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Published in: Annals of Surgical Oncology 11/2019

01-10-2019 | Soft Tissue Sarcoma | Sarcoma

Assessing the Role of Neoadjuvant Chemotherapy in Primary High-Risk Truncal/Extremity Soft Tissue Sarcomas: An Analysis of the Multi-institutional U.S. Sarcoma Collaborative

Authors: Mohammad Y. Zaidi, MD, MS, Cecilia G. Ethun, MD, MS, Thuy B. Tran, MD, George Poultsides, MD, Valerie P. Grignol, MD, J. Harrison Howard, MD, Meena Bedi, MD, Harveshp Mogal, MD, Jennifer Tseng, MD, Kevin K. Roggin, MD, Konstantinos Chouliaras, MD, Konstantinos Votanopoulos, MD, Brad Krasnick, MD, Ryan C. Fields, MD, Shervin Oskouei, MD, Nickolas Reimer, MD, David Monson, MD, Shishir K. Maithel, MD, Kenneth Cardona, MD, FACS

Published in: Annals of Surgical Oncology | Issue 11/2019

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Abstract

Background

The role of neoadjuvant chemotherapy (NCT) for high-risk soft tissue sarcoma (STS) is questioned. This study aimed to define which patients may experience a survival advantage with NCT.

Methods

All the patients from the U.S. Sarcoma Collaborative database (2000–2016) who underwent curative-intent resection of high-grade, primary truncal/extremity STS size 5 cm or larger were included in this study. The primary end points were recurrence-free survival (RFS) and overall survival (OS).

Results

Of the 4153 patients, 770 were included in the study. The median tumor size was 10 cm, and 669 of the patients (87%) had extremity tumors. The most common histology was undifferentiated pleomorphic sarcoma (UPS), found in 42% of the patients. Of the 770 patients, 216 (28%) received NCT. The patients who received NCT had deeper, larger tumors (p < 0.001). Of the patients with tumors 5 cm or larger and 8 cm or larger, NCT was not associated with improved RFS or OS. However for the patients with tumors 10 cm or larger, NCT was associated with improved 5-year RFS (51% vs 40%; p = 0.053) and 5-year OS (58% vs 47%; p = 0.043). By location, the patients with extremity tumors 10 cm or larger but not truncal tumors had improved 5-yearr RFS (54% vs 42%; p = 0.042) and 5-year OS (61% vs 47%; p = 0.015) with NCT. According to histology, no subtype had improved RFS or OS with NCT, although the patients with UPS had a trend toward improved 5-year RFS (56% vs 42%; p = 0.092) and 5-year OS (66% vs 52%; p = 0.103) with NCT.

