Management of recurrent or refractory Ewing sarcoma: A systematic review of phase II clinical trials in the last 15 years
- Authors:
- Published online on: May 7, 2019 https://doi.org/10.3892/ol.2019.10328
- Pages: 348-358
Abstract
Introduction
Ewing sarcoma (EWS) is a small-round-blue-cell tumor that is derived from primordial mesenchymal stem cells, which often originate from the bone marrow (1). The incidence of EWS is one case in one million people in the US (1). The current standard first-line chemotherapy for EWS includes vincristine, doxorubicin, cyclophosphamide (VDC), ifosfamide and etoposide (IE), also termed VDC/IE (2,3), or vincristine, ifosfamide, doxorubicin and etoposide (VIDE) (4). The use of these chemotherapy regimens has resulted in the 5-year survival rate increasing from 59 to 78% in children and young adolescents, and from 20 to 60% in adults (5). However, there is currently no standardized second-line treatment for recurrent or refractory EWS. Various methods, including classical cytotoxic agents, targeted therapy, such as anti-angiogenesis small molecular tyrosine kinase inhibitors (aaTKIs), and immunotherapy, such as check-point inhibitors, have been tested in these progressed cases. Unfortunately, the prognosis for these patients remains poor (5,6). The majority of phase I trials for these methods have demonstrated acceptable safety profiles, but have failed to reach the primary endpoint in the phase II trials. In the last two decades, only one phase II trial testing these new drugs has progressed to phase III; however, there is no published data available. Until now, there has not been a standard second-line regimen following progression from the first-line treatment. As a rare disease with a number of different treatment options, it can be time-consuming for doctors to obtain useful information. In the present study, the outcomes of various treatment regimens for relapsed or refractor Ewing sarcoma, the optimal sequence of drugs following VDC/IE or VIDE treatment, and the promising management techniques expected in future trials were investigated. The records of phase II and phase I/II clinical trials in the last 15 years were reviewed according to PRISMA methodology (7).
Materials and methods
Searching strategy
Four data sources were initially searched using the following search terms: i) (Condition or disease ‘Ewing sarcoma’ OR ‘Ewing family of tumors’) AND (phase ‘Phase 2’) AND (study start from ‘01/01/2003’ to ‘10/01/2018’) on ClinicalTrials.gov; ii) (‘Ewing sarcoma’ OR ‘Ewing family of tumors’) AND (‘Phase 2’ OR ‘Phase II’) AND (date-publication ‘2003:2018’) on PubMed; iii) (‘Ewing sarcoma’ OR ‘Ewing family of tumors’) AND (trial phase ‘Phase two’) AND (data range ‘2003-01-01’ to ‘2018-10-01’) on Clinicaltrialsregister.eu (EudraCT); and iv) ‘Ewing sarcoma’ in the abstracts available on the American Society of Clinical Oncology (ASCO) website. The final search was performed on October 15, 2018. As there were no phase III trials with published results available using the aforementioned search strategy, only phase II trials were included in the present study. There was only one phase III trial identified that is currently recruiting, which opened in April 2018 (no. NCT03495921); a multicenter, 1:1 randomized phase III study of intradermal autologous Vigil immunotherapy in combination with irinotecan and temozolomide.
Eligibility criteria
After the initial screening, the following eligibility criteria were used in further investigation: i) Patients had recurrent disease or their cancer was deemed refractory to previous first-line chemotherapy (VDC/IE or VIDE); ii) trials focused on EWS patients, or had one EWS stratum; iii) antitumor activity was assessed using a primary or secondary endpoint; and iv) language was limited to English. The aforementioned four data sources were searched sequentially. Finally, duplications among or inside each database were removed.
Data collection and analysis
The systematic search in each database was performed by two different individuals. Disagreements were resolved by discussion. The following information was extracted from each trial: i) General information, including date, identification number, principle investigators and centers; ii) drug information, including name and dose; iii) trial design, including phase, randomization, population, study status and statistical design; iv) participant enrollment, including the estimated and effective enrollment in each stage (for multiple-stage design), age, mean time from initial diagnosis to protocol enrollment and prior lines of systemic anticancer therapy; and v) endpoints, including the criteria of response, patients evaluated for efficacy, response rate and survival rate. Response to therapy was recorded as complete response, partial response, stable disease and progression of disease. The objective response rate (ORR) was defined as the rate of complete response and partial response. The records of phase II and phase I/II clinical trials in the last 15 years were reviewed according to PRISMA methodology (7).
