What is the role of regional chemotherapy in BSTTs?

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Introduction

The major goal of treating sarcoma in the extremities is to achieve long-term control and to preserve function wherever possible. This is particularly important as amputation does not improve survival rates in patients with large (>5cm) deep-seated high grade sarcomas. Limb salvage offers significant benefit to the patient and community in terms of function, work productivity, rehabilitation and overall cost.

Surgical therapy remains problematic for patients with large primary tumours and those with bulky recurrent disease. Local recurrence rates are directly related to the type and extent of surgery and/or radiotherapy undertaken and range between 10-80%. Criteria of irresectability include multifocal primary tumours, multiply recurrent limb tumours, fixation to or invasion into neurovascular bundles and/or bone and tumour recurrences in previously irradiated areas.

Isolated limb perfusion (ILP) has been used in patients with extremity STS for > 40 years. In the majority of patients, this approach has been used as a limb-sparing alternative when amputation was considered the only treatment option.

The proposed advantages of ILP include: isolation from the systemic circulation which permits administration of high dose cytotoxic chemotherapy; tumouricial effects of hyperthermia and potentially down-staging of STS which may permit subsequent limb sparing surgery.

Several contentious questions persist in relation to the appropriate drug or drug combinations, the use of tumour necrosis factor – alfa (TNFα), the use of ILP in the pre-operative setting and the use of isolated limb infusion (ILI) as an alternative to isolated limb perfusion (ILP).[1]

Several large studies from European centres suggest that ILP with combination melphalan and TNFα should be considered as first line therapy for patients with large high grade primary extremity STS. However, it is not possible to subject this treatment to a true randomised control trial as STS is a relatively rare condition.[2]

Australian experience with ILP is limited to only a few specialised centres. TNFα is not currently available in Australia due to licencing issues.

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Role of ILP in limb salvage, prior to consideration of amputation

No randomised controlled trial or other comparative study was available comparing ILP with other treatment options (e.g. pre-operative or amputation) for locally unresectable soft tissue sarcoma (STS).

The best available evidence (i.e. largest series) comes from a retrospective, multicentre study involving eight European centres,[3] each of which used a standardised protocol with melphalan and TNFα in 186 patients.

Clinical complete response was observed in 33 patients (18%), partial in 106 patients (57%), stable disease in 42 (22%) and tumour progression in five patients (3%). In 126 patients (68%) the tumour remnant was surgically excised after ILP. In patients undergoing post ILP resection, histopathological responses were: complete response 29%, partial 53%, no change 16%, tumour progression 2%. The limb salvage rate was 82%. Regional toxicity was found to be moderate in most (171 patients). One patient developed grade V toxicity and required amputation. Systemic toxicity was moderate and no therapeutic interventions were required.

These findings are consistent with other series from different institutions, reporting overall response rates for ILP in unresectable STS varying between 77% to 94%, with acceptable regional and systemic toxicity.[4][5]

ILP is also warranted for patients with metastatic disease, and advanced local extremity disease, as an alternative to amputation.[6]

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Efficacy of ILP with melphalan alone vs melphalan + TNFα

ILP is provided in a limited number of Australian centres. Some centres provide a simplified version of ILP called isolated limb infusion (ILI). ILI utilises a low-pressure hypoxic circuit rather than an oxygenated pressurised perfusion circuit. One Australian study reports a series of 21 patients with extremity STS undergoing ILI. The overall response rate was 90% and the overall limb salvage rate 76%.[7] Systemic leakage monitoring is not performed with ILI, making it unsuitable for use with TNFα.

Melphalan is the standard cytotoxic aged used in ILP. Other cytotoxic agents such as cisplatin and doxorubicin have been used and report similar efficacy. More recently TNFα has been used in combination with melphalan to increase efficacy rates. TNFα has indirect antitumour effects on the tumour vascular bed.[1] Although most single centre series report higher response rates with melphalan + TNFα for extremity sarcoma, there are no randomised studies comparing with melphalan. The toxicity profile of TNFα mandates systemic leakage monitoring. TNFα is not available in Australia for ILP.

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Evidence summary and recommendations

Evidence summary Level References
Isolated limb perfusion is an effective limb-sparing option for patients with unresectable extremity soft tissue sarcoma. In selected patients it may provide an alternative to amputation; as either a 'downstaging' strategy for otherwise unresectable disease, or as a palliative strategy. IV [4], [5], [3], [1]
The efficacy of isolated limb perfusion (ILP) with melphalan is increased when combined with TNFα*. IV [1]

* TNFα is not licenced in Australia.

Evidence-based recommendationQuestion mark transparent.png Grade
Isolated limb perfusion (ILP) may be considered as a palliative alternative to amputation in patients with extremity soft tissue sarcoma.
D



Practice pointQuestion mark transparent.png

The toxicity of isolated limb perfusion (ILP) with melphalan is increased when combined with TNFα.


Practice pointQuestion mark transparent.png

ILP may be considered to downstage extremity soft tissue sarcoma when primary amputation would otherwise be considered.

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Issues requiring more clinical research study

A number of gaps in the evidence have been identified. These include:

  • What is the ideal cytotoxic drug (or combination) for isolated limb perfusion (ILP)?
  • What is the role of ILP in the neo-adjuvant setting?


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References

  1. 1.0 1.1 1.2 1.3 Eggermont AM, Schraffordt Koops H, Liénard D, Kroon BB, van Geel AN, Hoekstra HJ, et al. Isolated limb perfusion with high-dose tumor necrosis factor-alpha in combination with interferon-gamma and melphalan for nonresectable extremity soft tissue sarcomas: a multicenter trial. J Clin Oncol 1996 Oct;14(10):2653-65 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8874324.
  2. 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 Jul 15;117(14):3235-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21246524.
  3. 3.0 3.1 Eggermont AM, Schraffordt Koops H, Klausner JM, Kroon BB, Schlag PM, Liénard D, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience. Ann Surg 1996 Dec;224(6):756-64; discussion 764-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8968230.
  4. 4.0 4.1 Lejeune FJ, Pujol N, Liénard D, Mosimann F, Raffoul W, Genton A, et al. Limb salvage by neoadjuvant isolated perfusion with TNFalpha and melphalan for non-resectable soft tissue sarcoma of the extremities. Eur J Surg Oncol 2000 Nov;26(7):669-78 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11078614.
  5. 5.0 5.1 Noorda EM, Vrouenraets BC, Nieweg OE, van Coevorden F, van Slooten GW, Kroon BB. Isolated limb perfusion with tumor necrosis factor-alpha and melphalan for patients with unresectable soft tissue sarcoma of the extremities. Cancer 2003 Oct 1;98(7):1483-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14508836.
  6. Grünhagen DJ, Brunstein F, Graveland WJ, van Geel AN, de Wilt JH, Eggermont AM. Isolated limb perfusion with tumor necrosis factor and melphalan prevents amputation in patients with multiple sarcomas in arm or leg. Ann Surg Oncol 2005 Jun;12(6):473-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15864484.
  7. 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 Oct;15(10):2749-56 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18648882.

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Appendices

Further resources