IMI 28

Comparison of first line chemotherapy regimens for advanced soft tissue sarcoma: a network meta- analysis

Qingling Hua, Guojie Xu, Lei Zhao & Tao Zhang
Cancer center, Union hospital, Tongji medical college, Huazhong university of science and technology, Wuhan, China

The best first line chemotherapy regimen for advanced soft tissue sarcoma (ASTS) remains inconclusive. Here, we aimed to find the best first line chemotherapy regimen by performing a network meta-analysis. Regimens were compared in terms of overall survival (OS), overall response rate(ORR), progression free sur- vival (PFS), and toxicity. Twenty-eight eligible trials with a total of 6928 patients were included. EC (epirubi- cin cisplatin) was considered as the better regimen for advanced STS with probability of 61.9% in terms of OS. However, this regimen only have been evaluated in a single small trial and tend to have more hemato- logical toxicities than doxorubicin. No regimen was superior to doxorubicin with significant statistical difference in terms of PFS and ORR, even aldoxorubicin behaved better than doxorubicin in the network analysis. Collectively, doxorubicin still can be selected preferentially for the first line chemotherapy for patients.

Introduction
Soft tissue sarcoma(STS) belongs to a group of malignant neoplasms derive from mesenchymal tis- sue. During the past decades, the evolving treat- ment strategy for STS significantly improved its local control. Whereas, about half of STS patients still die from the recurrence and metastasis within 10 years1.Until now, the standard strategy recom- mended by worldwide guidelines for the first line chemotherapy for advanced STS is doxorubicin. The effectiveness of doxorubicin for STS has been demonstrated by previous studies2. To find more effective agents for advanced STS, a number of studies have been conducted in the past decades. Among the studied regimens, several drugs such as ifosfamide, dacarbazine, and their combinations with doxorubicin have benefits for advanced STS with response rate ranging from 15%-40%3,4.
In 2014, European Organization and Treatment of Cancer Soft Tissue and Bone Sarcoma Group published a RCT with 455 patients comparing doxo- rubicin plus ifosfamide with doxorubicin alone3. This trial showed significantly higher progression-free survival(PFS) for the combination regimen group compared with the single doxorubicin group (7.4 months versus 4.6 months, hazard ratio (HR) 0.74(95%CI:0.60–0.90), p ¼ 0.003). Patients in the combination arm had a higher overall response rate(ORR) (26% versus 14%, p < 0.0006) than doxo- rubicin alone arm. However, in terms of overall survival(OS) between two arms, the difference wasnot statistically significant(HR 0.83 (95.5%CI 0.67–1.03), p ¼ 0.076). A smaller trial including 126 patients performedby Chawlaet al. generated similar results5. In this trial, aldoxorubicin(INNO-206), a novel prodrug of doxorubicin, was compared with doxorubicin. The median PFS and ORR of patients in aldoxorubicin group was higher than doxorubicin group(5.6 months vs2.76 months, P ¼ 0.02; and 25% vs 0%respectively). Median OS of aldoxorubicin was15.8 months(95%CI, 13.0 to not available) and doxorubicin had a median OS of 14.3 (95% CI, 8.6-20.6; P ¼ 0.21) months. Based on the outcomes of the previous trials, webelieve that doxorubicin plus ifosfamide and aldox- orubicin may be better regimens for advanced STS. However, these two regimens have not been com- pared in a head-to-head trial. Similarly, numbers of agents and regimens were tested in other trials, assome of them were compared with a common regi- men, doxorubicin, nevertheless, others were not. Given the various comparisons of these different regimens, the best treatment strategy for advanced STS are still unknown. Network meta-analysis (NMA) is the most appropriate method to detect the best regimen, since it allows indirect comparisons of regimens which have not been investigated in head-to-head trials6. By using this method, we get a way to com- pare outcomes data of regimen A and regimen B extracted from different trials that included either regimen A or regimen B and a common regimen C. The objective of this study is to identify the best first line chemotherapy regimen for advanced STS by comparing the different regimens using the method of NMA. The original data of ORR, PFS, OS, and toxicity were pooled to generate a rank of chemotherapy regimens studied in past years. The primary endpoint of this study was OS. Secondary endpoints were PFS, ORR and severe adverse events (grade 3 to 4). Methods This study was performed according to the pre- ferred reporting items for systematic reviews and meta-analysis (PRISMA) and the PRISMA exten- sion statement for network meta-analysis7. This analysis was previously designed and a protocol with a register number (CRD42020173822) was presented in the PROSPERO website. Study selec- tion, data extraction, and quality assessment were accomplished by two authors independently (QLH and GJX). They resolved debates by meeting when required. Data sources and searches PubMed, EMBASE, and Cochrane libraries were retrieved to select studies published from inception to March 2020. Sarcoma, advanced, metastatic, unresectable, chemotherapy and their combinations were used as search terms. These search terms were adjusted for each database when required. The elaborate search strategies were written in Supplement File. Two reviewers (QLH and GJX) preliminarily screen the titles and abstracts of pub- lications to exclude irrelevant studies. Later, the full text and references were reviewed thoughly to identify eligible articles. Study selection The inclusion criteria of our analysis consists of: (a)advanced STS proved by pathology; (b)random- ized controlled clinical trials; (c)comparing different first line chemotherapy regimens for advanced STS. The exclusion criteria were (a)adjuvant chemother- apy; (b)second line chemotherapy or beyond, (c)not randomized trials; (d) singe arm trial; (e)partici- pants involving osteosarcoma, chondrosarcoma,Ewing’s sarcoma, gastrointestinal stromal tumour or Kaposi’s sarcoma; (f)without adequate data toabstract overall response of tumour and hazard ratios (HRs) of survival (g)unpublished reports (f)children and elderly. The nearest publication was included if there were many articles about the same study. Data extraction A standard form was previously made to abstract data from the trials included in our meta-analysis. These data were collected: study ID, first author, date of publication, total number of patients, tumour