Interventions were classified into four groups: i) Classical cytotoxic chemotherapy, either alone or in combination with other cytotoxic drugs; ii) targeted therapy, including TKIs that target different molecules or pathways, either alone or in combination with cytotoxic drugs; iii) immunotherapy, including monoclonal antibodies, immune checkpoint blockade and antitumor viruses, either alone or in combination with the previous two groups; and iv) other therapy. For phase I/II trials, only participants in the phase II part were analyzed.
Results
Study selection. Overall, 465 trials were identified following the initial screening (Fig. 1). The first step involved an eligibility assessment, and 343 trials were excluded for the following reasons: i) The studies were not phase II clinical trials (n=156), that is, they were phase I clinical trials (n=55), retrospective clinical trials (n=6), case reports (n=12), literature reviews or meta-analyses (n=49), preclinical studies (n=33) or papers presenting methodologies (n=1); ii) non-interested enrollment (n=76), including trials for patients with chemo-naïve metastatic disease (n=57) and trials for other diseases (n=19); iii) there was no EWS stratum available (n=79); iv) endpoints were used that did not include the antitumor activity of the drugs (n=25), including local control of radiotherapy (n=6), engraftment (n=2) and toxicity (n=17); and v) others (n=6), including one trial that closed before enrolling any participants and five trials that were reported in languages other than English.
The second step involved the removal of duplications (n=59). Duplicate trials were removed sequentially in order of ClinicalTrials.gov (n=1), PubMed (n=22), EudraCT (n=14) and ASCO (n=22). One trial was registered twice on ClinicalTrials.gov (no. NCT00154388 and NCT00031915) with the final result was reported in one paper (8). Finally, 64 trials were included in the present study (Fig. 1).
Study characteristics
The general characteristics of the 64 trials included in the present study are summarized in Table I. They were classified into four groups: Chemotherapy (n=27), targeted therapy (n=17), immunotherapy (n=17) and stem cell transplantation (n=3; Fig. 2). Of the 64 trials, 37 were completed (at least EWS stratum was completed) and had published results with an abstract (n=10) or full-text (n=27) available. The ORR was assessed in 36 trials, which were then further analyzed.
Results of trials with published final reports
There were 19 trials enrolled that used chemotherapeutic agents (Table II). The best ORR results (>15%) were identified in the following trials: Irinotecan with an ORR of 71 (9) or 38% (10); ifosfamide, cisplatin and etoposide (ICE), 51% (11); cisplatin and etoposide, 18% (12); and trabectedin, 15% (13) and docetaxel, 15% (14).
There were eight trials that used targeted therapy in the present study and six drugs were assessed. The majority of these trials did not reach their primary endpoints in phase I and failed to enter phase II (Table III). Only one trial using regorafenib demonstrated a clinical response, with an ORR of 11% (15).
There were nine trials enrolled in the present study that used immunotherapy, in which IGF-1R was administrated as monotherapy (n=6) or in combination with temsirolimus (n=3). The best result was identified in the combination group (ORR, 29%) (16). However, all the other eight trials revealed a poor ORR of ≤15%. Five of the nine trials closed before entering phase II due to a lack of efficacy (Table IV).
Conflicting results from the same regimen
Although the participants were strictly limited to recurrent or refractory EWS, conflicting results were observed for the same drug or regimen. For trabectedin, a promising result was reported in an ASCO abstract (13) with an ORR of 15%, whereas in 2012 another trial revealed no response (ORR, 0%) (17). The same dose and response criteria were used in each trial. A similar phenomenon was identified in irinotecan, where the ORR varied from 0 (18), to 38 (10), to 71% (9). All three trials utilized the World Health Organization criteria to assess objective response rates (ORR). However, different irinotecan administration strategies were utilized in these three trials, from 50 mg/m2/dose for 5 days, repeated every 3 weeks; to 20 mg/m2/dose for 5 days per week for 2 weeks, repeated every 4 weeks; to 16 mg/m2/dose for 5 days per week for 2 weeks, repeated every 3 weeks. The combination of cixutumumab and temsirolimus was administered with the same variations, and an ORR of 12% (or 29% if a regression of 20–30% was recorded as minor response) was reported in adults in 2012 (16), 15% in adults in 2013 (19) and 0% in children and young adults in 2015 (20). The same dose of cixutumumab was used in the three trials, with the only difference being a lower dose of temsirolimus of 8–10 mg/m2 (equivalent to an adult flat dose of 14 mg) in children and young adults, compared with a 25 mg flat dose in adults. Furthermore, over half of the adults required a decreased dose amount due to toxicity levels, and 29% of them required a second reduction (19).
