Preoperative accelerated radiotherapy combined with chemotherapy in a defined cohort of patients with high risk soft tissue sarcoma: a Scandinavian Sarcoma Group study

Kirsten Sundby Hall, Øyvind S Bruland, Bodil Bjerkehagen, Elisabet Lidbrink, Nina Jebsen, Hans Hagberg, Karin Papworth, Oskar Hagberg, Clement Trovik, Henrik Bauer, Mikael Eriksson, Kirsten Sundby Hall, Øyvind S Bruland, Bodil Bjerkehagen, Elisabet Lidbrink, Nina Jebsen, Hans Hagberg, Karin Papworth, Oskar Hagberg, Clement Trovik, Henrik Bauer, Mikael Eriksson

Abstract

Background: We recently reported outcomes from a Scandinavian Sarcoma Group adjuvant study (SSG XX group A) conducted on localized and operable high risk soft tissue sarcoma (STS) of the extremities and trunk wall. SSG XX, group B, comprised of patients in a defined cohort with locally advanced STS considered at high risk for intralesional surgery. These patients received preoperative accelerated radiotherapy, together with neoadjuvant and adjuvant chemotherapy. Herein we report the results of this group B.

Methods: Twenty patients with high-grade, locally advanced and deep STS located in lower extremities (n = 12), upper extremities (5) or trunk wall (3) were included. The median age was 59 years and 14 patients were males. The treatment regimen consisted of 6 cycles of doxorubicin (60 mg/m2) and ifosfamide (6 g/m2), with three cycles given neoadjuvantly, and preoperative radiotherapy (1, 8 Gyx2/daily to 36 Gy) between cycles 2 and 3. After a repeated MRI surgery was then conducted, and the remaining 3 chemotherapy cycles were given postoperatively at 3 weeks intervals. Survival data, local control, toxicity of chemotherapy and postoperative complications are presented.

Results: Median follow-up time for metastasis-free survival (MFS) was 2.8 years (range 0.3-10.4). The 5-year MFS was 49.5% (95% confidence interval [CI] 31.7-77.4). The median follow-up time was 5.4 years (range 0.3-10.4) for overall survival (OS). The 5-year OS was 64.0% (95% CI 45.8-89.4). The median tumour size was 13 cm, with undifferentiated pleomorphic sarcoma (n = 10) and synovial sarcoma (n = 6) diagnosed most frequently. All patients completed surgery. Resection margins were R0 in 19 patients and R1 in 1 patient. No patients had evidence of disease progression preoperatively. Three patients experienced a local recurrence, in 2 after lung metastases had already been diagnosed. Eleven patients (55%) had postoperative wound problems (temporary in 8 and persistent in 3).

Conclusions: Preoperative chemotherapy and radiotherapy were associated with temporary wound-healing problems. Survival outcomes, local control and toxicities were deemed satisfactory when considering the locally advanced sarcoma disease status at primary diagnosis. Trial registration This study was registered at ClinicalTrials.gov Identifier NCT00790244 and with European Union Drug Regulating Authorities Clinical Trials No. EUDRACT 2007-001152-39.

Keywords: Accelerated; Adjuvant; Chemotherapy; Preoperative; Radiotherapy; Soft tissue sarcoma; Survival; Toxicity.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Treatment schedule. Chemotherapy (CT): ≥ 18 and 2, 4-h infusion (IV); Day 1, 2 and 3: ifosfamide 2 g/m2/day as 2-h infusion, dose per cycle 6 g/m2 [with an equal dose of 2-mercaptoethane sulphonate sodium (MESNA)]. ≥ 70 and ≤ 75 years: doxorubicin 50 mg/m2 and ifosfamide 5 g/m2 (given as above). Granulocyte colony-stimulating factor was given routinely after each cycle
Fig. 2
Fig. 2
SSG XX, group B, time schedule for chemotherapy, radiotherapy and surgery
Fig. 3
Fig. 3
Metastases-free survival (Kaplan–Meier Curve; % with 95% CI = confidence interval) of 20 patients with high risk soft tissue sarcoma and a median follow-up 2.8 years
Fig. 4
Fig. 4
Overall survival (Kaplan–Meier Curve; % with 95% CI = confidence interval) of 20 patients with high risk soft tissue sarcoma and a median follow-up 5.4 years

