Abstract
Background/Aim: Soft tissue sarcomas are rare and heterogenous malignancies with high recurrence rates following resection and a poor prognosis in advanced stages. Eribulin is used in metastatic soft tissue sarcoma patients, who have failed first line chemotherapy and has been approved for patients with pretreated advanced liposarcoma (LPS) in the United States and Europe following the publication of data of a phase III trial. In addition, no data are available for eribulin as postoperative treatment after potentially curative surgery. We, thus, retrospectively evaluated efficacy and tolerability of adjuvant eribulin in patients with LPS not suitable for intensive chemotherapy in the routine clinical setting. Patients and Methods: In this retrospective single center analysis, efficacy and safety of eribulin were retrospectively evaluated in five high risk LPS patients. Results: Eribulin as treatment was administered to five patients with LPS following surgical resection. Median progression-free survival and overall survival were 12.3 months and 44.3 months, respectively. Toxicity was generally manageable, and grade 3+4 events were rare. Conclusion: Postoperative eribulin may be feasible in selected high risk LPS patients, who are not candidates for intensive chemotherapy regimens. Further prospective trials, however, are needed.
Soft tissue sarcomas (STS) are a heterogenous group of malignant tumors of mesenchymal origin that account for approximately 1% of adult malignancies (1). Most STS patients present with initially localized disease and the most common histological subtypes are liposarcoma (LPS) and leiomyosarcoma (LMS) (2). However, 30-60% of patients develop local recurrence or distant metastases in the course of the disease, and survival in advanced disease stages is poor (3-5).
In case of initially localized disease, therapy of choice is surgical resection often followed by radiation therapy. The benefit of neoadjuvant or adjuvant chemotherapy is still unknown, and its use is not generally recommended (6). However, in certain situations, pre- or postoperative chemotherapy may be the treatment of choice after individualized multidisciplinary risk evaluation (7). In inoperable locally advanced or metastatic STS (mSTS), chemotherapy, usually containing anthracyclines, is the therapy of choice. Additionally, ifosfamide may be added to an anthracycline-based therapy, depending on the individual histological subtype and risk profile (6, 8). Further available systemic treatment options for mSTS include dacarbazine, gemcitabine, docetaxel, eribulin as well as novel agents, such as trabectedin and pazopanib (9-15).
In a randomized phase III study comparing eribulin with dacarbazine in patients with previously treated metastatic LPS and LMS, overall survival (OS) was significantly improved in the eribulin cohort (p=0.0169), whereas grade 3/4 toxicities were comparable with good tolerance in both treatment arms (11), suggesting eribulin as a suitable agent in pretreated patients with these subtypes.
To date, no prospective results on the potential use of eribulin in earlier treatment-lines have been published, especially in the postoperative setting following potentially curative resection of LPS. In view of this, we conducted this retrospective single-center analysis to assess the potential efficacy and tolerability of eribulin in high risk LPS patients, who are not candidates for more intensive chemotherapy regimens following resection of the tumor.
Patients and Methods
Patients and design. Clinical records of all patients older than 18 years with histopathologically verified LPS who received eribulin between 2014 and 2020 were screened for demographic and treatment characteristics, response, and safety. Information of patients given eribulin as therapy following potentially curative surgery was extracted from routine charts, including histology, sex, age, stage and localization and type of surgery. Outcome of therapy was assessed in terms of progression-free survival (PFS) and OS calculated from the first administration of eribulin, and also side effects.
Eribulin was administered at the standard dose of 1.23 mg/m2 intravenously over 2-5 minutes on day 1 and day 8 with a cycle interval of 21 days. Antiemetic prophylaxis included dexamethasone and ondansetron administered prior to eribulin application and on the following day. Additional supportive therapy for side effect management, including G-CSF prophylaxis was applied according to clinical requirements. Dose was reduced to 1.1 mg/m2 for: grade 4 neutropenia lasting more than 4 days or associated with fever or infection, grade 4 thrombocytopenia, or any grade 3 and 4 non-hematological toxicities.
