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A noninterventional, multicenter, prospective phase IV study of trabectedin in patients with advanced soft tissue sarcoma

Buonadonna, Angelaa; Benson, Charlotteb; Casanova, Josec; Kasper, Berndd; López Pousa, Antonioe; Mazzeo, Filomenaf; Brodowicz, Thomasg; Penel, Nicolash

doi: 10.1097/CAD.0000000000000560
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This prospective, noninterventional study is the first phase IV trial designed to evaluate trabectedin in patients with advanced soft tissue sarcoma in real-life clinical practice across Europe. To be included in the study, patients must have received more than or equal to one cycle of trabectedin and be currently on treatment. The primary endpoint was progression-free survival as defined by investigators. The secondary endpoints included objective response rate, disease control rate, time to progression and the growth modulation index (GMI), overall survival, and an assessment of the cancer-related symptoms and safety. A total of 218 patients from 41 European centers were evaluated. Patients received a median of six cycles per patient, mostly on an outpatient basis (n=132; 60.6%). The median progression-free survival was 5.9 months, with 70 and 49% of patients free from progression at 3 and 6 months after treatment, respectively. Three (1.4%) patients achieved a complete response and 55 (25.2%) patients achieved a partial response for an objective response rate of 26.6%. A total of 85 (39.0%) patients had disease stabilization for a disease control rate of 65.6%. The median GMI was 0.8, with 5.1 and 38.8% of patients with a GMI of greater than 1.1 to less than 1.33 and greater than or equal to 1.33, respectively. The median overall survival was 21.3 months. Febrile neutropenia (2.3% of patients), neutropenia, nausea, and pneumonia (1.4% each) were the most common trabectedin-related grade 3/4 serious adverse drug reactions. Trabectedin confers clinically meaningful long-term benefits to patients with multiple soft tissue sarcoma histotypes, being either comparable or better than those observed previously in clinical trials, and with a manageable safety profile.

aDepartment of Oncology, Medical Oncology, CRO, National Cancer Institute (IRCCS), Aviano (PN), Italy

bSarcoma Unit, Medical Oncology, Royal Marsden Hospital, London, UK

cLocomotive Apparatus Tumor Unit, Orthopedic Service, Coimbra University Medical Center, Coimbra, Portugal

dSarcoma Unit, Interdisciplinary Tumor Center, Mannheim University Medical Center, University of Heidelberg, Germany

eMedical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

fMedical Oncology, L'Institut Roi Albert II, Bruxelles, Belgium

gClinical Division of Oncology, Medical University Vienna - General Hospital, Austria

hCentre Oscar Lambret, General Oncology, Lille, France

Correspondence to Nicolas Penel, MD, Department of General Oncology, Centre Oscar Lambret, 3, Frédéric Combemale, 59000 Lille, France Tel: +33 320 295 920; fax: +33 320 295 963; e-mail: n-penel@o-lambret.fr

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

Received June 27, 2017

Accepted August 18, 2017

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Introduction

Soft tissue sarcoma (STS) is an acronym for a group of rare, heterogeneous mesenchymal cancers that include around 50 different histological types of cancers arising from extraskeletal connective tissues, which represent ∼1% of all adult tumors and 10–15% of pediatric malignancies 1,2.

Trabectedin (Yondelis) is a semisynthetic drug isolated originally from the sea squirt Ecteinascidia turbinata. It has a complex mechanism of action that, in addition to inducing direct growth inhibition and death of malignant cells, also has selective anti-inflammatory and immunomodulatory properties because of the inhibition of factors that promote tumor growth, angiogenesis, and metastasis 3–5. Trabectedin was the first marine-derived antineoplastic drug approved in 2007 in the European Union and in over 70 countries across the world for the treatment of patients with advanced STS after failure of anthracyclines and ifosfamide, or for patients who are unsuited to receive these agents 6. In 2015, following the analysis of a phase III trial in patients with advanced liposarcoma or leiomyosarcoma (commonly abbreviated as L-sarcomas) after failure of previous anthracycline-containing chemotherapy, trabectedin was also approved by the US Food and Drug Administration. The approval was based on the results of a pivotal, randomized, open-label, active-controlled, multicenter phase III study that evaluated the efficacy and safety of trabectedin compared with dacarbazine, an active comparator used in the treatment of patients with advanced STS 7. Clinical benefit with trabectedin has been also found in other histological types of sarcomas 8. It is noteworthy that the efficacy of trabectedin is also supported by the results of a phase II randomized, open-label study of trabectedin versus best supportive care performed in patients with translocation-related sarcoma who were unresponsive or intolerant to standard chemotherapy regimens 9. The efficacy of trabectedin in adults with advanced STS has also been shown in three nonrandomized, single-arm, multicenter phase II trials with unselected patients with recurrent disease 10–12, chemotherapy-naive patients with unresectable advanced disease 13, and in compassionate-use programs 14–16.