Risk of bias
Selection bias
The mean time from the initial diagnosis to recurrence or progression varied from 19 to 43 months (21,22). With available data, almost all participants had more than two lines of prior systemic anticancer therapy, except in the cisplatin/etoposide trial (12) and in one of the cixutumumab trials (16). The median prior line of systemic therapy varied among trials (range 1–6).
Detection bias
In the 36 trials that reported their results and used ORR as an endpoint, response evaluation criteria in solid tumors (RECIST) was the most commonly used criteria (27 trials), including 13 that used RECIST version 1.1 (23), nine that used RECIST version 1.0 (24), four that used a non-specific version of RECIST and one that used RECIST version 1.1 and the World Health Organization (WHO) criteria (25,26) at the same time and observed no difference in the outcome from different criteria. For the remaining nine trials, seven used the WHO criteria alone, one used the Choi criteria (27) and one was not available.
Publication bias
According to the registration system, two trials started enrolling participants 10 years ago; however, no published results were available. One trial investigated exatecan (no. NCT00055952), which started in January 2003, and the other investigated hematopoietic stem cell transplantations (no. NCT00998361), which started in June 2009. There was no specific reason given for the unpublished results (Table V).
Location bias and language bias
Trials registered in the domestic clinical trials registration system were not screened. There were five trials registered in languages other than English, which were then excluded.
Time lag bias
Several trials assessing new drugs are still ongoing and the results have not yet been reported, including targeted therapy (aaTKIs, PI3K/mTOR and poly(ADP-ribose) polymerase) and immunotherapy (checkpoint blockade, oncolytic virus; Table V).
Multiple publication bias
Duplicated studies were identified and removed following abstract and/or full text screening.
Discussion
The present study investigated what can be learned from prospective phase II trials, and what can be expected from ongoing clinical trials. A comprehensive systematic review was performed with the aim of determining the optimal sequence of drugs following the use of VDC/IE or VIDE.
Cytotoxic chemotherapy. New drugs and regimens have been investigated more recently, but the most promising results still came from chemotherapy (e.g., irinotecan) based on available data. In addition to phase II trials (9,10,18), retrospective studies have provided more evidence on irinotecan/temozolomide (IT), which had ORRs as high as 34, 68 and 55% (28,29), and a median time to progression of 5.5 (30) and 3.0 months (29). At first, two patients showed an initial response but relapsed following withdrawal of the drug for 5 and 6 months, respectively (28). After recommencing the same IT regimen, the two patients achieved a second PR; one that lasted for at least another 15 cycles and the other another 22 cycles (28). On the basis of the success of IT, more clinicians use it as the first choice of treatment following the failure of VDC/IE or VIDE.
Targeted therapy
As for targeted therapy, classical agents arising from leukemia regimens, such as imatinib or dasatinib, did not exhibit any activity in patients with EWS. Only regorafenib, which has a stronger anti-angiogenesis effect, demonstrated promising clinical activity in patients with EWS. Further trials for other types of aaTKI, including pazopanib, cabozantinib and apatinib, which have shown some activity in other types of sarcoma (31–33), are ongoing and the results of which are anticipated. For patients who were refractory to first-line chemotherapy, pazopanib was reported to be effective in a set of case series (34–37). Early results from the cabozantinib trial (no. NCT02243605) in patients with EWS look promising, and an ORR of 28.1% in 32 patients was observed, as well as a high tumor burden reduction rate of 71% (38). For apatinib, which is also a strong aaTKI (39), an ORR of 70% (7/10) was observed in an off-label set of patients with EWS (33). Based on these data, it was concluded that aaTKIs require further investigation.
Except for monotherapy, preclinical studies have demonstrated the synergistic antiproliferative and pro-apoptotic activity of irinotecan or topotecan and aaTKIs in vitro, and the improvement of the in vivo anticancer activity on angiogenesis, endothelial and cancer cells, such as pancreatic (40) and ovarian cancer cells (41). Based on the non-overlapped adverse effects of irinotecan (42,43) and aaTKIs (44,45), these studies suggested a possible translation of this combination into the clinic. A phase I study of axitinib and irinotecan combined with 5-fluorouracil and leucovorin in patients with advanced colorectal cancer described an acceptable toxicity profile (46). Another phase I trial that used a triplet combination of pazopanib, irinotecan and cetuximab in patients with refractory metastatic colorectal cancer also provided evidence for a manageable safety profile (47). Based on this evidence, trials have been designed that use IT in combination with aaTKIs to maximize antitumor activity (no. NCT03416517).