References

    1. Kraybill WG, Harris J, Spiro IJ, Ettinger DS, DeLaney TF, Blum RH, et al. Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. J Clin Oncol. 2006;24(4):619–625. doi: 10.1200/JCO.2005.02.5577.
    1. Grobmyer SR, Maki RG, Demetri GD, Mazumdar M, Riedel E, Brennan MF, et al. Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol. 2004;15(11):1667–1672. doi: 10.1093/annonc/mdh431.
    1. Palassini E, Ferrari S, Verderio P, De Paoli A, Martin Broto J, Quagliuolo V, et al. Feasibility of preoperative chemotherapy with or without radiation therapy in localized soft tissue sarcomas of limbs and superficial trunk in the Italian Sarcoma Group/Grupo Español de Investigación en Sarcomas Randomized Clinical Trial: three versus five cycles of full-dose epirubicin plus ifosfamide. J Clin Oncol. 2015;33(31):3628–3634. doi: 10.1200/JCO.2015.62.9394.
    1. Casali PG, Abecassis N, Aro HT, Bauer S, Biagini R, Bielack S, et al. Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv51–iv67. doi: 10.1093/annonc/mdy096.
    1. Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113(3):573–581. doi: 10.1002/cncr.23592.
    1. Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, et al. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol. 2012;13(10):1045–1054. doi: 10.1016/S1470-2045(12)70346-7.
    1. Frustaci S, Gherlinzoni F, De Paoli A, Bonetti M, Azzarelli A, Comandone A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol. 2001;19(5):1238–1247. doi: 10.1200/JCO.2001.19.5.1238.
    1. Petrioli R, Coratti A, Correale P, D'Aniello C, Grimaldi L, Tanzini G, et al. Adjuvant epirubicin with or without ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol. 2002;25(5):468–473. doi: 10.1097/00000421-200210000-00009.
    1. Gronchi A, Frustaci S, Mercuri M, Martin J, Lopez-Pousa A, Verderio P, et al. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol. 2012;30(8):850–856. doi: 10.1200/JCO.2011.37.7218.
    1. Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G, et al. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017;18(6):812–822. doi: 10.1016/S1470-2045(17)30334-0.
    1. Sundby Hall K, Bruland ØS, Bjerkehagen B, Zaikova O, Engellau J, Hagberg O, et al. Adjuvant chemotherapy and postoperative radiotherapy in high-risk soft tissue sarcoma patients defined by biological risk factors—A Scandinavian Sarcoma Group study (SSG XX) Eur J Cancer. 2018;99:78–85. doi: 10.1016/j.ejca.2018.05.011.
    1. Trovik CS, Bauer HC, Berlin O, Tukiainen E, Erlanson M, Gustafson P, et al. Local recurrence of deep-seated, high-grade, soft tissue sarcoma: 459 patients from the Scandinavian Sarcoma Group Register. Acta Orthop Scand. 2001;72(2):160–166. doi: 10.1080/000164701317323417.
    1. Jebsen NL, Trovik CS, Bauer HC, Rydholm A, Monge OR, Hall KS, et al. Radiotherapy to improve local control regardless of surgical margin and malignancy grade in extremity and trunk wall soft tissue sarcoma: a Scandinavian sarcoma group study. Int J Radiat Oncol Biol Phys. 2008;71(4):1196–1203. doi: 10.1016/j.ijrobp.2007.11.023.
    1. Jebsen NL, Bruland ØS, Eriksson M, Engellau J, Turesson I, Folin A, et al. Five-year results from a Scandinavian sarcoma group study (SSG XIII) of adjuvant chemotherapy combined with accelerated radiotherapy in high-risk soft tissue sarcoma of extremities and trunk wall. Int J Radiat Oncol Biol Phys. 2011;81(5):1359–1366. doi: 10.1016/j.ijrobp.2010.07.037.
    1. Broders AC, Hargrave R, Meyerding HW. Pathological features of soft tissue fibrosarcoma with special reference to the grading of its malignancy. Surg Gynecol Obstet. 1939;69:267–280.
    1. Bjerkehagen B, Wejde J, Hansson M, Domaski H, Böhling T. SSG pathology review experiences and histological grading of malignancy in sarcomas. Acta Orthop. 2009;80(334):31–36.
    1. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens FE. WHO classification of tumours of soft tissue and bone. Lyon: IARC Press; 2013.
    1. Scandinavian Sarcoma Group Homepage. Lund. 2020. . Accessed 1 June 2020.
    1. Kaplan EK, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481. doi: 10.1080/01621459.1958.10501452.
    1. Hryniuk WM, Goodyear M. The calculation of received dose intensity. J Clin Oncol. 1990;8(12):1935–1937. doi: 10.1200/JCO.1990.8.12.1935.
