Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial

European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group and the European Society for Hyperthermic Oncology

Research output: Contribution to journalArticle

Abstract

Importance: Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes.

Objective: To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival.

Design, Setting, and Participants: Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014.

Interventions: After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide alone, or combined with regional hyperthermia.

Main Outcomes and Measures: The primary end point was local progression-free survival. Secondary end points included treatment safety and survival, with survival defined from date of randomization to death due to disease or treatment. Patients lost to follow-up were censored at the date of their last follow-up.

Results: A total of 341 patients were randomized, and 329 (median [range] age, 51 [18-70] years; 147 women, 182 men) were eligible for the intention-to-treat analysis. By December 2014, 220 patients (67%; 95% CI, 62%-72%) had experienced disease relapse, and 188 (57%; 95% CI, 52%-62%) had died. Median follow-up was 11.3 years. Compared with neoadjuvant chemotherapy alone, adding regional hyperthermia improved local progression-free survival (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86; P = .002). Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.98; P = .04) with 5-year survival of 62.7% (95% CI, 55.2%-70.1%) vs 51.3% (95% CI, 43.7%-59.0%), respectively, and 10-year survival of 52.6% (95% CI, 44.7%-60.6%) vs 42.7% (95% CI, 35.0%-50.4%).

Conclusions and Relevance: Among patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted.

Trial Registration: clinicaltrials.gov Identifier: NCT00003052.

Original languageEnglish
Pages (from-to)483-492
Number of pages10
JournalJAMA oncology
Volume4
Issue number4
DOIs
Publication statusPublished - Apr 1 2018

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Sarcoma
Fever
Randomized Controlled Trials
Drug Therapy
Disease-Free Survival
Survival
Ifosfamide
Recurrence
Neoplasms
Phase III Clinical Trials
Induced Hyperthermia
Intention to Treat Analysis
Neoadjuvant Therapy
Austria
Poisons
Anthracyclines
Lost to Follow-Up
Etoposide
Norway
Random Allocation

Cite this

European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group and the European Society for Hyperthermic Oncology (2018). Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial. JAMA oncology, 4(4), 483-492. https://doi.org/10.1001/jamaoncol.2017.4996

Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma : The EORTC 62961-ESHO 95 Randomized Clinical Trial. / European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group and the European Society for Hyperthermic Oncology.

In: JAMA oncology, Vol. 4, No. 4, 01.04.2018, p. 483-492.

Research output: Contribution to journalArticle

European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group and the European Society for Hyperthermic Oncology 2018, 'Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial', JAMA oncology, vol. 4, no. 4, pp. 483-492. https://doi.org/10.1001/jamaoncol.2017.4996
European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group and the European Society for Hyperthermic Oncology. Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial. JAMA oncology. 2018 Apr 1;4(4):483-492. https://doi.org/10.1001/jamaoncol.2017.4996
European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group and the European Society for Hyperthermic Oncology. / Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma : The EORTC 62961-ESHO 95 Randomized Clinical Trial. In: JAMA oncology. 2018 ; Vol. 4, No. 4. pp. 483-492.
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abstract = "Importance: Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes.Objective: To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival.Design, Setting, and Participants: Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014.Interventions: After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide alone, or combined with regional hyperthermia.Main Outcomes and Measures: The primary end point was local progression-free survival. Secondary end points included treatment safety and survival, with survival defined from date of randomization to death due to disease or treatment. Patients lost to follow-up were censored at the date of their last follow-up.Results: A total of 341 patients were randomized, and 329 (median [range] age, 51 [18-70] years; 147 women, 182 men) were eligible for the intention-to-treat analysis. By December 2014, 220 patients (67{\%}; 95{\%} CI, 62{\%}-72{\%}) had experienced disease relapse, and 188 (57{\%}; 95{\%} CI, 52{\%}-62{\%}) had died. Median follow-up was 11.3 years. Compared with neoadjuvant chemotherapy alone, adding regional hyperthermia improved local progression-free survival (hazard ratio [HR], 0.65; 95{\%} CI, 0.49-0.86; P = .002). Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone (HR, 0.73; 95{\%} CI, 0.54-0.98; P = .04) with 5-year survival of 62.7{\%} (95{\%} CI, 55.2{\%}-70.1{\%}) vs 51.3{\%} (95{\%} CI, 43.7{\%}-59.0{\%}), respectively, and 10-year survival of 52.6{\%} (95{\%} CI, 44.7{\%}-60.6{\%}) vs 42.7{\%} (95{\%} CI, 35.0{\%}-50.4{\%}).Conclusions and Relevance: Among patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted.Trial Registration: clinicaltrials.gov Identifier: NCT00003052.",
author = "Issels, {Rolf D} and Lindner, {Lars H} and Jaap Verweij and R{\"u}diger Wessalowski and Peter Reichardt and Peter Wust and Pirus Ghadjar and Peter Hohenberger and Martin Angele and Christoph Salat and Zeljko Vujaskovic and Soeren Daugaard and Olav Mella and Ulrich Mansmann and D{\"u}rr, {Hans Roland} and Thomas Kn{\"o}sel and Sultan Abdel-Rahman and Michael Schmidt and Wolfgang Hiddemann and Karl-Walter Jauch and Claus Belka and Alessandro Gronchi and {European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group and the European Society for Hyperthermic Oncology}",
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T1 - Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma

T2 - The EORTC 62961-ESHO 95 Randomized Clinical Trial

AU - Issels, Rolf D

AU - Lindner, Lars H

AU - Verweij, Jaap

AU - Wessalowski, Rüdiger

AU - Reichardt, Peter

AU - Wust, Peter

AU - Ghadjar, Pirus

AU - Hohenberger, Peter

AU - Angele, Martin

AU - Salat, Christoph

AU - Vujaskovic, Zeljko

AU - Daugaard, Soeren

AU - Mella, Olav

AU - Mansmann, Ulrich

AU - Dürr, Hans Roland

AU - Knösel, Thomas

AU - Abdel-Rahman, Sultan

AU - Schmidt, Michael

AU - Hiddemann, Wolfgang

AU - Jauch, Karl-Walter

AU - Belka, Claus

AU - Gronchi, Alessandro

AU - European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group and the European Society for Hyperthermic Oncology

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Importance: Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes.Objective: To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival.Design, Setting, and Participants: Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014.Interventions: After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide alone, or combined with regional hyperthermia.Main Outcomes and Measures: The primary end point was local progression-free survival. Secondary end points included treatment safety and survival, with survival defined from date of randomization to death due to disease or treatment. Patients lost to follow-up were censored at the date of their last follow-up.Results: A total of 341 patients were randomized, and 329 (median [range] age, 51 [18-70] years; 147 women, 182 men) were eligible for the intention-to-treat analysis. By December 2014, 220 patients (67%; 95% CI, 62%-72%) had experienced disease relapse, and 188 (57%; 95% CI, 52%-62%) had died. Median follow-up was 11.3 years. Compared with neoadjuvant chemotherapy alone, adding regional hyperthermia improved local progression-free survival (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86; P = .002). Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.98; P = .04) with 5-year survival of 62.7% (95% CI, 55.2%-70.1%) vs 51.3% (95% CI, 43.7%-59.0%), respectively, and 10-year survival of 52.6% (95% CI, 44.7%-60.6%) vs 42.7% (95% CI, 35.0%-50.4%).Conclusions and Relevance: Among patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted.Trial Registration: clinicaltrials.gov Identifier: NCT00003052.

AB - Importance: Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes.Objective: To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival.Design, Setting, and Participants: Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014.Interventions: After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide alone, or combined with regional hyperthermia.Main Outcomes and Measures: The primary end point was local progression-free survival. Secondary end points included treatment safety and survival, with survival defined from date of randomization to death due to disease or treatment. Patients lost to follow-up were censored at the date of their last follow-up.Results: A total of 341 patients were randomized, and 329 (median [range] age, 51 [18-70] years; 147 women, 182 men) were eligible for the intention-to-treat analysis. By December 2014, 220 patients (67%; 95% CI, 62%-72%) had experienced disease relapse, and 188 (57%; 95% CI, 52%-62%) had died. Median follow-up was 11.3 years. Compared with neoadjuvant chemotherapy alone, adding regional hyperthermia improved local progression-free survival (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86; P = .002). Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.98; P = .04) with 5-year survival of 62.7% (95% CI, 55.2%-70.1%) vs 51.3% (95% CI, 43.7%-59.0%), respectively, and 10-year survival of 52.6% (95% CI, 44.7%-60.6%) vs 42.7% (95% CI, 35.0%-50.4%).Conclusions and Relevance: Among patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted.Trial Registration: clinicaltrials.gov Identifier: NCT00003052.

U2 - 10.1001/jamaoncol.2017.4996

DO - 10.1001/jamaoncol.2017.4996

M3 - Article

C2 - 29450452

VL - 4

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EP - 492

JO - JAMA oncology

JF - JAMA oncology

SN - 2374-2437

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