To date, no prospective, noninterventional studies with trabectedin have been carried out in a real-life setting, with a more diverse patient population with advanced STS than the population recruited in clinical trials. Therefore, the international, prospective, noninterventional Y-IMAGE study was principally designed to evaluate the use of trabectedin in patients with advanced STS and its efficacy and safety in routine clinical practice across nine European countries. Moreover, the response rates and time-to-event endpoints obtained in this study were compared with those reported in other clinical trials and expanded-access programs.

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Patients and methods

Study design

The aim of this noninterventional, prospective, observational, multicenter, phase IV study was to evaluate the treatment outcomes as assessed in routine clinical practice on patients with advanced STS. Patients were treated with trabectedin (Yondelis; PharmaMar, S.A., Madrid, Spain) according to the Summary of Product Characteristics (SPC) in the local language. According to the real-life observational nature of the study, there was no involvement with any treatment decisions for the patients included in the study as they were treated as per routine clinical practice and without any additional per protocol instructions. The choice of therapy had to be made before the patient’s inclusion in the study. This trial was implemented in 41 recruiting sites with the aim of having a good geographical representation of patients across Europe and within countries. The primary endpoint of this study was to assess progression-free survival (PFS) in advanced STS patients treated with trabectedin measured by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0/1.1 17,18 and/or Choi criteria 19. The secondary endpoints included objective response rate (ORR), treatment duration, and the disease control rate (DCR), defined as the percentage of patients with a radiological complete response (CR) or partial response and/or stable disease (SD), and an assessment of the cancer-related symptoms. The secondary endpoints also included time-to-event variables [time to progression (TTP) and overall survival (OS)], the evaluation of the growth modulation index (GMI), where information on a previous therapy’s TTP was available, and safety.

All study procedures were carried out in accordance with the Declaration of Helsinki, guidelines for Good Pharmacoepidemiology Practice, and local regulations on clinical trials, and were approved by the institutional review boards of each participating center. Signed informed consents were obtained from all study participants before registration.

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Patients and treatments

All eligible patients had to be on treatment with trabectedin and to have received a minimum of one cycle of trabectedin before their inclusion in the study. Eligible patients were adults (≥18 years old) with histologically proven and measurable advanced STS. Exclusion criteria included patients with contraindications to the use of trabectedin as defined in the SPC, previous exposure to trabectedin, concomitant chemotherapy or any other experimental treatment, and patients with a presence of any previous treatment-related toxicity (with the exception of alopecia).

Trabectedin was administered in accordance with the SPC and the treating clinician’s discretion depending on the patient’s conditions and previous chemotherapy. The recommended dose of trabectedin for the treatment of STS is 1.5 mg/m2 body surface area, administered as an intravenous infusion over 24 h with a 3-week interval between cycles. Pretreatment with corticosteroids (e.g. dexamethasone 20 mg intravenously 30 min before trabectedin) was considered mandatory for all patients receiving trabectedin. Additional antiemetics were administered in accordance with local practice, as needed, and as specified in the SPC. There were no predefined limits to the number of trabectedin cycles administered and treatment could continue as long as the treating physician judged that there was clinical benefit, even in the presence of apparent disease progression in target disease, or consent withdrawal. Once trabectedin treatment was discontinued, patients could have been treated with subsequent anticancer therapies or supportive care as per the treating clinician’s best clinical judgment.