Conclusion

For the patients with high-grade STS, NCT was associated with improved RFS and OS when tumors were 10 cm or larger and located in the extremity. However, no histiotype-specific advantage was identified. Future studies assessing the efficacy of NCT may consider focusing on these patients, with added focus on histology-specific strategies.
Literature
1.
go back to reference Davis LE, Ryan CW. Preoperative therapy for extremity soft tissue sarcomas. Curr Treat Options Oncol. 2015;16:25.CrossRefPubMed Davis LE, Ryan CW. Preoperative therapy for extremity soft tissue sarcomas. Curr Treat Options Oncol. 2015;16:25.CrossRefPubMed
2.
go back to reference Singh AS, Eilber FC. Neoadjuvant therapy for soft-tissue sarcomas: one size does not fit all. Oncology Williston Park. 2016;30:107–8.PubMed Singh AS, Eilber FC. Neoadjuvant therapy for soft-tissue sarcomas: one size does not fit all. Oncology Williston Park. 2016;30:107–8.PubMed
3.
go back to reference Weitz J, Antonescu CR, Brennan MF. Localized extremity soft tissue sarcoma: improved knowledge with unchanged survival over time. J Clin Oncol. 2003;21:2719–25.CrossRefPubMed Weitz J, Antonescu CR, Brennan MF. Localized extremity soft tissue sarcoma: improved knowledge with unchanged survival over time. J Clin Oncol. 2003;21:2719–25.CrossRefPubMed
4.
go back to reference Bramwell VH, Mouridsen HT, Santoro A, Blackledge G, Somers R, Verwey J, et al. Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol. 1987;23:311–21.CrossRefPubMed Bramwell VH, Mouridsen HT, Santoro A, Blackledge G, Somers R, Verwey J, et al. Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol. 1987;23:311–21.CrossRefPubMed
5.
go back to reference Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay JY, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15:415–23.CrossRefPubMed Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay JY, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15:415–23.CrossRefPubMed
6.
go back to reference Lorigan P, Verweij J, Papai Z, Rodenhuis S, Le Cesne A, Leahy MG, et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007;25:3144–50.CrossRefPubMed Lorigan P, Verweij J, Papai Z, Rodenhuis S, Le Cesne A, Leahy MG, et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007;25:3144–50.CrossRefPubMed
7.
go back to reference 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;13:1045–54.CrossRefPubMed 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;13:1045–54.CrossRefPubMed
8.
go back to reference Benjamin RS. Adjuvant and neoadjuvant chemotherapy for soft tissue sarcomas: a personal point of view. Tumori. 2017;103:213–6.CrossRefPubMed Benjamin RS. Adjuvant and neoadjuvant chemotherapy for soft tissue sarcomas: a personal point of view. Tumori. 2017;103:213–6.CrossRefPubMed
9.
go back to reference Rothermundt C, Fischer GF, Bauer S, Blay JY, Grünwald V, Italiano A, et al. Pre- and postoperative chemotherapy in localized extremity soft tissue sarcoma: a European Organization for Research and Treatment of Cancer Expert Survey. Oncologist. 2018;23:461–7.CrossRefPubMed Rothermundt C, Fischer GF, Bauer S, Blay JY, Grünwald V, Italiano A, et al. Pre- and postoperative chemotherapy in localized extremity soft tissue sarcoma: a European Organization for Research and Treatment of Cancer Expert Survey. Oncologist. 2018;23:461–7.CrossRefPubMed
10.
go back to reference Gortzak E, Azzarelli A, Buesa J, Bramwell VH, Van Coevorden F, Van Geel AN, et al. A randomised phase II study on neo-adjuvant chemotherapy for “high-risk” adult soft-tissue sarcoma. Eur J Cancer. 2001;37:1096–103.CrossRefPubMed Gortzak E, Azzarelli A, Buesa J, Bramwell VH, Van Coevorden F, Van Geel AN, et al. A randomised phase II study on neo-adjuvant chemotherapy for “high-risk” adult soft-tissue sarcoma. Eur J Cancer. 2001;37:1096–103.CrossRefPubMed
11.
go back to reference 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;18:812–22.CrossRefPubMed 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;18:812–22.CrossRefPubMed
12.
go back to reference Kraybill WG, Harris J, Spiro IJ, Ettinger DS, DeLaney TF, Blum RH, et al. Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. Cancer. 2010;116:4613–21.CrossRefPubMedPubMedCentral Kraybill WG, Harris J, Spiro IJ, Ettinger DS, DeLaney TF, Blum RH, et al. Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. Cancer. 2010;116:4613–21.CrossRefPubMedPubMedCentral
13.
go back to reference 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;24:619–25.CrossRefPubMed 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;24:619–25.CrossRefPubMed
14.
go back to reference Meyer JM, Perlewitz KS, Hayden JB, Doung YC, Hung AY, Vetto JT, et al. Phase I trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates. Clin Cancer Res. 2013;19:6902–11.CrossRefPubMed Meyer JM, Perlewitz KS, Hayden JB, Doung YC, Hung AY, Vetto JT, et al. Phase I trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates. Clin Cancer Res. 2013;19:6902–11.CrossRefPubMed
15.
go back to reference Spencer RM, Junior SA, Ferreira FO, Stevanato Filho PR, Kupper BE, Silva ML, et al. Neoadjuvant hypofractionated radiotherapy and chemotherapy in high-grade extremity soft tissue sarcomas: phase 2 clinical trial protocol. JMIR Res Protoc. 2017;6:e97.CrossRefPubMedPubMedCentral Spencer RM, Junior SA, Ferreira FO, Stevanato Filho PR, Kupper BE, Silva ML, et al. Neoadjuvant hypofractionated radiotherapy and chemotherapy in high-grade extremity soft tissue sarcomas: phase 2 clinical trial protocol. JMIR Res Protoc. 2017;6:e97.CrossRefPubMedPubMedCentral
16.