    1. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) Int J Radiat Oncol Biol Phys. 1995;31(5):1341–1346. doi: 10.1016/0360-3016(95)00060-C.
    1. Gronchi A, Stacchiotti S, Verderio P, Ferrari S, Martin Broto J, Lopez-Pousa A, et al. Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. Ann Oncol. 2016;27(12):2283–2288. doi: 10.1093/annonc/mdw430.
    1. Gronchi A, Palmerini E, Quagliuolo V, Broto JM, Pousa AL, Grignani G, et al. Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: final results of a randomized trial from Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) sarcoma groups. J Clin Oncol. 2020;38(19):2178–2186. doi: 10.1200/JCO.19.03289.
    1. Pasquali S, Palassini E, Stacchiotti S, Casali PG, Gronchi A. Neoadjuvant treatment: a novel standard? Curr Opin Oncol. 2017;29(4):253–259. doi: 10.1097/CCO.0000000000000372.
    1. Gronchi A, Verderio P, De Paoli A, Ferraro A, Tendero O, Majò J, et al. Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall. Ann Oncol. 2013;24(3):817–823. doi: 10.1093/annonc/mds501.
    1. O'Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359(9325):2235–2241. doi: 10.1016/S0140-6736(02)09292-9.
    1. Zagars GK, Ballo MT, Pisters PW, Pollock RE, Patel SR, Benjamin RS. Preoperative vs. postoperative radiation therapy for soft tissue sarcoma: a retrospective comparative evaluation of disease outcome. Int J Radiat Oncol Biol Phys. 2003;56(2):482–488. doi: 10.1016/S0360-3016(02)04510-8.
    1. Müller DA, Beltrami G, Scoccianti G, Frenos F, Capanna R. Combining limb-sparing surgery with radiation therapy in high-grade soft tissue sarcoma of extremities—is it effective? Eur J Surg Oncol. 2016;42(7):1057–1063. doi: 10.1016/j.ejso.2016.02.004.
    1. Willeumier JJ, Rueten-Budde AJ, Jeys LM, Laitinen M, Pollock R, Aston W, et al. Individualised risk assessment for local recurrence and distant metastases in a retrospective transatlantic cohort of 687 patients with high-grade soft tissue sarcomas of the extremities: a multistate model. BMJ Open. 2017;7(2):e012930. doi: 10.1136/bmjopen-2016-012930.
    1. Lansu J, Groenewegen J, van Coevorden F, van Houdt W, van Akkooi ACJ, van Boven H, et al. Time dependent dynamics of wound complications after preoperative radiotherapy in Extremity Soft Tissue Sarcomas. Eur J Surg Oncol. 2019;45(4):684–690. doi: 10.1016/j.ejso.2018.09.001.
    1. O'Sullivan B, Davis AM, Turcotte R, Wunder J, Catton C, Kandel R, et al. Five years results of a randomized phase III trial of pre-operative vs post-operative radiotherapy in extremity soft tissue sarcoma. J Clin Oncol. 2004;22(14 suppl):9007. doi: 10.1200/jco.2004.22.90140.9007.
    1. Pisters PW. Preoperative chemotherapy and split-course radiation therapy for patients with localized soft tissue sarcomas: home run, base hit, or strike out? J Clin Oncol. 2006;24(4):549–551. doi: 10.1200/JCO.2005.04.3026.
    1. Davis AM, O'Sullivan B, Turcotte R, Bell R, Catton C, Chabot P, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol. 2005;75(1):48–53. doi: 10.1016/j.radonc.2004.12.020.
    1. Dickie CI, Parent AL, Griffin AM, Fung S, Chung PW, Catton CN, et al. Bone fractures following external beam radiotherapy and limb-preservation surgery for lower extremity soft tissue sarcoma: relationship to irradiated bone length, volume, tumor location and dose. Int J Radiat Oncol Biol Phys. 2009;75(4):1119–1124. doi: 10.1016/j.ijrobp.2008.12.006.
    1. Haas RL, Delaney TF, O'Sullivan B, Keus RB, Le Pechoux C, Olmi P, et al. Radiotherapy for management of extremity soft tissue sarcomas: why, when, and where? Int J Radiat Oncol Biol Phys. 2012;84(3):572–580. doi: 10.1016/j.ijrobp.2012.01.062.
    1. Nevala R, Tukiainen E, Tarkkanen M, Böhling T, Blomqvist C, Sampo M. (Neo)adjuvant chemotherapy and interdigitated split-course hyperfractionated radiation in high risk soft tissue sarcoma—results from a large single-institution series. Sci Rep. 2019;9(1):7304. doi: 10.1038/s41598-019-43794-3.
    1. Spalek M, Koseła-Paterczyk H, Borkowska A, Wągrodzki M, Szumera-Ciećkiewicz A, Cieszanowski A, et al. OC-0069 5x5 Gy with chemotherapy in borderline resectable soft tissue sarcomas: early results of a trial. Radiother Oncol. 2019;133:S31–S32. doi: 10.1016/S0167-8140(19)30489-X.

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