The Activity of Chemotherapy in Inflammatory Myofibroblastic Tumors: A Multicenter, European Retrospective Case Series Analysis

Abstract

Background This study aimed to review the activity of cytotoxic chemotherapy in patients with inflammatory myofibroblastic tumors (IMTs) treated at nine European sarcoma reference centers. Materials and Methods Patients of any age, with histologically proven IMT, treated with anthracycline‐based methotrexate plus/minus vinorelbine/vinblastine (MTX‐V) or other chemotherapeutic regimens between 1996 and 2018 were retrospectively reviewed. Diagnosis was confirmed at the local level by an expert pathologist. Response was retrospectively assessed by local investigators by RECIST v1.1. Progression‐free survival (PFS), relapse‐free survival (RFS), and overall survival (OS) were computed by Kaplan‐Meier method. Results Thirty‐eight patients were included. Twenty‐five patients (8 localized, 17 advanced disease) received an anthracycline‐based regimen; 21 were evaluable for response. Overall response rate (ORR) was 10/21 (47.6%). At a 70.8‐month median follow‐up (FU), median RFS and median OS were not reached (NR) in patients with localized disease; median PFS and median OS were 6.3 (interquartile range [IQR]: 1.9–13.4) and 21.2 (IQR: 7.7–40.7) months in patients with advanced disease. Thirteen patients received MTX‐V (4 localized, 9 advanced disease), all evaluable for response. ORR was 7/13 (53.8%). At a 56.6‐month median FU, median RFS and median OS were 42.5 (IQR: 12.9–61.2) months and NR (no death events) in patients with localized disease, and NR (IQR: 24.9 to NR) and 83.4 months (IQR: 83.4 to NR) in patients with advanced disease. In the “other‐regimens group,” responses were seen in 3/4 patients treated with oral cyclophosphamide and 1/2 with docetaxel/gemcitabine. Conclusion Anthracycline‐based and MTX‐V regimens are very effective in IMT, with a similar ORR in both groups. MTX‐V achieved a prolonged disease control. Responses were also seen with oral cyclophosphamide and docetaxel/gemcitabine, but few patients were treated with these schedules. Implications for Practice Inflammatory myofibroblastic tumor (IMT) is an ultrarare sarcoma with known sensitivity to anaplastic lymphoma kinase (ALK) inhibitors in ALK‐fused cases, although ALK inhibitors are not licensed in the disease. The current knowledge on the activity of cytotoxic chemotherapy is limited. This multi‐institutional retrospective study on pediatric and adult patients with IMT shows that cytotoxic chemotherapy, and in particular anthracycline‐based and methotrexate plus/minus vinorelbine/vinblastine regimens, represents a treatment option and can be considered in IMT patients irrespectively from ALK status. This study provides a benchmark for future studies on new medical therapies.

Soft tissue and visceral sarcomas: ESMO–EURACAN–GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up☆

“…38,39  Methotrexate plus vinorelbine/vinblastine were retrospectively shown to have activity in inflammatory myofibroblastic tumour. 59 Table 1 lists systemic agents that have shown activity, either preliminary or partial, in selected sarcoma types, and have not entered standard practice and/or they are not approved/reimbursed in all European countries. Thus, if available, their use may be considered in the clinical balance within individualised patient-physician shared decisions.…”

Outstanding Response in a Patient With ROS1-Rearranged Inflammatory Myofibroblastic Tumor of Soft Tissues Treated With Crizotinib: Case Report

“…NGS may be more appealing in this scenario because can also detect other gene fusions characteristic for IMT such as PDGFR, RET, FN1–IGF1R and other rarer mutations, that may be possible targetable mutations in ALK/ROS1-negative IMTs ( 18 , 20 , 37 , 38 ). The molecular assessment of IMTs is, therefore, crucial to choose the best target treatment ( 15 , 16 ).…”

“…For unresectable or metastatic disease there is no standard-of-care, although many systemic chemotherapeutic regimens have been investigated and showed activity in several trials and case reports (6)(7)(8)(9)(10)(11)(12)(13)(14). An overall response rate (ORR) of about 50-60% after firstor second-line treatment was reported in studies on different types of chemotherapy, including anthracycline-based and vinorelbine/vinblastine-based regimens (15,16).…”

In Reply

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We are glad to answer P. Schöffski's comments [1] on our article on cytotoxic chemotherapy in advanced inflammatory myofibroblastic tumor (IMT) [2].With regard to pathologic diagnosis, we believe that in our retrospective study, the risk of misclassification was minimized by involving three major sarcoma reference centers in the U.K. and France and centralizing pathologic review of cases from the other six Italian centers on a network basis. ALK status by immunohistochemistry and/or of fluorescence in situ hybridization was required for all cases.With regard to the "informed consent to treatment," this was actually written, whereas each institutional review board approved the retrospective case series analysis according to local rules.We understand that our response rate was "in sharp contrast with retrospective data collected in the EORTC trial CREATE" [3].

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