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Study evaluations

The individual participant study duration began with the first trabectedin dose and continued for up to 12 months after the informed consent signature date or until patient discontinuation for any reason or the patient’s death. Following the treatment period, the safety follow-up period continued for 30 days after the last on-study trabectedin administration, until resolution of any treatment-related toxicity, patient death, or withdrawal of informed consent. Moreover, an optional survival follow-up period, extended from the safety follow-up until the last patient visit, was used for the evaluation of patients’ survival status (e.g. alive, lost to follow-up or dead) and subsequent post-trabectedin treatments (including active treatment, supportive care, and/or surgical intervention).

The results of imaging and response evaluations were collected at baseline (within 30 days before the first trabectedin treatment cycle or the earliest imaging assessment following the first cycle), during each cycle of the study (if they were available), and at trabectedin discontinuation. The final imaging was the assessment performed closest to the follow-up period and before initiation of any other chemotherapy treatment. In addition, symptomatic tumor responses reported by the patients (e.g. less/more/no change in pain and asthenia, and feel better/worse/no change) were also collected throughout the study period.

A spontaneous reporting system of treatment-emergent adverse drug reactions (ADR) and serious adverse drug reactions (SADR) that occurred after the first dose of trabectedin (other drugs were not considered) and repeated at the treating clinician’s typical schedule until 30 days after administration of the last dose of trabectedin was used for this study. An ADR was defined as any undesirable medical occurrence or worsening of a pre-existing medical condition that occurs after initiation of trabectedin that the treating clinician considers to be treatment related. An ADR was defined as a SADR if it fulfilled at least one of the following major criteria: (a) fatal, (b) life-threatening, (c) required inpatient hospitalization or prolongation of existing hospitalization, (d) resulted in persistent or significant disability/incapacity, (e) congenital anomaly/birth defect, and (f) other medically important serious reactions. SADRs were coded using the Medical Dictionary for Regulatory Activities (MedDRA), v.15.0, and graded according to medical record documentation as 1 (mild), 2 (moderate), 3 (severe), 4 (disabling or life-threatening consequences), and 5 (death).

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Statistical methods

A sample size of 150 patients was planned for inclusion in the study, which was considered as the number of patients necessary to estimate PFS and PFS at 6 months with sufficient accuracy. The primary analyses assessing efficacy and safety were carried out on the full analysis set (FAS), defined as all the patients enrolled into the study who received at least one dose of trabectedin. Time-to-event endpoints (PFS, TTP, and OS) and their fixed-time estimations were estimated according to the Kaplan–Meier method and were compared using the log-rank test. All P values were descriptive in nature and the significance level selected was 0.05. The TTP, PFS, and OS analyses were defined as the time interval from the first administration of trabectedin to the earliest date of disease progression or disease-related death as reported by the investigator for TTP or until the earliest date of disease progression or death, irrespective of cause (whichever occurred first) for PFS, whereas OS was defined as the time between the start of trabectedin and patient death from any cause. Patients considered lost to follow-up, with no reported disease progression and alive, were censored at the day of the last visit. Although they were planned in the protocol, comparisons between PFS assessments measured by RECIST and Choi criteria were not performed because of the very limited number of patients evaluated as per Choi criteria.

The GMI was calculated as defined by Von Hoff 20. An intrapatient comparison of successive TTP was expressed as the following ratio: GMI=TTP under trabectedin/TTP for treatment before trabectedin. The TTP for treatment before trabectedin was calculated from the start date of previous chemotherapy treatment to progressive disease (PD). Patients who did not report PD as best response before trabectedin were assumed to have a PD the day before the first administration of trabectedin (assuming that all pretreated participants were progressing). We have explored two potential thresholds for GMI, GMI greater than 1.1 and GMI greater than 1.33, as indicators of clinical benefit.