The analysis was approved by the Independent Local Ethics Committee of the Medical University of Vienna Austria (EC Nr. 1207/2021) and was performed in accordance with the declaration of Helsinki and Good Clinical practice-Guidelines. Due to the retrospective nature, this analysis was approved as a non-interventional retrospective study, therefore, no written informed consent according to institutional guidelines was needed.
Assessments. Patients who received at least two full cycles of eribulin after resection of LPS and underwent subsequent restaging via computed tomography and/or magnetic resonance tomography were eligible for the response analysis. Potential recurrence or the development of metastases was assessed by routine radiological local and systemic imaging performed every two cycles of therapy and at 3-month intervals after the end of therapy according to institutional practice.
For patients who received adjuvant eribulin, 6 cycles were generally planned, however, this could have been extended to 9 cycles, depending on the individual risk profile and tolerability of eribulin. Toxicity was recorded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (16).
Statistical analysis. PFS was calculated from the date of eribulin initiation until the date of progression or death of any cause. OS was calculated from the start of therapy with eribulin until death of any cause. Survival curves were plotted using the Kaplan-Meier method, and survival curves were compared using the log-rank test. All statistical analyses were performed using the program IBM SPSS statistics Version 27 (IBM, Armonk, NY, USA).
Results
Patient characteristics. Our analysis identified a total of 5 patients (male=4; female=1) with histologically verified localized LPS treated with postoperative eribulin between July 2014 and December 2020. Median age for the population was 61 years (range=48-70 years). Three patients were diagnosed with dedifferentiated LPS and 2 patients with pleomorphic LPS. These two histological subtypes are associated with high risk of developing distant metastasis when compared to well-differentiated and myxoid LPS. Primary location of LPS was the abdominal cavity in four patients, while the remaining patient had primary disease in the thoracic wall. R0 resection was achieved in two patients and three patients underwent R1 resection. A median of six cycles of eribulin were administered (range=6-9 cycles). Four patients received six cycles and the remaining patient received nine cycles of eribulin.
Two patients had been pretreated with an anthracycline due to breast cancer and Wilms Tumor, respectively, with the cumulative anthracycline-dose precluding further application. An additional patient initially received anthracycline therapy after initial resection of primary disease. This patient developed lung metastasis and underwent complete surgical pulmonary metastasectomy and received eribulin in this setting, i.e., as second adjuvant therapy. The remaining two patients were given eribulin due to reduced left ventricular ejection fraction (LVEF).
Outcome. Four patients developed relapse of LPS in the course of disease, whereas the remaining patient is still in complete remission 24 months after initiation of therapy. The localizations of relapses were the retroperitoneum (n=3), the diaphragm (n=1) and the lung (n=1). Median PFS and OS were 12.3 months (95%CI=5.6-18.9 months) and 44.3 months (95%CI=3.8-84.8 months), respectively. Baseline characteristics are outlined in Table I. At the time of analysis, three (60%) patients were still alive, whereas two (40%) patients had died due to progressive disease.
Patient baseline characteristics.
Toxicity. All five patients were included in the safety analysis. A summary of adverse events is given in Table II. Most of the toxicities were grade 1+2. Among hematological toxicities, the most frequent adverse events were grade 1+2 anemia and neutropenia in two patients each. Frequent grade 1+2 non-hematological adverse events were fatigue, nausea, and peripheral polyneuropathy in two patients. One patient each experienced creatinine and bilirubin elevation.
Eribulin associated side effects.
Discussion
The objective of this retrospective single-center analysis was to assess efficacy and tolerability of eribulin in the postoperative setting in patients with LPS. Eribulin is a structurally modified analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. It induces cell-cycle arrest as well as tumor regression and has shown promising efficacy in different phase II and III trials after failure of anthracycline-based chemotherapy (11, 17, 18). Eribulin was first investigated for the use in STS in a phase II trial in 2011 that included 128 participants with LPS, LMS, synovial sarcoma and other STS subtypes. The overall response rate was 3%, 5%, 5%, and 4%, respectively, and PFS at 12 weeks was 46.9%, 31.6%, 21.1% and 19.2% (19). Based on these findings, a phase III trial of eribulin versus dacarbazine in “L-sarcoma” patients (i.e., LPS and LMS) previously treated with at least two standard chemotherapy regimens was performed. This trial included 452 participants, and the median OS was significantly improved by eribulin when compared to dacarbazine (13.5 months vs. 11.5 months; p=0.0169). However, PFS remained unchanged (2.6 months vs. 2.6 months). Since only the LPS subgroup showed a survival benefit (median OS 15.6 vs. 8.4 months in LPS and 12.7 vs. 13 months in LMS), eribulin is currently approved for advanced and non-resectable LPS patients after previous treatment with anthracyclines in the United States and the European Union (11). Eribulin versus dacarbazine in the LMS-subtype was further investigated in a subgroup phase III analysis including 309 patients. As suggested by the data of the primary phase III trial, median OS and PFS did not differ between both therapy arms (12.7 vs. 13.0 months; p=0.57 and 2.2 vs. 2.6 months; p=0.58, respectively) (20).
