Uterine Leiomyosarcoma: Systemic Therapy Effectiveness
Overview
Uterine leiomyosarcoma (uLMS) is an aggressive type of mesenchymal tumor linked to a bleak prognosis. The primary treatment for advanced uLMS is systemic chemotherapy, although the most effective regimen remains uncertain. To address this, we conducted an extensive analysis, including both meta-analysis and metaregression, aiming to evaluate diverse treatment approaches for advanced, metastatic, and relapsed uterine leiomyosarcoma. Our study focused on key indicators like objective response rate (ORR) and disease control rate (DCR).
Employing a rigorous frequentist random effects meta-analysis model, we meticulously compared the outcomes of various treatment regimens for advanced uLMS. Our analysis incorporated data from 51 reports, encompassing 1664 patients. Among those who underwent adjuvant chemotherapy, gemcitabine and docetaxel emerged as the most commonly administered drugs. Notably, our findings highlighted that first-line monotherapy utilizing alkylating agents (pooled ORR=0.48; 95% confidence interval [CI]: 0.44–0.52) and second-line monotherapy employing protein kinase inhibitors (pooled ORR=0.45; 95% CI: 0.39–0.52) yielded favorable prognostic outcomes.
Furthermore, our research indicated that combinations such as anthracycline plus alkylating therapy (pooled DCR=0.74; 95% CI: 0.67–0.79) and gemcitabine plus docetaxel (pooled DCR=0.70; 95% CI: 0.63–0.75) exhibited substantial benefits when utilized as first-line and second-line chemotherapies, respectively. Within subgroups, our analyses identified dual-regimen treatments involving anthracycline plus alkylating therapy and gemcitabine plus docetaxel as pragmatic therapeutic choices for International Federation of Gynecology and Obstetrics stages III–IVb with distant metastases, as assessed by computed tomography (p=0.001).
Furthermore, our study indicated that neoadjuvant chemotherapy and local radiotherapy demonstrated favorable outcomes for patients with earlier stages of distant relapsed uterine leiomyosarcoma (p<0.001). These findings offer a foundational platform for the formulation of novel therapeutic strategies, potentially guiding clinical practices towards improved prognoses for individuals grappling with advanced, metastatic, and relapsing uLMS.
Introduction
Uterine leiomyosarcoma (uLMS) stands as the most prevalent subtype of uterine sarcoma, affecting around 0.8 cases per 100,000 persons yearly. It primarily targets women between 20% to 65% by the age of 40, presenting a malignancy linked to the uterus. Early-stage uLMS often entails a standard treatment of hysterectomy. Despite clinical risk factors assisting in diagnosis and prognosis, the overall outlook remains grim. Notably, the 5-year survival rate surpasses 50% for early stages, with FIGO stages I and II exhibiting 75.8% and 60.1% rates respectively. In contrast, stages III and IV, marked by refractory disease and high recurrence, witness survival rates of 34.9% and 28.7% at 5 years.
Despite surgical intervention and treatment, uterine leiomyosarcoma patients face a daunting 50% to 70% risk of relapse. As a result, therapeutic guidelines issued by the National Comprehensive Cancer Network and FIGO differ based on stage: observation for FIGO stage I, systemic therapy for stage II, and adjuvant chemotherapy for stages III and IV. Non-targeted alkylating agents such as Adriamycin, dacarbazine, trabectedin, pazopanib, eribulin, and vinorelbine feature prominently in monotherapy or combination therapy for FIGO stages II and III. Molecular-targeted and immune checkpoint therapies are explored for advanced, metastatic, and relapsing uLMS.
The combination of olaratumab and adriamycin showed potential for FIGO stages III and IV, although recent data have been conflicting. Protein kinase inhibitors (PKIs) like pazopanib and sorafenib displayed promise in trials but are yet to be clinically established. Variable response rates are reported for non-targeted alkylating therapy and anthracycline, while immunotherapy such as pembrolizumab and lenvatinib demonstrated limitations.
High relapse rates and challenges in continued treatment warrant effective modalities, especially for metastatic uLMS. The study’s objective is to conduct a comprehensive comparative meta-analysis and meta-regression analysis using a large uterine leiomyosarcoma patient cohort. It aims to ascertain the most effective therapeutic options for advanced, metastatic, and relapsing cases, considering factors like age, FIGO stage, and previous therapies. This research aims to inform optimal treatment strategies, address inconsistencies, guide clinical practice, and ultimately enhance patient outcomes and quality of life through evidence-based personalized treatment plans.