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Results

Patient disposition and characteristics

From 21 November 2012 to 28 June 2014, a total of 218 out of 229 enrolled patients from 41 European sites received trabectedin and were included in the FAS population. More than two-thirds of all patients were enrolled in Italy (30.6%), Germany (15.3%), and France and UK (11.8% each). The FAS included 95 (43.6%) men and 123 (56.4%) women with a median age of 58 years (range: 21–79 years) (Table 1). The median number of administered trabectedin cycles at enrollment and before signing the informed consent was 1 (range: 0–27). A good Eastern Cooperative Oncology Group performance status score of 0/1 was recorded in 154 (70.6%) patients. Most patients had a nontranslocation-related sarcoma (n=164, 75.2%) with leiomyosarcoma (42.2%), liposarcoma (23.4%), and synovial sarcoma (10.6%) being the most prevalent histological types of sarcomas. The vast majority of patients (n=196, 89.9%) had received a median of 1 previous line of chemotherapy (range: 0–6), mostly with anthracyclines with or without ifosfamide (83.9%), whereas 22 (10.1%) patients were chemotherapy naive at study entry.

Table 1

Table 1

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Extent of exposure

Patients received a median of 6 trabectedin cycles per patient, with 124 (56.9%) patients receiving 6 or more cycles and up to a maximum of 44 cycles (Table 2). Patients received a median dose intensity of 0.7 mg/week (range: 0.2–1.1 weeks) and a median cumulative dose of 14.7 mg/m2 (range: 1.8–116.4 mg/m2) over a median treatment duration of 5.3 months (range: 0.7–44.2 months), which represented 75.0% (range: 31.1–105.1%) of the planned dose intensity. The number of patients treated on an outpatient basis (n=132, 60.6%) doubled those who received inpatient cancer treatment (n=64, 29.4%). The most common cause for discontinuation was disease progression (n=155, 71.1%), followed by maximal clinical benefit achieved (n=12, 5.5%) and because of an ADR (n=11, 5.0%).

Table 2

Table 2

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Primary efficacy endpoint

In the FAS, a total of 176 progression or death events (80.7% of patients) were recorded, whereas 42 (19.3%) patients who were alive or were not assessed for disease progression at the time of this analysis were censored. Irrespective of the method of evaluation, the median PFS was 5.9 months [95% confidence interval (95% CI): 4.9–7.8], with 70% (95% CI: 63–75) and 49% (95% CI: 42–55) of patients free from progression at 3 and 6 months after treatment, respectively (Fig. 1).

Fig. 1

Fig. 1

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Other efficacy endpoints

During the treatment, the median time between response assessments was 10.9 weeks, with an interquartile range of 8–14 weeks. For the overall trabectedin activity, three (1.4%) patients achieved a CR and 55 (25.2%) patients achieved a partial response, reaching the ORR of 26.6%. In addition, 85 (39.0%) patients had SD as a best result for a DCR of 65.6% (Table 3). More than half of the patients reported no change in symptomatic response for pain (n=123, 56.4%), asthenia (n=119, 54.6%), and how they felt (n=112, 51.4%) (Table 4). In the FAS, 173 (79.4%) patients died because of the disease and/or presented disease progression, resulting in a median TTP of 5.9 months (95% CI: 4.9–8.1). The 196 patients who previously failed previous chemotherapy treatment obtained a median TTP of 6.0 months (95% CI: 4.2–7.8). The median GMI was 0.8 (range: 0.0–42.5). A total of 110 (56.1%) patients experienced a GMI 1.1 or less, 10 patients (5.1%) a GMI of greater than 1.1 to less than 1.33, and 76 (38.8%) patients a GMI 1.33 or more. Furthermore, after 101 death events, treatment with trabectedin in the FAS population resulted in a median OS of 21.3 months (95% CI: 18.8–24.3).

Table 3

Table 3

Table 4

Table 4

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Safety

Overall, 172 (78.9%) patients in the FAS had at least one trabectedin-related ADR of any grade. Nausea (31.2% of patients), neutropenia (29.8%), fatigue (25.2%), anemia and asthenia (19.7% each), vomiting (12.8%), leukopenia, and alanine aminotransferase increase (10.6% each) were the most common ADRs encountered with trabectedin. Treatment-emergent SADRs were uncommon as a total of 22 (10.1%) patients presented with at least one SADR of any grade associated with a very low incidence of relevant clinical consequences (Table 5). Of these, grade 3/4 SADRs were reported in 18 patients and one case of fatal pulmonary embolism (grade 5) was registered. Febrile neutropenia (2.3% of patients), neutropenia, nausea, and pneumonia (1.4% each) were the most common trabectedin-related grade 3/4 SADRs. Overall, other SADRs were infrequent and manageable. Ten (9.9%) patients died within 30 days of the last dose of trabectedin. No deaths attributed to treatment-related ARDs were reported.

