The objective of this systematic review was to comprehensively review available evidence on the efficacy and safety of treatments used for advanced STS following prior therapy with anthracycline- and/or ifosfamide for advanced disease. Due to the paucity of RCT evidence in this anthracyline pre-treated setting, this review included RCTs and non-randomised studies (prospective and retrospective) to allow for a detailed description of the evidence supporting these interventions being used for the management of patients with pre-treated advanced STS.
The available RCT evidence (from six studies) suggests that pazopanib, trabectedin, and the combination of gemcitabine and dacarbazine are effective treatments for pre-treated patients with advanced STS. These agents were also among those identified as potentially active second-line treatments in a recent analysis of Phase II studies by Penel and colleagues [91
]. Pazopanib has demonstrated a significant advantage over placebo with an increase of 3 months in median PFS [18
]. Treatment with q3w 24-hour dosing schedule of trabectedin was associated with significantly greater median PFS and TTP compared with the qw 3-hour schedule [22
], and the combination of gemcitabine and dacarbazine was more effective than dacarbazine monotherapy in terms of 3-month PFS rate, median PFS, and median OS [20
]. These findings should be interpreted in view of the fact that the evidence comes from Phase II studies except for the pazopanib PALETTE study. The primary aim of Phase II trials is to evaluate if the intervention under investigation demonstrates clinical activity and is well tolerated, and hence, they do not provide a definitive answer regarding the clinical benefit of the intervention in question. Further, post-study therapy was documented in three of the six included RCTs and this may have potentially confounded the OS results [18
In view of limited RCT evidence, data from non-randomised studies was evaluated. The 52 prospective non-randomised studies included in the review suggested anti-tumour activity (3-month PFS rate ≥39%, and/or 6-month PFS rate ≥14%, [90
], and/or ORR ≥10%) of several therapies including: single-agent ifosfamide [77
] and dacarbazine [73
], and that of the combinations, etoposide plus ifosfamide [86
] and cisplatin plus ifosfamide [85
]. Antitumour activity of gemcitabine monotherapy [75
] and gemcitabine plus docetaxel [88
] in patients with uterine leiomyosarcoma was also indicated by the non-RCT evidence. The results observed from the non-randomised evidence should be interpreted in light of the inherent limitations associated with this study design. RCTs involve randomisation which minimises the selection bias and confounding, and are therefore the most rigorous way of determining comparative efficacy.
Despite the systematic approach employed in this review, it was limited by the identification of only a small number of RCTs and the lack of comparability in terms of sample size, study design, and patient populations across both the RCTs and non-randomised studies. The patient population included in the RCT by van Oosterom and colleagues varied from those recruited in other RCTs [29
]. The study by van Oosterom and colleagues included a mixed patient population of both first-line and second-line patients, with limited subgroup data for the patients treated in the second-line setting [29
]. Most importantly, the RCT evidence was restricted by the fact that there was a lack of head-to-head trials of active agents. Due to the paucity of evidence, indirect and mixed treatment comparison of the included interventions were also not possible as no studies evaluating a common intervention were identified, except the two placebo-controlled trials, wherein an indirect analysis was not feasible due to incompatibility of the data (lack of comparability of the study designs and patient population in these studies) [18
]. Although, the review also included 52 prospective non-randomised studies, these studies were small in terms of sample size with majority of studies including less than 50 patients. For several treatments, only single studies were available. When there were multiple studies evaluating a single intervention, variability was often observed in the efficacy and safety results, primarily attributed to differences in patient characteristics and assessment criteria used to evaluate efficacy measures.