histology, arms and treatment regimens, adverse effects associated with different regimens, ORR of tumour, HRs and 95%CIs of OS and PFS. ORR contain complete response and partial response according to the standards of RECIST or WHO. OS was defined as the date from random- ization until death (by any cause). PFS was defined as the time from randomization until first disease progression or death(by any cause). Until the date of last follow-up, patients without progression or death were censored on that time. Original inten- tion-to-treat data were abstracted from publica- tions whenever possible. To approach the time-to- event analyses, HRs of OS and PFS were calcu- lated by the method of Parmar8. In cases noenough information to calculate HRs but Kaplan–Meier curves were presented, the curves were digitized and HRs were estimated byenguage digitizer. Quality assessment Cochrane risk-of-bias tool was taken to evaluate the bias of included trials9.Individual study was assessed according to 6 items including sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other sources of bias. Data synthesis and statistical analysis Network meta-analysis was performed using a net- work package developed according to the theories of a classical frequentist setting in stata 13.0. We used a three step method to appraise the inconsist- ency between studies. Firstly, global inconsistency was evaluated by design-by-treatment model. Secondly, node splitting analysis was taken to test local inconsistency in the whole network on certain comparisons. At last, inconsistency factor (IF) was calculated in each loop to assess the absolutedifference between direct and indirect estimates for comparisons in loops. Probability values of each regimens as the best one for STS were summarized as surface under the cumulative ranking curves(SUCRA). A two-tailed P value of <0.05 was con-sidered statistically significant. Results Selection process The study identification and selection process was presented in Figure 1. Four hundred and seventy three unduplicated studies were identified according to the preset criteria. Of these trials, 415 were pre- liminarily excluded after reviewing the titles and abstracts. The full text of remaining 58 articles were reviewed thereafter. At the end of selectionprocess, there were 28 studies met our previously defined criteria3,5,10–35. Two studies were excluded since their data were not available36,37. Two retro-spective studies and four reviews were also excluded2,38–42. Coens et al.’s study was excluded because it only reported quality-of-life results43. Twelve studies were discarded since the authors only investigated second line chemotherapy foradvanced STS44–55. Pautier et al.’s study is a single- arm study56. Bramwell et al.’s study was excludedas it involved patients received mixed line chemo- therapy57. Four studies were excluded since itrecruited mesothelioma, chondrosarcoma, Ewing’s sarcoma or alveolar soft part sarcoma58–61. Hartmann et al.’s study targeted elderlypatients62and Kawai et al.’s study focussed on translocation-related sarcomas63. The line of chemotherapy in Pinedo et al.’s study wasunclear64. Schoenfeld et al. reported survival curve without equidistant point in vertical axis, thus we failed to calculate data from the figure by enguage digitizer65. Characteristics of included studies Characteristics of all the included studies were pre- sented in Table 1. The eligible 28 studies consist of21 two-arm trials and 7 three-arm trials. In 19 studies, doxorubicin was compared with other regi- mens. Two studies investigated both first and second line chemotherapy30,31. All the included 28 studies reported ORR data. Verweij et al. did not report OS data, while PFS data were not presented in three studies11,17,30,32. Twelve studies reported tumour response data according to RECIST and the others were based on the standards of WHO. We defined OR as complete response plus partial response. In 12 studies, PFS was defined as the time period from randomization to the first docu- mented tumour progression or death by any cause3,5,15,16,18,19,23,25,27,28,33,34. Six studies defined PFS as the time period from randomization to thefirst documented tumour progression13,20–22,30,31. Inthe study of Antman et al., PFS was calculated from first day of chemotherapy to the first docu- mentation of progression10. PFS was not definitely defined in 5 trials12,14,24,26. Quality assessment included studies based on Cochrane handbook was illustrated in SupplementaryTable S1. High grade is the most common type of histology of included patients(52.1%), whereas intermediate and low grade constitute 36.4% and 8.2% patients respectively. Leiomyosarcoma, liposarcoma and synovial sarcoma were most common histology types in 31.3%, 11.7%, and 6.8% patients respectively. Network Meta-analyses Survival OS data of 28 studies including 28 regimens were pooled in our study. Of note, doxorubicin was compared with other regimens in 21 trials. The geometry of regimens network is illustrated in Supplementary Figure S1. The design-by-treatment model using OS data showed no global incon- sistency(p ¼ 0.635). The node splitting methodshowed no local inconsistency (p > 0.05) of OS.
Inconsistency factor for each loop showed no loop inconsistency. After that, consistency model was established since no evident inconsistency was detected. Estimates of regimens compared with doxorubicin were listed in Figure 2. Nearly all the regimens have no significant difference of effect foradvanced STS with a exception of EC (epirubi- cin þ cisplatin). EC showed a better effectivenesswith HR of 0.53 (95%CI:0.36-0.92) compared with doxorubicin alone. Probability values summarized from SUCRA showed that EC (epirubi-cin þ cisplatin) was the best regimen for advancedSTS in terms of OS with probability of 58.4%.
PFS data of 27 studies including 26 regimens were pooled in our analysis. Supplementary Figure S2 presented the network geometry in terms of PFS. No evidence of the absence of inconsistency was found according to the methods described above. Consistency model was conducted and com- parisons between doxorubicin and other regimens were illustrated in Figure 3. Only docetaxel showed a worse role among the regimens for advanced STS(HR ¼ 2.56, 95%CI:1.11-5.9). The remaining regi-mens revealed similar effect for advanced STS com- pared with doxorubicin. Probability values summarized from SUCRA showed the rank of reg- imens for STS in terms of PFS. Aldoxorubicin was considered as the best regimen for advanced STS with probability of 40.8%.

