Efficacy and safety of pharmacological interventions in second- or later-line treatment of patients with advanced soft tissue sarcoma: a systematic review

The key patient and study design characteristics of the six included RCTs are presented in Table 1. All included RCTs were Phase II trials, except for the PALETTE study, which was the only Phase III RCT [18, 19]. All the studies included in the review aimed to evaluate the activity and safety of the interventions under investigation, with PFS being the primary outcome in two studies [18‐21] and TTP [22‐26], response [27], and 12-week progression-free rate [28], as the primary outcomes in one study each. There was no primary endpoint identified in the remaining one study [29]. The secondary outcome measures evaluated across these studies included OS, response, DOR, TTR, dose reductions/interruptions, safety, and withdrawals.

The number of patients randomised across all RCTs was greater than 50, except for the study by Pacey and colleagues that randomised five patients [28]. Of the five patients randomised in this study, one patient was chemotherapy-naive and hence did not meet the inclusion criteria of the review. In addition, this small-sized study was not a true RCT [28]. All the patients initially received sorafenib in a 12-week open-label run-in period following which patients with ≥25% tumour shrinkage continued sorafenib, those with ≥25% tumour growth discontinued, and the remaining patients were randomised to treatment with sorafenib (2 patients) or placebo (2 patients) [28]. In terms of the patient population recruited across these studies, leiomyoscaroma was the most commonly enrolled subtype of STS followed by liposarcoma and undifferentiated pleomorphic sarcoma. Across all the included RCTs, at least 90% of patients received prior treatment in an advanced setting, except for the study by van Oosterom and colleagues [29]. This study recruited a mixed population of patients previously treated in an adjuvant or advanced setting, with limited subgroup data for the patients previously treated in the advanced setting [29].

The quality assessment of the included RCTs using the comprehensive critical appraisal tool based on the NICE and Cochrane’s critical appraisal tool is detailed in an additional file (see Additional file 3). None of the RCTs included in the review were identified as being at a high risk of bias.

Table 2 summarises the various efficacy/activity results observed across the included RCTs. The RCTs included in the review have been examined separately according to the phase of the trial.

The only Phase III trial included in the review was the PALETTE trial evaluating pazopanib (N=246) versus placebo (N=123) in advanced STS patients (excluding GIST, liposarcoma and other subtypes). The data presented here are from an analysis conducted by the manufacturer for regulatory purposes [18, 19] and differ slightly from an analysis conducted by the study’s collaborative partner [30, 32] as a consequence of small differences in censoring rules and data handling. A summary of these minor differences in results between analyses can be found in Additional file 4. This trial demonstrated a significantly prolonged primary endpoint of PFS (per independent review) for pazopanib compared with placebo (Hazard Ratio (HR): 0.35 [95% CI: 0.26 - 0.48]; p<0.001) [18, 19]. The benefit in PFS was consistently observed across all three histological sub-types included in the study (leiomyosarcoma [p<0.001], synovial sarcoma [p=0.005], and other STS sub-types [p<0.001]). The best overall response based on the independent radiology review also favoured pazopanib. However, there was no statistically significant difference between pazopanib and placebo for median OS (HR: 0.87 [95% CI: 0.67 - 1.12]; p=0.256) [18, 19]. These results should be interpreted in view of the fact that patients treated with pazopanib and placebo received post-study therapy including trabectedin (25% vs. 32%), gemcitabine (17% vs. 23%), a taxane (10% vs. 18%) and ifosfamide (10% vs. 17%) that might have potentially confounded the OS results [19]. This was the only study to report quality of life data. Based on the EORTC QLQ-C30 questionnaire, no clinically meaningful or statistically significant differences in global health status were observed between pazopanib and placebo patients remaining on treatment at the assessment time points [18, 19].