With respect to the inclusion criteria of the review, this study was limited to trials evaluating adult patients with sub-types of STS (excluding GIST, Kaposi sarcoma, and Ewing’s family of tumours), who had received prior anthracycline and/or ifosfamide therapy for advanced disease. Based on the inclusion criteria of the review, key RCTs including Maki 2007 (gemcitabine vs. gemcitabine plus docetaxel) and Verweij 2000 (docetaxel vs. doxorubicin) and single arm studies including Sleijfer 2009 (pazopanib) and Bay 2006 (gemcitabine plus docetaxel) were excluded as these publications did not provide information fulfilling the inclusion criteria of the review [92
]. The study by Maki and colleagues included a mixed population of patients treated with zero to three prior chemotherapy regimens with no data specifically reported for patients receiving ≥1 chemotherapy regimen; in addition, the type of prior chemotherapy was unclear [92
]. The RCT by Verweij and colleagues was excluded from the review as the study included patients with GIST [93
]. In the study by Sleijfer and colleagues, the type of prior therapy was not reported [94
], while in the study by Bay and colleagues no sub-group data for patients receiving first-line and later-lines therapies was provided [95
]. Additionally, in the study by Bay and colleagues nearly 69% of patients were treated within the adjuvant setting [95
]. A further RCT (TAXOGEM study) investigating gemcitabine vs. gemcitabine plus docetaxel [27
], whilst identified in our review had not reported efficacy data at the cut-off date for the literature search and thus, while has done subsequently [96
], the findings do not contribute to our conclusions.
The primary aim of second and later line treatment of patients with advanced/metastatic soft tissue sarcoma is to delay disease progression and maintain quality of life for as long as possible. The use of an anti-tumour treatment rather than best supportive care should be extensively discussed with the patient and their caregivers. Until now, there has been no standard of care after failure of or intolerance to doxorubicin and/or ifosfamide. An adjusted indirect comparison would be the most appropriate way to compare results of RCTs, but in this case since none of the RCTs had common arms to enable a formal indirect comparison, close attention should be paid to the findings of the individual trials.
In only one trial did the chemotherapy regimen improve overall survival (the combination of gemcitabine plus dacarbazine over dacarbazine alone; Table ) [20
]. This trial was not designed to formally demonstrate an overall survival advantage, and therefore, this finding needs to be confirmed by an appropriately designed Phase III trial. Moreover, the sample size of the trial was limited (59 patients received the combination) and there is no other published study investigating this original combination [20
]. The full results of the TAXOGEM study [96
] are not included in our review for reasons explained earlier but demonstrate the activity of gemcitabine plus docetaxel in patients with leiomyosarcomas and may explain the frequent usage of this combination in clinical practice, especially in those with leiomyosarcomas at uterine sites.
The PALETTE trial has formally demonstrated the benefit of treating patients with anti-angiogenic agent over placebo in terms of PFS in a Phase III setting (Table ) [18
]. This constitutes a major breakthrough in sarcoma management. However, possibly due to the high usage rate of salvage treatment after progression, this improvement in PFS did not translate into an OS advantage (Table ).
The every 3 week (q3w) schedule of trabectedin was associated with improvement of PFS, but because of the planned crossover, there was no advantage in term of OS over the weekly schedule (Table ) [22
]. Moreover, the weekly schedule may be less convenient than the every 3 week schedule. It should be noted that trabectedin is not currently approved for use in sarcoma in all countries.
Because quality of life and toxicity concerns are of key importance in this setting, the consideration of tolerability and discontinuation rates is as important as efficacy. The traditional cytotoxic drugs commonly induce haematological toxicities whereas grade 3/4 toxicities seen with pazopanib included fatigue, elevated liver enzymes, and hypertension (Table ). The safety profiles of both approaches (chemotherapy versus pazopanib) appear to be distinct; this is of particular relevance when discussing the toxicity/benefit ratio with patients. Table suggests that discontinuations due to AEs may be more frequent with pazopanib, possibly because oncologists are less familiar with managing the side effects associated with this agent unlike the classical cytotoxic haemotological toxicities, which have been known for years. Discontinuations could also be related to the fact that pazopanib is given continuously unlike cytotoxic therapy, allowing less opportunity for resolution of toxicities.
This review demonstrates that non-randomised trials provide limited information (Table ). Randomised studies are preferred when designing new trials. The safety profiles of chemotherapy agents versus pazopanib are clearly different, so additional data including compliance, quality of life and cost are needed to fully understand the extent of the differences between chemotherapy and targeted agents.