Table 5

Table 5

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Subsequent therapies

After a median time from the last trabectedin dose to treatment switch of 11.1 weeks (range: 2.0–102.9 weeks), 112 (51.4%) patients received a subsequent anticancer therapy, 96 (44.1%) of whom received chemotherapy. The most common best responses following the subsequent treatment were PD (n=38, 17.4%) and SD (n=29, 13.3%). Moreover, 22 (10.1%) patients underwent a subsequent surgery after a median of 82.5 days (range: 29–518 days) after the last dose of trabectedin.

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Discussion

The Y-IMAGE study is the first noninterventional study that has prospectively evaluated trabectedin’s outcomes in routine clinical practice in patients with advanced STS. Despite the fact that the eligibility criteria of this study were less restrictive than those of clinical prospective trials, the study procedures followed the conditions detailed in the SPC of trabectedin. Therefore, the present results should be considered representative of patient demographics, clinical practice, and outcomes in real-life practice in Europe. However, although this was an unselected and quite diverse patient population, the number of patients with leiomyosarcoma or liposarcoma (65.6%) was comparable to that described in the literature 1. It also noteworthy that ∼10% of patients (n=22) received trabectedin as first-line treatment. Moreover, the study was carried out in nine European countries, ensuring coverage of per country variations in clinical practices and contributing toward more representative results.

In the present study, trabectedin administration resulted in a median PFS (primary endpoint) of 5.9 months (95% CI: 4.9–7.8), with 3-month and 6-month PFS rates of 70 and 49%, respectively. This benefit in disease control was observed across all European centers irrespective of the method of response assessment or disease histology, previous lines of systemic therapy, or any other clinical considerations (e.g. age or line of treatment). Overall, the 3-month and 6-month PFS rates observed in this study are consistent with earlier studies (Table 6) and largely exceeded the 3-month and 6-month PFS rates thresholds (i.e. 39 and 14%, respectively) established by the EORTC for active agents for the treatment of unselected STS 21. This level of activity across multiple studies with different designs suggests that the activity of trabectedin is similar across all sarcoma study populations. Interestingly, the benefit in disease control in the Y-IMAGE study was particularly similar to trabectedin activity observed in patients with translocation-related sarcomas, which reported a median PFS of 5.6 months and 3-month and 6-month PFS rates of 70.3 and 44%, respectively 9.