Tumour response
A total of 29 regimens were compared in 28 studies for ORR. The network geometry of ORR wasshowed in Supplementary Figure S3. The results of design-by-treatment model, node splitting method and inconsistency factor showed no inconsistency in terms of ORR in these studies. Consistency model was conducted and comparisons between doxorubicin and other regimens were showed in Figure 4. Docetaxel, brostallicin and carminomycin were worse than doxorubicin alone with statistic- ally significance. The other regimens showed no better or worse effect compared with doxorubicin alone. Probability values summarized from SUCRA showed that aldoxorubicin was the best regimen for advanced STS with probability of 33.2%.

Toxicity
Only severe toxicity(grade3-4) were included in our study. Hematological toxiciteis were common in the included studies. Toxicity data about anemia, granulocytopenia/neutropenia and thrombocytopenia were reported in most trials(18, 21 and 20 studies respectively). After excluding the unconnected regimens, the remaining treatments were included to establish consistency models. No significant inconsistency was detected. The inciden- ces of anemia and thrombocytopenia were similar in patients received these regimens included in models. Four regimens (pegtlated liposomal doxo- rubicin, brostallicin, docetaxel, doxorubicin plus evofosfamide) have less granulocytopenia/neutro- penia events compared with doxorubicin. The remaining regimens have similar incidence of gran- ulocytopenia/neutropenia compared with doxorubi- cin. Pegtlated liposomal doxorubicin was considered as the best regimen with least granulo- cytopenia/neutropenia events with probability of 92.6%. The incidence of granulocytopenia/neutro- penia of aldoxorubicin was not reported.
Aldoxorubicin has similar incidence of anemia and thrombocytopenia compared with doxorubicin. The incidence of anemia, granulocytopenia/neutropenia and thrombocytopenia for EC compared with doxorubicin were 37.2% vs13.8%, 100% vs 31.4%and 75.8% vs 5.6% respectively.
The types of reported non-hematological toxicities associated with regimens were significantly diverse in different studies. Here, we pooled the data of nausea/ vomiting and diarrhea that were provided in the majority of included trials(23 and 14 trials respect- ively). No inconsistency in the regimens investigated in these studies was found. Seven regimens (doxoru-bicin þ dacarbazine þ actinomycin,doxorubicin þ da- carbazine þ cyclophosphamide, doxorubicin þ palifosfamide, trabectedin þ doxorubicin, reduced dose of (doxorubicin þ dacarbazine þ ifosfamide), doxorubicin þ dacarbazine þ ifosfamideanddoxorubicin þ dacarbazine) have more nausea/vomit- ing events than doxorubicin. The remaining regimens have similar incidence of nausea/vomiting compared with doxorubicin. The incidence of diarrhea were similar of those regimens included in models. Pegtlated liposomal doxorubicin was considered as the best regimen with least nausea/vomiting events with probability of 42.3%. What’s more, aldoxorubi- cin and EC have similar incidence of nausea/vomiting and diarrhea compared with doxorubicin.