PFS rate at 3 months was the primary activity measure in the GEIS study comparing the combination of gemcitabine and dacarbazine (N=59) against dacarbazine monotherapy (N=54) [20, 21]. The PFS rate at 3 months was significantly better for gemcitabine plus dacarbazine than dacarbazine monotherapy (p=0.001). Similar results, favouring the combination, were observed in terms of the secondary efficacy endpoints evaluated including median PFS (HR: 0.58 [95% CI: 0.39 - 0.86]; p=0.005), median OS (HR: 0.56 [95% CI: 0.36 - 0.90]; p=0.014), and response rate [20, 21]. Fifty-three percent of patients initially treated with dacarbazine monotherapy and 51% of patients treated with the combination of gemcitabine and dacarbazine received post-study therapy comprising mainly gemcitabine-based regimens, trabectedin, and taxanes [20, 21].

TTP was the primary activity endpoint in the study by Demetri and colleagues evaluating the two dosing schedules of trabectedin [22‐26]. Median TTP favoured the trabectedin q3w 24-hour dosing schedule (N=136) over the qw 3-hour dosing schedule (N=134) when assessment was made by investigator (4.2 months vs. 2.5 months; HR: 0.668 [95% CI: 0.506 – 0.883]; p=0.0042) and IRC (3.7 months vs. 2.3 months; HR: 0.734 [95% CI: 0.554 - 0.974]; p=0.03) [22‐26]. In terms of the secondary activity measures, median PFS was significantly longer with the q3w 24-hour schedule than the qw 3-hour schedule (p=0.0418), while no significant differences between the two dosing schedules were observed in median OS (HR: 0.843 [95% CI: 0.653 - 1.090]; p=0.1920) [22‐26]. The PFS rate, 1-year OS rate, and ORR also favoured the q3w 24-hour dosing schedule over the qw 3-hour dosing schedule. Forty-nine patients in this study received post-study therapy by crossing-over to the other schedule (35 patients crossed-over after progression as allowed by the protocol [29 patients from qw 3-hour arm to q3w 24-hour arm, and 6 patients from q3w 24-hour arm to qw 3-hour arm] and 14 patients before progression [following independent data monitoring committee recommendation, all from qw 3-hour to q3w 24-hour arm]) [22‐26].

Limited activity data were obtained from the remaining three RCTs included in the review [27‐29]. The study by van Oosterom and colleagues evaluating two different ifosfamide regimens provided no subgroup efficacy data including OS, TTP, PFS, and response duration specifically for patients previously treated in an advanced setting [29]. Similarly, in the study by Pacey and colleagues, although the PFS rate at 12 weeks was the primary activity endpoint, the study did not report data for patients randomised to sorafenib or placebo. The only activity data reported in this study was SD in all four patients receiving sorafenib or placebo at 12 weeks [28]. Activity data were also not reported in the conference abstract for the TAXOGEM study by Pautier and colleagues [27].

Overall, AEs were not consistently reported across the RCTs included in the review. The most commonly reported grade 3/4 AEs (≥5%) in association with pazopanib in the Phase III PALETTE trial were fatigue (14%), lymphopenia (10%) tumour pain (8%), increased alanine transaminase (ALT) (10%), increased aspartate aminotransferase (AST) (8%), hypertension (7%), dyspnoea (6%), anaemia (6%), decreased appetite (6%), and diarrhoea (5%) [18, 19]. Across the Phase II trials, haematological AEs were commonly experienced with treatments including dacarbazine, gemcitabine plus dacarbazine, and trabectedin. In addition to haematological AEs, ≥5% of patients experienced grade 3/4 ALT increase, creatinine phosphokinase increase, and fatigue with the two dosing schedules of trabectedin [22‐26] and grade 3/4 asthenia with gemcitabine plus dacarbazine and dacarbazine monotherapy [20, 21]. Grade 3/4 nausea, vomiting, and AST increase were also experienced by ≥5% of patients treated with trabectedin 24-hour schedule [22‐26]. Summaries for grade 3 and/or 4 AEs reported in >1% patients across the included studies are shown in Table 3.

