 ml buffered Ringer's solution, and 5000IU of heparin sulfate added to the perfusate.

During limb perfusion, FiO2 was set at 100% with a sweep rate of 500 ml/min. The PO2 was maintained above 350 mmHg. All perfusion aimed for packed cell volume of approximately 22% in the limb/perfusate. The temperature of the limb was raised to 38.5°C or higher utilizing a Jostra heater/cooler TM (Marquet Company). Regional hyperthermia of 38.5°C–39.5°C was confirmed by cutaneous temperature probes placed on the perfused limb. No leakage monitoring was performed; however, core body temperature was measured by the use of thermal intravesical probes. Systemic and limb activated clotting times (ACT) were monitored throughout the procedure.

After 15 min of warming, melphalan (Alkeran®) was injected over a further 15-min period into the perfusion circuit. Doses were calculated at 1.0 mg/kg body weight for lower limb perfusion and 0.5 mg/kg body weight for upper limb perfusion. Perfusion was maintained for a total time of 60 min following which venous lines were drained, washout performed with Albumex and buffered Ringers' solution. Bypass was then discontinued, cannulas removed, and vessels repaired by direct closure. Protamine sulfate was administered and dose adjusted to the activated partial thromboplastin time.

Postoperative protocol

Before October 2010, all ILP patients were admitted to a high dependency unit (HDU) overnight (n = 7), with neurovascular observations performed on a regular basis. All cases performed after October 2010 (n = 20) were transferred directly to a general surgical ward postoperatively.

Patients were encouraged to mobilize day 1 postoperatively and discharged once mobilizing independently. The six patients who underwent synchronous groin dissection were discharged with a drain in situ, with home nursing review. All patients were reviewed 7 days following surgery and a full blood count performed. Assessment of response by the clinical review was performed at 6 weeks.

Standard World Health Organization criteria were used for classifying response rates with a CR defined as complete clinical or radiological resolution of disease; partial response (PR) defined as clinical or radiological reduction of disease by 50% or greater; and an objective response as that not amounting to a PR. The remaining patients were categorized as having either stable disease or progressive disease (PD). Both time to recurrence/metastasis and overall survival were measured in months from the date of ILP. Where applicable, preoperative imaging was performed and repeated at 6 weeks using RECIST criteria to assess response.


  Results Top


Patient and tumor characteristics

The demographics, histology, and staging details for all patients undergoing ILP are shown in [Table 1].
Table 1: Response rates and survival outcomes

Click here to view


Of the 26 procedures, 20 were performed for melanoma, five for sarcoma, and one for multifocal basal cell carcinoma (BCC). Six patients within the melanoma group had known nodal metastases and underwent synchronous groin dissection.

Twenty-five perfusions were for the lower limb (all through the femoral artery), one for upper limb (brachial artery). One lower limb perfusion was undertaken as a repeat procedure at 59 months' postprimary procedure after a good response ILP previously. The median age was 61 years (17–88). There were 13 males and 12 females.

The goal perfusion temperature was between 38.5°C and 39.5°C, and this was achieved in all procedures. Goal duration of 30 min at the target temperature was also attained in all patients.

The median inpatient stay was 3 days (range 1–22). The initial seven cases were all admitted to HDU overnight routinely for postoperative monitoring. One patient was admitted to the intensive care unit (ICU) secondary to postoperative hypotension of unknown cause.

Morbidity

No patient died within 30 days of surgery. One patient was readmitted to hospital with febrile neutropenia, attributed to melphalan toxicity, which necessitated admission to ICU and administration of granulocyte colony-stimulating factor (G-CSF). Further, the patient was given G-CSF for asymptomatic neutropenia diagnosed on routine complete blood picture.

Local toxicity was scored using the Wieberdink system.[9] One melanoma patient developed Grade III toxicity following a second perfusion to the same limb; no other Grade III or IV toxicities were recorded within this cohort.

One patient in the sarcoma cohort developed a Grade V acute tissue reaction necessitating amputation. This patient had massive irresectable primary sarcoma encasing tibial and popliteal vasculature. Following perfusion, extensive necrosis resulted in a compartment syndrome, which was not amenable to fasciotomy, given the extensive tumor involvement. A second patient in the sarcoma cohort demonstrated a good early response but (>30 days postprocedure) developed osteonecrosis and bone sepsis secondary to the previous radiotherapy, necessitating amputation. Histology demonstrated no viable tumor in the limb with 100% tumor necrosis in response to ILP. No other sarcoma patient developed Grade III or greater toxicity.

Outcomes

Melanoma

Of the 19 melanoma patients, 12 demonstrated CR at 6 weeks (patient who underwent repeat treatment showed CR twice), seven PR, and one no response. Ten patients subsequently developed recurrence disease in the treated limb. Fourteen patients developed metastatic disease. At a median follow-up of 26 months, 11 patients are known to be deceased; three are lost to follow-up for survival data. Five melanoma patients remain alive without disease. The mean survival from the procedure was 43 months (5–131) [Table 1].