go back to reference Tseng WW, Zhou S, To CA, Thall PF, Lazar AJ, Pollock RE, et al. Phase 1 adaptive dose-finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcoma. Cancer. 2015;121:3659–67.CrossRefPubMedPubMedCentral Tseng WW, Zhou S, To CA, Thall PF, Lazar AJ, Pollock RE, et al. Phase 1 adaptive dose-finding study of neoadjuvant gemcitabine combined with radiation therapy for patients with high-risk extremity and trunk soft tissue sarcoma. Cancer. 2015;121:3659–67.CrossRefPubMedPubMedCentral
17.
go back to reference Bedi M, King DM, Shivakoti M, Wang T, Zambrano EV, Charlson J, et al. Prognostic variables in patients with primary soft tissue sarcoma of the extremity and trunk treated with neoadjuvant radiotherapy or neoadjuvant sequential chemoradiotherapy. Radiat Oncol. 2013;8:60.CrossRefPubMedPubMedCentral Bedi M, King DM, Shivakoti M, Wang T, Zambrano EV, Charlson J, et al. Prognostic variables in patients with primary soft tissue sarcoma of the extremity and trunk treated with neoadjuvant radiotherapy or neoadjuvant sequential chemoradiotherapy. Radiat Oncol. 2013;8:60.CrossRefPubMedPubMedCentral
18.
go back to reference Grobmyer SR, Maki RG, Demetri GD, Mazumdar M, Riedel E, Brennan MF, et al. Neoadjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol. 2004;15:1667–72.CrossRefPubMed Grobmyer SR, Maki RG, Demetri GD, Mazumdar M, Riedel E, Brennan MF, et al. Neoadjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol. 2004;15:1667–72.CrossRefPubMed
19.
go back to reference Mahmoud O, Tunceroglu A, Chokshi R, Benevenia J, Beebe K, Patterson F, et al. Overall survival advantage of chemotherapy and radiotherapy in the perioperative management of large extremity and trunk soft tissue sarcoma; a large database analysis. Radiother Oncol. 2017;124:277–84.CrossRefPubMed Mahmoud O, Tunceroglu A, Chokshi R, Benevenia J, Beebe K, Patterson F, et al. Overall survival advantage of chemotherapy and radiotherapy in the perioperative management of large extremity and trunk soft tissue sarcoma; a large database analysis. Radiother Oncol. 2017;124:277–84.CrossRefPubMed
20.
go back to reference Mullen JT, Kobayashi W, Wang JJ, Harmon DC, Choy E, Hornicek FJ, et al. Long-term follow-up of patients treated with neoadjuvant chemotherapy and radiotherapy for large, extremity soft tissue sarcomas. Cancer. 2012;118:3758–65.CrossRefPubMed Mullen JT, Kobayashi W, Wang JJ, Harmon DC, Choy E, Hornicek FJ, et al. Long-term follow-up of patients treated with neoadjuvant chemotherapy and radiotherapy for large, extremity soft tissue sarcomas. Cancer. 2012;118:3758–65.CrossRefPubMed
21.
go back to reference Pasquali S, Colombo C, Pizzamiglio S, Verderio P, Callegaro D, Stacchiotti S, et al. High-risk soft tissue sarcomas treated with perioperative chemotherapy: improving prognostic classification in a randomised clinical trial. Eur J Cancer. 2018;93:28–36.CrossRefPubMed Pasquali S, Colombo C, Pizzamiglio S, Verderio P, Callegaro D, Stacchiotti S, et al. High-risk soft tissue sarcomas treated with perioperative chemotherapy: improving prognostic classification in a randomised clinical trial. Eur J Cancer. 2018;93:28–36.CrossRefPubMed
22.
go back to reference Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual (7th ed.). New York: Springer; 2010. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual (7th ed.). New York: Springer; 2010.
23.
go back to reference Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK (eds) AJCC Cancer Staging. 8th ed. vol. 8. New York: Springer; 2017. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK (eds) AJCC Cancer Staging. 8th ed. vol. 8. New York: Springer; 2017.
24.
go back to reference Mack LA, Crowe PJ, Yang JL, Schachar NS, Morris DG, Kurien EC, et al. Preoperative chemoradiotherapy (modified Eilber protocol) provides maximum local control and minimal morbidity in patients with soft tissue sarcoma. Ann Surg Oncol. 2005;12:646–53.CrossRefPubMed Mack LA, Crowe PJ, Yang JL, Schachar NS, Morris DG, Kurien EC, et al. Preoperative chemoradiotherapy (modified Eilber protocol) provides maximum local control and minimal morbidity in patients with soft tissue sarcoma. Ann Surg Oncol. 2005;12:646–53.CrossRefPubMed
25.
go back to reference Pasquali S, Pizzamiglio S, Touati N, Litiere S, Marreaud S, Kasper B, et al. The impact of chemotherapy on survival of patients with extremity and trunk wall soft tissue sarcoma: revisiting the results of the EORTC-STBSG 62931 randomised trial. Eur J Cancer. 2019;109:51–60.CrossRefPubMed Pasquali S, Pizzamiglio S, Touati N, Litiere S, Marreaud S, Kasper B, et al. The impact of chemotherapy on survival of patients with extremity and trunk wall soft tissue sarcoma: revisiting the results of the EORTC-STBSG 62931 randomised trial. Eur J Cancer. 2019;109:51–60.CrossRefPubMed
Metadata
Title
Assessing the Role of Neoadjuvant Chemotherapy in Primary High-Risk Truncal/Extremity Soft Tissue Sarcomas: An Analysis of the Multi-institutional U.S. Sarcoma Collaborative
Authors
Mohammad Y. Zaidi, MD, MS
Cecilia G. Ethun, MD, MS
Thuy B. Tran, MD
George Poultsides, MD
Valerie P. Grignol, MD
J. Harrison Howard, MD
Meena Bedi, MD
Harveshp Mogal, MD
Jennifer Tseng, MD
Kevin K. Roggin, MD
Konstantinos Chouliaras, MD
Konstantinos Votanopoulos, MD
Brad Krasnick, MD
Ryan C. Fields, MD
Shervin Oskouei, MD
Nickolas Reimer, MD
David Monson, MD
Shishir K. Maithel, MD
Kenneth Cardona, MD, FACS
Publication date
01-10-2019
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 11/2019
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-019-07639-7

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