Immunotherapy
Immunotherapy based on anti-insulin-like growth factor 1 receptor (IGF-1R) antibody was somewhat disappointing. Preclinical studies have revealed the IGF-1R pathway as promising new targets for EWS (48,49) and these observations have led to several clinical studies. However, given the non-optimal results from these trials, almost all health providers have stopped further investigation on IGF-1R antibody. Efforts have been made to look for biomarkers and narrow down the population who may benefit from the use of IGF-1R antibody. A multi-center study classified patients into different subtypes based on IGF-1R expression via immunohistochemistry (19), but there was no overall effect on outcome. Although in patients with EWS who were IGF-1R-negative had improved median PFS, it may be explained by the less aggressive biological behavior rather than real response to therapy.
Another type of immunotherapy with checkpoint blockade remains ongoing. Tumor mutation burden is considered an important factor for immune checkpoint blockade therapy (50,51). However, from the view of biological nature and genomic landscape, EWS does not belong to hyper-mutated tumors with a mutation frequency of <10 mutation/Mb (52), and only EWS-ETS gene rearrangements were identified in the majority of tumors (53,54). The role of the immune checkpoint blockade remains to be defined by well-designed clinical trials.
Limitations
The time to recurrence is the most important prognostic factor for patients with recurrent EWS. Patients who relapsed >2 years from the initial diagnosis had a 5-year survival of 30%, compared with 7% for patients that relapsed within 2 years (5,6). Patients in different trials experienced recurrence at different time points and may impact final oncological outcomes.
Different criteria have been used to assess drug response. The WHO criteria, RECIST 1.0 (a simplified version of the WHO criteria) and its newer version, RECIST 1.1, continue to be based on changes in tumor size. All these three criteria have a similar evaluation power for solid tumors (25,55). In the 37 trials with published results that were investigated in the present study, 36 used at least one of the three aforementioned criteria and provided a fair comparison among the trials. In the dasatinib trial (56), the Choi criteria were selected as the tumor response criteria, which the authors believed was associated with improved outcome in patients with gastrointestinal stromal tumors that were treated with TKIs (57). The significant differences observed between the Choi and RECIST criteria were due to the addition of change in tumor density in computed tomography scans and a smaller magnitude of change in tumor size to score response. From that point, more responses were scored using the Choi criteria, although only one partial response was recorded in all 17 participants with EWS (56).
Abundant trials assessing new drugs are still ongoing and no results have been reported yet (Table V). Although classical targeted drugs such as imatinib and IGF-1R antibody demonstrated no activity in patients with EWS, aaTKIs appear more promising from the early revealed data, either as monotherapy or in combination with cytotoxic drugs. Therefore, more evidence is required to draw a robust conclusion for the new drugs.
Although abundant new drugs for targeted therapy and immunotherapy have been tested in the last 15 years, the best response came from traditional cytotoxic chemotherapy, particularly irinotecan-based regimens. Targeted therapy with aaTKIs either alone or in combination with chemotherapy require further investigation. Currently, immunotherapy is not recommended for off-label use.
Acknowledgements
Not applicable.
Funding
The present study was funded by the Beijing Municipal Science and Technology Project (grant no. Z181100001718054).
Availability of data and materials
Not applicable.
Authors' contributions
JX and LX performed the systematic search. XS and SD reviewed the original phase 2 trial studies. WG designed the study. XT designed the data extraction sheet and final tables, provided supportive data from COG and ESMO meetings and revised the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
EWS |
Ewing sarcoma |
NCT | |
EudraCT |
Clinicaltrialsregister.eu |
ASCO |
American Society of Clinical Oncology |
ORR |
objective response rate |
aaTKIs |
anti-angiogenesis small molecular tyrosine kinase inhibitors |
IGF-1R |
anti-insulin-like growth factor 1 receptor |
VDC |
vincristine, doxorubicin, cyclophosphamide |
IE |
ifosfamide and etoposide |
ICE |
ifosfamide, cisplatin and etoposide |
RECIST |
response evaluation criteria in solid tumors |
IT |
irinotecan/temozolomide |
CR |
complete response |
PR |
partial response |
PFS |
progression free survival |
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