Method
This quantitative meta-analysis was meticulously conducted, adhering to the guidelines stipulated by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The approach involved a thorough exploration of pertinent literature across various databases, including MEDLINE’s PubMed, Embase, Wiley, ISI Web of Science, Science Direct, Google Scholar, and the VIP database. Without imposing language or geographical restrictions, the search was executed independently by two authors (I.I. and M.N.S.) until November 15, 2022. The goal was to comprehensively evaluate the impact of systemic therapies on advanced, metastatic, or unresectable uterine leiomyosarcoma cases.
The search utilized medical subject heading terms encompassing “therapy,” “chemotherapy,” “immunotherapy,” “targeted therapy,” “hormonal therapy,” coupled with “uterine sarcoma,” “uterine leiomyosarcoma,” or “uLMS.” Solely articles in English were included in the analysis, ensuring uniformity in language comprehension. Furthermore, to ensure a robust scope, relevant articles and their corresponding reference lists underwent comprehensive examination. The selection process of works involved rigorous scrutiny by two independent researchers. This diligent methodology forms the foundation of the study’s reliability and validity.
The process of article selection and analysis was rigorous and systematic. Initial scrutiny was focused on the titles and abstracts of chosen articles, guided by the principles of population, intervention, control, and outcomes. This preliminary assessment was conducted by two independent investigators, I.I. and M.N.S. Subsequently, a comprehensive examination of the full articles took place. This thorough evaluation encompassed various key demographics and clinicopathologic parameters, including the author’s name, publication year, patient ethnicities, study country, sample size, design, phase, FIGO disease stage, RECIST-defined endpoints, utilized drugs, and summary estimates. Authors of selected studies were even contacted for additional relevant information. Any discrepancies were addressed through discussion, and if consensus couldn’t be reached, a third investigator, S.I., was consulted to facilitate resolution.
To enhance study comprehensiveness, reference lists were also scrutinized for potential additional studies. Once the defined criteria were met, attention was directed toward the study of uterine leiomyosarcoma, the most prevalent subtype in the analyzed trials, and one with robust sample representation.
The quality of the selected studies was assessed using the Newcastle-Ottawa scale (NOS) and the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) protocols. NOS scores were employed to classify studies as high-quality (≥6 points), and those with scores ≤4 were excluded. Study bias was evaluated based on the Cochrane Collaboration tool, utilizing seven questions with “yes,” “no,” or “unclear” responses.
A meta-regression analysis was executed to comprehend the sources of observed heterogeneity among studies. This analysis aimed to uncover the impact of factors such as patient age, publication year, reported overall survival (OS), and the effects of neoadjuvant chemotherapy or local radiotherapy on the differences in ORR and DCR of patients with advanced uLMS undergoing current therapy. Moreover, meta-regression models were employed to explore the associations between study-specific ORRs and DCRs and variables such as participant ages, primary endpoints, timeframe for assessing weight changes, previous therapies, and the proportion of baseline samples included in the analysis. This meticulous analysis framework aimed to provide comprehensive insights and ensure the reliability of the study’s findings.
Inclusion Criteria
The inclusion criteria were meticulously defined for this study. These criteria encompassed the following aspects: studies published exclusively in English and containing a minimum of five patients in their sample size. Additionally, the research samples had to be confirmed as uLMS through rigorous histopathological diagnostic analyses. The effectiveness of therapeutic interventions was to be evaluated based on the established response evaluation criteria in solid tumors (RECIST). This framework embraces essential measures such as complete response, partial response, stable disease, and progressive disease. The key indicators for assessment were the objective response rate (ORR), defined as the combination of complete response and partial response, and the disease control rate (DCR), encompassing complete response, partial response, and stable disease. Lastly, both randomized trials and observational studies were eligible for inclusion, provided they encompass patients dealing with advanced, recurrent, or progressive uterine leiomyosarcoma. This stringent set of criteria served to ensure the quality and relevance of the studies considered in the analysis.
Exclusion Criteria
The exclusion criteria were thoughtfully established to ensure the precision and relevance of the study. These criteria encompassed the following: articles pertaining to the pediatric population and those solely focused on early-stage disease, carcinosarcoma, or other types of uterine cancers. Additionally, works falling into categories such as case reports, case series, review articles, editorials, early-phase trials, and miscellaneous reports were excluded. Non-English articles were not considered, and the elimination of duplicate or overlapping content was a priority. Moreover, articles lacking adequate and essential key data required for treatment assessment and p-value calculation were deemed ineligible. The exclusion criteria also encompassed articles presenting ambiguous mixed results and unspecified treatment regimens within the context of uterine leiomyosarcoma data. This stringent selection process was vital in maintaining the integrity and reliability of the study’s outcomes.
