LUGANO-COPENHAGEN - Neoadjuvant chemotherapy with an anthracycline plus ifosfamide was associated with significant survival gains in patients with soft tissue sarcoma of the trunk or extremities who are at high-risk of recurrence, in an interim analysis that led to the early discontinuation of a trial presented today at the ESMO 2016 Congress in Copenhagen.
The study compared this chemotherapy with tailoring chemotherapy regimens to histology sub-types.
“The benefit of adjuvant chemotherapy in soft tissue sarcoma has been debated a lot over recent years because of contradictory study outcomes,” said principal investigator Dr Alessandro Gronchi, Chair of the Sarcoma Surgery at the National Cancer Institute, Milan, Italy.
In this multi-center study, researchers recruited 287 patients with high-risk soft tissue sarcoma of the trunk or extremities, from five histological subtypes which represent around 80% of all soft tissue sarcomas arising in an extremity or trunk wall.
Patients were randomized 1:1 either to three cycles of epirubicin (120 mg/sqm) plus ifosfamide (9 g/sqm), or three cycles of one of five histologically-tailored regimens: gemcitabine+docetaxel in undifferentiated pleomorphic sarcoma; trabectedin in high-grade myxoid liposarcoma; high-dose prolonged-infusion ifosfamide in synovial sarcoma; etoposide+ifosfamide in malignant peripheral nerve sheath tumors; or gemcitabine+dacarbazine in leiomyosarcoma. All regimens were given pre-operatively.
After a median follow-up of 12.3 months, patients randomized to epirubicin plus ifosfamide showed significantly higher probability of relapse-free survival at 46 months compared to patients randomized to a histology-driven regiment (0.62 vs. 0.38, p=0.004), and of overall survival (0.89 vs. 0.64, p=0.033).
“In this 80% of patients who have a high-risk soft tissue sarcoma of the trunk or extremeties, it is worthwhile considering chemotherapy with epirubicin plus ifosfamide because their prognosis is improved by 20%,” Gronchi said. “We look forward to further follow-up of this trial to provide confirmation of this interim analysis as this is the first time that convincing evidence favoring the use of neoadjuvant chemotherapy is provided.”
While the study failed to show any benefit from histologically-tailored regimens, sub-group analysis did suggest that patients with high-grade myxoid liposarcoma who were treated with trabectedin had similar progression-free and overall survival to those treated with epirubicin plus ifosfamide.
“Trabectedin is far less toxic than conventional chemotherapy, so we will now expand this subgroup to assess if there is no difference between the two in terms of outcomes,” Gronchi said, pointing out that histology-driven therapy was not associated with any detrimental effects.
Commenting on the study, Professor Thomas Brodowicz, Program Director of the Bone and Soft Tissue-Sarcoma Unit at the Medical University Vienna, Austria, said, “Investigators wanted to show a one-third reduction in the relapse risk in favour of histology-driven therapy, so that means the trial did not meet the primary objective.”
“What we can conclude out of this is that the neoadjuvant anthracycline plus ifosfamide is better than the histology-driven regimens, but the question still is, is it better in comparison to no treatment?” Dr Brodowicz asked. “Furthermore, are three cycles of histology-driven therapy enough and is the neoadjuvant approach the right approach for all high risk patients?”
Brodowicz commented that there had been a lot of interest in histology-driven regimens for metastatic disease, and that while the results of this study in localised disease were negative, the conclusions could not be extended to metastatic disease.
“As it was not apparent that the histology-driven therapy could have been associated with any detrimental effect per se, the main interest of these findings (if confirmed by a longer follow-up) is proof that using a neo-adjuvant therapy in patients affected by high risk soft tissue sarcoma of the extremities or trunk wall, is associated with a clear-cut overall and relapse-free survival advantage, as compared with any other available strategy, including no treatment,“ Gronchi concluded.
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Notes to Editors
References
Abstract LBA6_PR Full-dose neoadjuvant anthracycline+ifosfamide chemotherapy is associated with a relapse-free survival and overall surviva benefit in localized high-risk adult soft tissue sarcom of the extremities and trunk wall: interim analysis of a prospective randomized trial, ‘will be presentedby Dr. Alessandro Gronchi during Presidential Symposium 3 on Monday 10.10.2016 at 16:30 (CEST).