Table 6

Table 6

The benefit of trabectedin in PFS was also supported by other secondary endpoints as trabectedin therapy resulted in higher than expected overall ORR (26.6%), which compares favorably with previous clinical study reports (Table 6). This is probably because of the noninterventional nature of this study where, different from clinical prospective trials, the patients’ responses were neither centrally reviewed nor confirmed as per RECIST. Most patients who benefited from trabectedin treatment experienced SD as their best response (39%). Consequently, the DCR (65.6%), which included objective disease shrinkage and SD, also supports the important anticancer activity of trabectedin. Recognizing that comparisons cannot be established, and merely with the aim of putting the findings yielded here in a wider context, the DCR of patients treated in the Y-IMAGE study is comparable with those observed in other clinical trials and expanded-access programs (Table 6). There is limited published literature on the evaluation of cancer-related symptoms in patients with metastatic sarcoma. In our study, more than a half of the patients reported no symptomatic worsening, whereas ∼15% of patients reported less pain and asthenia and 22% of them felt well (i.e. better) during the disease remission and trabectedin treatment. These data could indicate low symptomatic worsening under trabectedin treatment and when the symptoms worsened, this was caused by the natural course of disease as 71% of patients discontinued the treatment because of disease progression (Table 4). It is noteworthy that ∼70% of patients received trabectedin in an outpatient setting, suggesting a good performance status in most of them. The characteristic late and long-lasting responses, such as prolonged stabilization of tumor growth and dormancy of metastases reported with trabectedin, were in line with a high median GMI of 0.8 observed in this study, with 5.1 and 38.8% of patients with a GMI of greater than 1.1 to less than 1.33 and a GMI 1.33 or more, respectively. As GMI measures the tumor growth delay, it is probably a more suitable indicator of delayed growth following trabectedin treatment than traditional response measures. High GMI rates in the present study compare favorably with those from a retrospective analysis that reported a median GMI of 0.6, with 7.5 and 29.0% of patients with a GMI of greater than 1.1 to less than 1.33 and a GMI 1.33 or more, respectively 22. Subsequent anticancer therapy and chemotherapy was administered to 51.4 and 44.1% of patients, respectively, which is in line with the results reported in a large phase III study (47% of patients) 7. Finally, a median OS of 21.3 months was found to be one of the highest ever reported with trabectedin in patients with STS (Table 6). Comparable results in terms of PFS and OS were reported recently in a phase II trial investigating the clinical benefit of continuation of trabectedin treatment until progression or intolerance versus interruption of therapy after six treatment cycles in patients with advanced STS 23. The therapeutic benefit of treatment maintenance with trabectedin was associated with markedly improved PFS (7.2 months, 95% CI: 4.0–12.7 vs. 4.0 months, 95% CI: 2.5–5.5; log-rank P=0.0200) and OS (27.9 months, 95% CI: 22.8–33.6 vs. 16.5 months, 95% CI: 13.0–22.2; log-rank P=0.12) compared with the interruption group. It is noteworthy that trabectedin retained its activity after a treatment break as the patients allocated in the interruption arm who were rechallenged with trabectedin on progression obtained comparable responses as those treated continuously. Still, the authors could not recommend trabectedin interruption in patients free from PD and when tolerance is acceptable as early discontinuation of trabectedin may result in rapid disease progression 24.

On the basis of the noninterventional setting of this study, we must acknowledge that the timing for response assessment was not previously fixed, but was according to the clinician’s usual clinical practice; only the patients who had already been on treatment with trabectedin (≥1 cycle of trabectedin) were enrolled, and the findings of the study were neither centrally reviewed nor confirmed according to RECIST; therefore, they must be interpreted with caution as they may be subject to bias.

The results of two interim analyses of data from Y-IMAGE study also evaluated the efficacy of trabectedin in elderly patients 25 and when used in earlier lines of treatment 26. In line with previously published data from a retrospective pooled analysis of five phase II trials 27, the authors reported that trabectedin in a real-life setting is a feasible treatment for STS patients irrespective of patient age, with meaningful clinical benefits and an acceptable safety profile both in young and in elderly patients 25. Also consistent with the results from a phase II study 28, the other interim analysis confirmed that trabectedin efficacy can be optimized when it is administered earlier in the course of the disease, allowing patients to benefit from a long-term treatment with trabectedin and to achieve longer disease control with respect to patients who are treated later 26.

The safety and tolerability of trabectedin were consistent with extensive previous experience and reports reflecting the well-characterized transient and noncumulative toxicities of bone marrow suppression and hepatotoxicity 29. However, we must acknowledge that, because of a spontaneous reporting system, low-grade treatment-emergent ADR might have been under-recorded. According to the SPC of trabectedin, there are no predefined limits to the number of cycles administered as it is indicated to continue the treatment while clinical benefit is noted 20. Here, more than 55% of the patients received 6 or more cycles of trabectedin, suggesting an acceptable safety profile that allowed prolonged treatment (i.e. ≤44 cycles administered over a period of 44 months). No new or unexpected adverse reactions or qualitative differences in the adverse reactions were observed.

In conclusion, the findings of this noninterventional, multicenter, prospective real-life study consistently support that trabectedin confers clinically meaningful long-term benefits to patients with multiple STS histotypes, being either comparable to or better than those observed previously in clinical trials.

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Acknowledgements

The authors would like to acknowledge Adnan Tanović for providing writing assistance for the manuscript.

This study was sponsored by PharmaMar SA, Spain.

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Conflicts of interest

Bernd Kasper has received honoraria from PharmaMar for presentations. The remaining authors have no conflicts of interest.

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Keywords:

observational; phase IV; sarcoma; soft tissue sarcoma; trabectedin

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