Overall, four of the six included RCTs reported data related to treatment discontinuations. In the Phase III PALETTE trial, pazopanib was associated with a higher proportion of patients discontinuing treatment due to AEs compared with placebo (Table 4) [19]. Across the Phase II RCTs, the proportion of patients discontinuing treatment due to AEs were comparable with the two dosing schedules of trabectedin [22‐26], while in the GEIS study none of the patients treated with gemcitabine plus dacarbazine discontinued therapy due to AEs [20, 21]. Summaries of the treatment discontinuations observed across the included RCTs are shown in Table 4.

A summary of the 52 prospective non-randomised studies with sample size more than 10 [33‐72] is presented in Table 5. Further details regarding the study design and patient characteristics for these studies are presented in an additional file (see Additional file 5). The list of retrospective studies and studies with a sample size less than 10 is also provided as an additional file (see Additional file 6).

The majority of the included prospective studies were Phase II trials with a variety of chemotherapeutic regimens evaluated across these studies. Ifosfamide was the most commonly evaluated monotherapy (nine studies) followed by gemcitabine (four studies), docetaxe l (three studies), paclitaxel (three studies), and trabectedin (three studies), while gemcitabine-based regimens were the most frequently evaluated combination therapy (five studies). Response, PFS, DOR, TTP, OS, and safety were the most commonly assessed outcomes in the included studies.

The quality assessment of the included non-randomised studies based on the Downs and Black checklist demonstrated that studies were reported reasonably well in terms of study question, methods, patient population, outcomes measures, and results [16].

Across the non-randomised evidence, there was heterogeneity in the efficacy results. For example, in nine studies assessing ifosfamide monotherapy, variable activity was observed in terms of response rate (4.8% [76] to 62.5% [81]) (Table 6). Although a wide variety of doses and schedules was used in these trials, with cumulative dose per cycle ranging from 8 to 14 mg/m², this did not have a clear impact on efficacy. Gemcitabine as monotherapy (four studies) and in combination therapy demonstrated a variable efficacy in terms of median OS (monotherapy: 6.0 months to 11.8 months; combination therapy: 14.7 months) and ORR (monotherapy: 6.7% to 21.2%; combination therapy: 3.8% to 50.0%). However, a superior response rate (>20%) was observed with gemcitabine monotherapy (21.2% vs. 6.7% to 11.1%) and gemcitabine plus docetaxel (25.5% to 50.0% vs. 8.3%) among patients with uterine leiomyosarcoma compared with patients with mixed STS subtypes (Table 6). Once more, there were no clear trends relating to dose of gemcitabine.

The only treatment that demonstrated a similar anti-tumour activity across different trials was trabectedin (three studies). Trabectedin was associated with a response rate ranging from 7.4% [84] to 8.5% [83] and median OS varying between 9.1 months [77] and 12.1 months [82]. Limited anti-tumour activity (ORR ≤5%) in pre-treated patients with STS was demonstrated by treatments including brostallicin, cisplatin, cyclophosphamide, dacarbazine, gefitinib, methotrexate, and sunitinib [90]. Summaries of the efficacy results for interventions evaluated across non-randomised studies are presented in Table 6.

Across the non-randomised studies identified in the review, haematological AEs were the most commonly reported AEs, particularly with therapies including docetaxel, gemcitabine, docetaxel plus gemcitabine, etoposide, carboplatin plus etoposide, cisplatin plus ifosfamide, and trabectedin. However, AEs were not reported in a sufficiently consistent manner for a meaningful comparison across studies. The details of the grade 3 and/or 4 AEs observed across these studies are provided in an additional file (see Additional file 7).

Data related to treatment discontinuations due to AEs were reported in only three of the included studies. Thus, it was difficult to draw any conclusions regarding the comparative tolerability of the evaluated interventions [74, 82, 83].