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Abstract for LBA6_PR
Full-dose neoadjuvant anthracycline + ifosfamide chemotherapy is associated with a relapse free survival (RFS) and overall survival (OS) benefit in localized high-risk adult soft tissue sarcomas (STS) of the extremities and trunk wall: Interim analysis of a prospective randomized trial
A. Gronchi1, S. Ferrari2, V. Quagliuolo3, J. Martin Broto4, A. Lopez-Pousa5, G. Grignani6, V. Ferraresi7, J-Y. Blay8, P. Rutkowski9, F.D. Merlo10, E. Marchesi11, P. Ledesma12, A.P. Dei Tos13, S. Bague Rosell14, J-M. Coindre15, C. Morosi16, S. Stacchiotti17, P. Picci18, P. Bruzzi19, P.G. Casali20
1Surgery, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 2Medical Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy, 3Surgery, Istituto Clinico Humanitas, Rozzano, Italy, 4Medical Oncology, Hospital Universitario Virgen del Rocio, Seville, Spain, 5Research, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 6Medical Oncology, Istituto di Candiolo-IRCCS-Fondazione Piemontese per la Ricerca sul Cancro-Onlus, Candiolo, Italy, 7Istituti Fisioterapici Ospedalieri, U.O. Oncologia Medica 1, Regina Elena National Cancer Institute, Rome, Italy, 8Medical Oncology, Centre Léon Bérard, Lyon, France, 9Soft Tissue/Bone Sarcoma and Melanoma, MSC Memorial Cancer Centre and Institute Maria Sklodowska-Curie, Warsaw, Poland, 10Biostatistics, IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, 11Laboratorio di Oncologia Sperimentale, Istituto Ortopedico Rizzoli, Bologna, Italy, 12None, Sofpromed Investigacion Clinica, Palma de Mallorca, Spain, 13Department of Pathology, Ospedale Regionale Ca' Foncello, Treviso, Italy, 14Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 15Pathology, Institute Bergonié, Bordeaux, France, 16Radiology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 17Department of Cancer Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 18Muscoloskeletal Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy, 19Epidemiology, IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, 20Adult Sarcoma Medical Oncology Unit, Istituto Nazionale Tumori, Milan, Italy
Background: An Italian Sarcoma Group randomized trial versus no chemotherapy was indicative of an OS benefit with 5 cycles of adjuvant full-dose epirubicin+ifosfamide in localized high-risk STS (JCO 2001;19:1238). A subsequent randomized trial showed no difference between 3 vs 5 cycles of the same neo-adjuvant regimen (JCO 2012;30:850).
Methods: This multicenter European randomized trial compared epirubicin 120 mg/sqm + ifosfamide 9 g/sqm versus an histology-driven regimen: gemcitabine+docetaxel in undifferentiated pleomorphic sarcoma (UPS); trabectedin in high-grade myxoid liposarcoma; high-dose prolonged-infusion ifosfamide in synovial sarcoma (SS); etoposide + ifosfamide in malignant peripheral nerve sheath tumors (MPNST); gemcitabine+dacarbazine in leiomyosarcoma (LMS). Patients had localized high-risk STS (grade = 3; size >5 cm; deep site) of extremities or trunk wall. Primary end-point was RFS. With an expected accrual of 350 randomized patients, the trial was powered to show a 1/3 reduction in the hazard risk of relapse in favor of histology-driven therapy (with 80% power at the 5% [1-sided] significance level). Yearly futility analyses were conducted.
Results: From May 2011 to May 2016, 287 patients were randomized (97 = UPS; 65 = myxoid liposarcoma; 70 = SS; 27 = MPNST; 28 = LMS). At the third futility analysis, with a median follow-up of 12.3 months, the RFS probability at 46 months was 0.62 and 0.38 (log rank p=0.004; figure 1) and OS probability at 46 months was 0.89 and 0.64 (log rank p=0.033; figure 2), in the standard and in the histology-driven arm, respectively. In agreement with the Independent Reviewing Committee, the study was closed in advance. The analysis is being updated and subgroup analyses will be reported.
Conclusions: This trial provides randomized evidence that a neo-adjuvant chemotherapy with 3 full-dose courses of an anthracycline plus ifosfamide full-dose regimen can be associated with an absolute benefit averaging 20% for both RFS and OS over a different chemotherapy regimen, in a population of STS patients selected by a risk of relapse averaging 60-70%.
Clinical trial identification: NCT01710176; EUDRACT 2010 – 023484 – 17
Legal entity responsible for the study: Italian Sarcoma Group
Funding: Eurosarc FP7 278472
Disclosure: All authors have declared no conflicts of interest.
Keywords: extremities, sarcoma, Adjuvant chemotherapy, survival