Sarcoma

There were two angiosarcoma patients in the cohort, both demonstrated PR at clinical review but subsequently developed local recurrence and metastatic disease. One malignant fibrous histiocytoma (MFH) patient demonstrated PR by clinical assessment but progressed with local recurrence and pulmonary metastasis. A second MFH patient showed CR [Figure 1]; however, necrosis attributed to radiation therapy necessitated limb amputation. Metastatic disease was later detected in this patient. One patient with spindle cell sarcoma reported CR but developed severe local recurrence requiring amputations and metastatic disease. Limb preservation was achieved in three patients (3/5). Mean survival from the procedure was 24 months (4–61) [Table 1]. The median follow-up was 15 months.
Figure 1: Positron-emission tomography scans of a sarcoma patient with a high-grade myxofibrosarcoma (malignant fibrous histiocytoma) preisolated limb perfusion and 6 weeks' postprocedure

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The BCC patient remains alive and well, 5 years' postprocedure.


  Discussion Top


ILP is an accepted, albeit uncommonly used, treatment for selected patients with locally advanced limb malignancy. Here, we have reported our recent experience with ILP in an Australian setting. The CR rate of 50% in the melanoma cohort was comparable the 40% CR previously reported[6], though it should be noted that published CR rates range from 6.7% to 80.8%.[10] Sarcoma CR rate of 40% was also comparable to the rate of 20% published by Hayes.

Adequate perfusion times for the procedure were achieved in all cases. In addition, the overall complication rate was comparable to other centers, suggesting that both efficacy and safety of ILP at our institution are acceptable.

A number of limitations of this retrospective study are acknowledged. As a tertiary center, many patients first presented to the royal adelaide hospital (RAH) with advanced disease. Consequently, data on the characteristics of the primary lesions (e.g., location, Breslow depth on initial resection, and adequacy of resection) were not available for eight cases. At the time of presentation, BRAF testing was not routinely available.

Furthermore, our cohort is small, heterogenous, subject to single-surgeon bias, and includes patients undergoing ILP alone, in addition to patients undergoing ILP and synchronous groin dissection. We are unable to comment on the relative benefit of therapeutic groin dissection in melanoma patients with In-transit metastases (ITM), although note should be made of the higher complication rate, a finding in keeping with general complications from groin dissection and a more advanced tumor stage.

Also of importance is the complementary role of ILI at our institution. Patient selection for ILP versus ILI was largely based on referral pattern and surgeon preference, although some patients considered unsuitable for ILP were referred for ILI.

The management of irresectable extremity malignancy, particularly in the absence of visceral metastases, remains challenging. In the last decade, the treatment of melanoma has been revolutionized by the development of two major classes of systemic therapy replacing cytotoxic chemotherapy as a standard treatment for metastatic or unresectable disease. These are (i) oral small-molecule inhibitors of the mitogen-activated protein kinase (MAPK) pathway, which is constitutively active in more than 90% of cases of metastatic melanoma; and (ii) monoclonal antibody (mAb) inhibitors of immune checkpoint molecules. However, these therapies are expensive and are subject to stringent Pharmaceutical Benefits Scheme conditions in Australia.

MAPK inhibitors are used typically in combination to inhibit both the oncogenic mutant BRAF and MEK intracellular signaling components of the MAPK pathway. Dabrafenib and vemurafenib are selective inhibitors of the mutant BRAF oncoprotein and show good results when combined with MEK inhibitors.

Median overall survival of 2 years has been achieved in two separate studies where dabrafenib was paired with trametinib[11] and vemurafenib paired with cobimetinib[12] in BRAF V600 mutation-positive metastatic melanoma.

The second class of novel therapeutic agents, mAb immune checkpoint inhibitors, work by blocking extracellular signaling interactions between the T-cell surface receptor molecules, CTLA4 and PD1, and their ligands on antigen-presenting cells or tumor cells. Overall survival increased to 10 months when unresectable melanoma patients were treated with anti-CTLA4 mAb ipilimumab (with and without a peptide vaccine) when compared to vaccine alone (6.4 months).[13]

The anti-PD1 mAbs, nivolumab and pembrolizumab, can rapidly shrink melanoma, in up to 40% of treatment-naïve patients. In patients responding to pembrolizumab, 64% of treatment responses were durable, and median response duration had not been reached.[14] Long-term survival is possible with anti-PD1 mAbs, with 35% of nivolumab-treated metastatic melanoma patients reported to be alive at 5 years.[15] Finally, immune checkpoint inhibitors may be more effective when combined; the combination of ipilimumab and nivolumab results in 2-year survival rates of 64% versus 59% and 45% for each of nivolumab and ipilimumab alone, respectively.[16]

However, this enthusiasm needs to be tempered by the fact that the efficacy of these modalities in treating nonvisceral satellite and in-transit metastases is not yet known. Results from trials are ongoing assessing the use of systemic chemotherapy in addition to ILI are not yet published (NCT02115243, NCT01323517); however, patients with extensive in-transit disease (in the absence of visceral metastases) are usually been excluded from these trials, and optimal treatment for this cohort remains unknown.