In our trial, the median PFS and OS were 12.3 and 44.3 months (11). It has to be mentioned that in our analysis, only patients with localized disease following surgical resection were included. Therefore, due to a lack of data on postoperative eribulin, the PFS and OS reported in this trial cannot be compared to previous findings.
To the best of our knowledge, this is the first report of eribulin in a postoperative setting as adjuvant therapy following surgical resection, even if the sample number is limited with only five patients with LPS receiving eribulin. Adjuvant chemotherapy after surgical resection of STS is controversial and is not generally recommended due to conflicting study data (6). However, some data have suggested a potential benefit in disease-free survival and OS, especially in high-risk tumors (21). Therefore, in tumors with an individually assessed high risk of death, adjuvant chemotherapy may be a feasible option to prolong the time to potential recurrence (6, 22). Nonetheless, since prospective data on this topic are scarce, decision on adjuvant chemotherapy should be carefully planned in a multidisciplinary tumor board. In our cohort, eribulin was chosen as an off-label postoperative chemotherapy in five high risk patients with dedifferentiated and pleomorphic LPS. Eribulin was chosen due to its favorable toxicity profile compared to other therapy options as well as favorable efficacy in metastatic LPS patients (11, 18). According to the current ESMO-guidelines, complete surgical resection is the treatment of choice in metachronous lung metastases. Data on chemotherapy after surgery are limited and conflicting, however, in case of high-risk disease, adjuvant therapy may be added (6). Median PFS and OS for adjuvant eribulin were 12.3 months (95%CI=5.6-18.9 months) and 44.3 months (95%CI=3.8-84.8), respectively. In comparison, Predina et al. reported a longer OS of 5.3 years (63.6 months) and a comparable PFS of 1.1 year (13.2 months) after surgical resection and adjuvant chemotherapy (chemotherapy protocols: doxorubicin/ifosfamide; vincristine, gemcitabine, docetaxel, carboplatin, and etoposide). In this trial, no difference in disease-free survival after pulmonary metastasectomy for STS with adjuvant chemotherapy versus no chemotherapy (p=0.88) was observed (23). In our cohort, one patient still has no visible disease after more than 3 years whereas the other 4 patients showed disease recurrence occurring in the retroperitoneum (n=3), the diaphragm (n=1) and the lung (n=1) – after a median of 12.3 months.
Side effects in our patient collective were few and manageable. The most common side effects were grade 1 + 2 hematological, (neutropenia and anemia), while non-hematological grade 1+2 side effects included fatigue, nausea, and peripheral polyneuropathy.
In summary, postoperative eribulin was well tolerated and may be a potential alternative to more aggressive chemotherapy regimens in specific high-risk LPS patients after surgical resection. However, further prospective trials with larger sample numbers are needed to further investigate the activity of eribulin in a postoperative setting in chemotherapy naïve patients with high-risk features.
Footnotes
Authors’ Contributions
Study concept and design were performed by Steinbrecher Oskar and Wolfgang Lamm. Steinbrecher Oskar and Petar Popov acquired the data. Analysis and interpretation of data were conducted by all Authors. Drafting of the manuscript was performed by Steinbrecher Oskar, Petar Popov, Wolfgang Lamm, and Thomas Brodowicz. Critical revision of the manuscript was carried out by all Authors.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received August 21, 2023.
- Revision received September 13, 2023.
- Accepted September 14, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.