Long-term outcomes of isolated limb perfusion with hyperthermia in patients with soft tissue sarcomas

In case of locally advanced soft tissue sarcomas of the extremities (STS), the large size of which does not allow resection with preservation of the limb, isolated regional perfusion (IRP) of the limb is considered as one of the effective treatment options.

Aim. To evaluate the long-term outcomes of IRP with melphalan under conditions of hyperthermia for treatment of locally advanced STS of the extremities.

Materials and methods. We conducted a prospective cohort clinical study that included 42 patients with STS of the extremities. All patients underwent IRP with melphalan, in one case – in combination with tumor necrosis factor alpha. Additional lymph node dissection was performed in 8 cases (19%). The 5-year overall survival was estimated by the Kaplan-Meier method.

Results. The median age of the patients was 50 years (from 24 to 80 years), women predominated – 32 (76%). STS of the upper limb was diagnosed in 14 patients (33%), of the lower limb in 28 (67%). G3 grade was verified in 34 (81%) patients, in the rest – G2. Most patients had a recurrent tumor – in 34 (81%) cases. All patients received previous treatment: surgery in combination with chemotherapy and / or radiation therapy – 36 (86%), chemotherapy alone – 2 (5%), surgery alone – 4 (9%) patients. Within 5 years, tumor recurrence developed in 20 (48%) patients, amputation was performed in 10 (24%) patients, distant metastases were diagnosed in 4 (10%) patients. The mean time to relapse after IPC was 9.3 ± 3.5 months. Overall survival at 1, 2, 3, 4, and 5 years was 98%, 88%, 86%, 74%, and 67%, respectively.

Conclusion. IRP under conditions of hyperthermia with melphalan is an effective method for the treatment of STS of the extremities: the overall 5-year survival rate is 67% with a low rate of amputations and metastasis.

1. Teras J., Mägi A., Teras M., et al. Soft tissue cancer management: isolated limb infusion for sarcoma. Visc Med. 2019 Dec; 35(6): 373–379. https://doi.org/10.1159/000495888. Epub 2019 Feb 13. PMID: 31934586; PMCID: PMC6944920

2. Jiménez Herevia A.E., Tavares de la Paz L.A., Hinojosa Ugarte D., Nieves Condoy J. Isolated limb perfusion on nonmelanoma skin cancer for limb salvage: A series of four cases. Cureus. 2020 Aug 24; 12(8): e9998. https://doi.org/10.7759/cureus.9998. PMID: 32983697; PMCID: PMC7511079

3. Hohenberger P., Wysocki W.M. Neoadjuvant treatment of locally advanced soft tissue sarcoma of the limbs: which treatment to choose? Oncologist. 2008 Feb; 13(2): 175–186. https://doi.org/10.1634/theoncologist.2007-0165. PMID: 18305063

4. Pennacchioli E., Deraco M., Mariani L., et al. Advanced extremity soft tissue sarcoma: prognostic effect of isolated limb perfusion in a series of 88 patients treated at a single institution. Ann Surg Oncol. 2007 Feb; 14(2): 553–559. https://doi.org/10.1245/s10434-006-9251-1. Epub 2006 Nov 23. PMID: 17122991

5. von Mehren M., Kane J.M., Agulnik M., et al. Soft tissue sarcoma, Version 2.2022, NCCN Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022 Jul; 20(7): 815–833. https://doi.org/10.6004/jnccn.2022.0035. PMID: 35830886

6. Carr M.J., Sun J., Zager J.S. Isolated limb infusion: Institutional protocol and implementation. J Surg Oncol. 2020 Jul; 122(1): 99–105. https://doi.org/10.1002/jso.25886. Epub 2020 Mar 11. PMID: 32162353

7. Eggermont A.M., Schraffordt Koops H., Klausner J.M., 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): 756–764; discussion 764–765. https://doi.org/10.1097/00000658-199612000-00011. PMID: 8968230; PMCID: PMC1235474

8. Харатишвили Т.К., Петроченко Н.С., Бохян Б.Ю. Сравнительное изучение клинической эффективности и безопасности метода изолированной перфузии конечностей с гипертермией у больных с саркомами мягких тканей. Саркомы костей, мягких тканей и опухоли кожи. 2016; (4): 32–39. EDN: YHHWOP

9. Hoven-Gondrie M.L, Bastiaannet E., van Ginkel R.J., et al. TNF dose reduction and shortening of duration of isolated limb perfusion for locally advanced soft tissue sarcoma of the extremities is safe and effective in terms of long-term patient outcome. J Surg Oncol. 2011 Jun 1; 103(7): 648–655. https://doi.org/10.1002/jso.21885. Epub 2011 Feb 17. PMID: 21337343

10. Neuwirth M.G., Song Y., Sinnamon A.J., et al. Isolated limb perfusion and infusion for extremity soft tissue sarcoma: a contemporary systematic review and meta-analysis. Ann Surg Oncol. 2017 Dec; 24(13): 3803–3810. https://doi.org/10.1245/s10434-017-6109-7. Epub 2017 Oct 11. PMID: 29022281

11. Trabulsi N.H., Patakfalvi L., Nassif M.O., et al. Hyperthermic isolated limb perfusion for extremity soft tissue sarcomas: systematic review of clinical efficacy and quality assessment of reported trials. J Surg Oncol. 2012 Dec; 106(8): 921–928. https://doi.org/10.1002/jso.23200. Epub 2012 Jul 17. PMID: 22806575

12. Bhangu A., Broom L., Nepogodiev D., et al. Outcomes of isolated limb perfusion in the treatment of extremity soft tissue sarcoma: a systematic review. Eur J Surg Oncol. 2013 Apr; 39(4): 311–319. https://doi.org/10.1016/j.ejso.2012.12.018. Epub 2013 Jan 23. PMID: 23351681

13. Deroose J.P., Eggermont A.M., van Geel A.N., 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 Oct 20; 29(30): 4036–4044. https://doi.org/10.1200/JCO.2011.35.6618. Epub 2011 Sep 19. PMID: 21931039

14. Jakob J., Smith H.G., Wilkinson M.J., et al. Regional chemotherapy by isolated limb perfusion prior to surgery compared with surgery and post-operative radiotherapy for primary, locally advanced extremity sarcoma: a comparison of matched cohorts. Clin Sarcoma Res. 2018 Jul 2; 8: 12. https://doi.org/10.1186/s13569018-0098-6. PMID: 29988594; PMCID: PMC6027577