Discussion
Several studies have been conducted to compare different first line regimens for advanced STS. Verma et al.’s study suggested that ifosfamide com-bined chemotherapy regimen significantly improvesthe tumour response rate (RR ¼ 1.52, p ¼ 0.009), whereas the difference of survival is not significant (RR ¼ 0.98, p ¼ 0.76)42. Bramwell et al.’s meta- analysis demonstrated that doxorubicin-based com- bination chemotherapy have no more benefits but more toxicities than single doxorubicin chemother- apy66. Tanaka et al.’s meta-analysis produced a similar outcomes with Bramwell et al.’s study67.
Our study is the first meta-analysis aiming to determine the best first-line chemotherapy for untreated advanced STS by comparing different regimens using NMA. Doxorubicin has been con- sidered as the standard first-line chemotherapy for advanced STS2. In the light of the present study, we demonstrated that EC had better OS than doxorubicin. Aldoxorubicin behaves better than doxorubicin and EC in terms of PFS and ORR, nevertheless the difference have no statistically sig- nificance. The remaining numerous chemotherapy regimens have no added benefit for STS compared to single agent doxorubicin according to our ana- lysis, even though some of them have marginalbenefits in single trial. It’s worth noting that EConly has been investigated in a single trial with lim- ited patients. More studies need to be conducted to further assess the role of EC for advanced STS. In addition, EC has more severe toxicities than doxo- rubicin. The trial comparing aldoxorubicin and doxorubicin did not meet its primary endpoint and this drug was not approved for use by the FDA. In other words, doxorubicin still can be selected pref- erentially for the first line chemotherapy for patients.
The overall effect of the existing regimens is poor, therefore novel therapies need to be devel- oped. STS is a group of heterogeneous diseases with different histological subtypes and responses to treatments. A number of authors have suggested that response to chemotherapy may vary withhistological subtypes, whereas only 13% of all RCTs in STS selected patients based on specific histology40. Potential deficiencies of these trials contain small number of patients for reliable statis- tical analysis and difference of pathology identification.
Meanwhile, several novel targeted drugs have been studied in other trials. Olaratumab, a platelet- derived growth factor receptor (PDGFR) monoclo- nal antibody have been evaluated in a phase 1 b and 2 trial performed by Tap et al.54. The patients (nearly half of them had been previously treated) received olaratumab plus doxorubicin achieved a highly significant improvement of 11.8 months in median OS compared with patients in doxorubicin group. However, the OS benefit of olaratumab failed to be confirmed in another informative phase III trial (ANNOUNCE) comparing olaratumab plus doxorubicin and placebo plus doxorubicin for advanced STS patients68. Other brand-new drugs such as ombrabulin, ridaforolimus, regorafenib and pazopanib have better PFS, which have been dem- onstrated in mounting trials including previously treated advanced STS44,45,52,55. Their potential for first line chemotherapy were evident, therefore tri- als focussing on first line chemotherapy should be conducted in the future.
Nowadays, immunotherapy is considered tohave broad prospects in cancer treatments69. Elevated expression of PD-L1 occurs in a substan- tial proportion of STS and is correlated with poor prognosis of STS70,71. Nivolumab plus ipilimumab have been demonstrated with promising effective- ness and manageable toxicities in certain types of STS72.
The report of toxicity is an evolving field that remains unsatisfactory in lots of RCTs. In our study, only common toxicities such as anemia, granulocytopenia/neutropenia, thrombocytopenianausea/vomiting and diarrhea were included to compare safeties of regimens investigated in differ- ent trials. EC have more incidence of anemia, gran- ulocytopenia/neutropenia and thrombocytopenia compared with doxorubicin, which may reduce its priority in the regimens for STS. Due to the dis- crepancy of toxicity report item, our results only partially illustrate the toxicities of regimens included in our study.
Several limitations of our analysis should benoted. The main weakness is the absence of a stat- istical analysis in terms of histological subtypes. We failed to perform a analysis according to the histological subtypes, since most trials reported efficacy in mixed histology patients and did not report individual patient data. What’s more, somestudies included a small number of patients who had received prior chemotherapy.
Taken together, EC and aldoxorubicin ranked better in NMA for advanced STS, whereas more studies need to be conducted to further evaluate these two regimens.doxorubicin still can be selected preferentially for the first line chemotherapy for patients.

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