There have also been recent developments in the efficacy of targeted agents for metastatic soft-tissue sarcoma. Although rare, characteristic chromosomal translocations and activating mutations mean that certain subtypes of soft-tissue sarcoma may be susceptible to molecularly targeted therapies. In a Phase II study conducted by the European Organization for Research and Treatment of Cancer, pazopanib (tyrosine kinase inhibitor) demonstrated progression arrest at 3 months and efficacy in patients with synovial sarcoma and leiomyosarcoma.[17] Other tyrosine kinases, such as dasatinib, and other ligand-targeted therapies remain under investigation.[18] As in melanoma, the emergence of an effective chemotherapy may render regional chemotherapy obsolete.

In contrast to ILI, ILP is a resource-intensive, time-consuming, and technically demanding procedure. It requires both surgical expertise and sophisticated perfusion resources. ILP is not commonly performed, and this carries implications for both training and caseload; this has particular relevance in the Australian setting where centers are typically low volume compared to European and American sites. Recent advances in systemic chemotherapy are likely to make ILP a relic of the past in future treatment of melanoma.


  Conclusions Top


This article reports the outcomes and efficacy of ILP for irresectable advanced limb malignancy in a single Australian center. As new treatments for melanoma and sarcoma enter the oncological armamentarium, they provide an opportunity for new combinations of regional and systemic therapies and may render the need for complex regional chemotherapeutic procedures obsolete. In this rapidly changing therapeutic landscape, the role of ILP needs to be reappraised.

Acknowledgment

The authors are grateful to Professor John Thompson for his review and comments on the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Creech O Jr., Krementz ET, Ryan RF, Winblad JN. Chemotherapy of cancer: Regional perfusion utilizing an extracorporeal circuit. Ann Surg 1958;148:616-32.  Back to cited text no. 1
    
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Read RL, Haydu L, Saw RP, Quinn MJ, Shannon K, Spillane AJ, et al. In-transit melanoma metastases: Incidence, prognosis, and the role of lymphadenectomy. Ann Surg Oncol 2015;22:475-81.  Back to cited text no. 2
    
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Smith HG, Cartwright J, Wilkinson MJ, Strauss DC, Thomas JM, Hayes AJ, et al. Isolated limb perfusion with melphalan and tumour necrosis factor α for in-transit melanoma and soft tissue sarcoma. Ann Surg Oncol 2015;22 Suppl 3:S356-61.  Back to cited text no. 4
    
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Giles MH, Coventry BJ. Isolated limb infusion chemotherapy for melanoma: An overview of early experience at the adelaide melanoma unit. Cancer Manag Res 2013;5:243-9.  Back to cited text no. 5
    
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Hayes AJ, Neuhaus SJ, Clark MA, Thomas JM. Isolated limb perfusion with melphalan and tumor necrosis factor alpha for advanced melanoma and soft-tissue sarcoma. Ann Surg Oncol 2007;14:230-8.  Back to cited text no. 6
    
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DePeralta DK, Boland GM. Melanoma: Advances in targeted therapy and molecular markers. Ann Surg Oncol 2015;22:3451-8.  Back to cited text no. 8
    
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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;18:905-10.  Back to cited text no. 9
    
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Thompson JF, Hunt JA, Shannon KF, Kam PC. Frequency and duration of remission after isolated limb perfusion for melanoma. Arch Surg 1997;132:903-7.  Back to cited text no. 10
    
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Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, et al. Cobimetinib Combined with vemurafenib in advanced BRAF V600-Mutant melanoma (COBRIM): Updated efficieny results from a randamised, double blind, phase 3 trial. The Lancet Oncol 2016:17:1248-60.  Back to cited text no. 12
    
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Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23.  Back to cited text no. 13
    
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Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521-32.  Back to cited text no. 14
    
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Del Vecchio M. AACR update on 5-year survival rates, efficacy and long-term safety in previously treated advanced/metastatic melanoma patients receiving mono-immunotherapy with nivolumab. Recenti Prog Med 2016;107:414-7.  Back to cited text no. 15
    
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Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 2016;17:1558-68.  Back to cited text no. 16
    
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Sleijfer S, Ray-Coquard I, Papai Z, Le Cesne A, Scurr M, Schöffski P, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: A phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol 2009;27:3126-32.  Back to cited text no. 17
    
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