Statistical Analysis
The systematic search and data integration were executed using EndNote Software version X9, ensuring methodical and organized data management. Numerical data were presented as mean (±standard deviation) or median (range), while qualitative variables were represented as numbers and percentages. Employing both random and fixed effects models, the study aimed to derive pooled estimates concerning the impact of distinct systemic regimens on the prognostic outcomes of advanced uterine leiomyosarcoma. These outcomes were evaluated based on objective response rate (ORR) and disease control rate (DCR), alongside their correlation with other prognostic factors.
To assess the degree of heterogeneity among the studies, the Cochrane Q statistic and Higgins I2 statistic were employed. A significance level of p<0.05 and/or I2>0% under fixed effects criteria was deemed statistically significant. Subgroup analyses were conducted using various parameters such as research design, median patient age, number of pharmacological agents in combination therapy, line of therapy, disease stage, and publication year. The objective was to identify the sources of heterogeneity within the studies’ results.
For all statistical analyses, the R software (version 4) and specific packages, including the “mada” package from The R Foundation, were employed. To assess potential publication bias, Begg’s funnel plots and Egger’s linear regression test were utilized, adding another layer of rigor to the analysis. This approach ensured a comprehensive and robust evaluation of the collected data while maintaining statistical integrity.
Result
The study employed a comprehensive systematic search strategy, rooted in the principles of population, intervention, control, and outcomes, to ensure a robust analysis. Out of an initial pool of 4031 studies, retrieved from both online databases (4022) and manual curation (9), two duplicates were excluded. A meticulous review of abstracts led to the exclusion of 3126 studies, categorized as reviews, meta-analyses, conferences, editorials, guidelines, letters, case reports, non-English articles, or studies involving cell or animal subjects. After this phase, 903 full-text articles were considered, and further exclusions ensued due to insufficient data (163), non-uterine cancer cases (583), and radiotherapy data (106). Ultimately, 51 studies were deemed suitable for the meta-analysis and meta-regression analysis.
These studies, published between 1979 and 2019, predominantly focused on American populations (74.5%), with a smaller representation of European (20%) and Asian (5.8%) populations. Various treatment approaches were explored, including alkylating agents in monotherapy or combinations, antimetabolites alone or with taxanes, anthracyclines alone or combined with alkylating agents, and protein kinase inhibitors (PKIs). Monotherapy and combination therapy each showed unique efficacy. Anthracycline plus alkylating agents and gemcitabine with docetaxel emerged as significant combinations. Alkylating agents, antimetabolites, and PKIs also demonstrated substantial efficacy as monotherapies.
The selected 51 reports were assessed for quality using NOS and QUADAS-2 protocols, revealing high-quality studies with scores of 7 or more out of 10. The systematic analysis revealed a considerable impact of different treatment regimens on advanced uterine leiomyosarcoma prognosis, with pooled estimates showing notable objective response rates (ORR) and disease control rates (DCR).
Subgroup analyses assessed the influence of prognostic factors on ORR and DCR, identifying variables contributing to overall heterogeneity. Notably, phase II and retrospective study designs, dual therapy, and specific combinations demonstrated significant pooled ORRs. Disease stage, treatment regimen, and specific therapy line were factors influencing the pooled DCRs. Furthermore, magnetic resonance imaging (MRI) and computed tomography (CT) were highlighted as effective monitoring methods for uterine leiomyosarcoma disease surveillance.
The meta-regression analysis delved into the association between overall survival (OS), neoadjuvant chemotherapy (NACT), and local radiotherapy, showing their significant influence on the ORR. The analysis underscored the positive impact of the current treatment on advanced-stage disease. While the analysis didn’t establish significant correlations with publication year or median patient age, it indicated the influence of these factors on advanced uterine leiomyosarcoma therapy.
Evaluation of diffusion bias demonstrated that the omission bias of ORR was statistically significant, prompting the use of adjusted estimates via the trim-and-fill method. Consequently, 13 studies were estimated as missing, yielding an adjusted ORR value.
In summation, the study’s rigorous methodology and meticulous analysis revealed a comprehensive understanding of the impact of various treatment regimens on advanced uLMS prognosis, highlighting influential factors and offering insights into optimal therapeutic strategies.
Conclusion
This groundbreaking study presents a comprehensive meta-analysis and meta-regression analysis that delves into the comparison of systemic therapeutic approaches for advanced, metastatic, and relapsing uterine leiomyosarcoma (uLMS). The results revealed noteworthy outcomes, showcasing the efficacy of certain treatment regimens.
The study highlighted the significantly improved objective response rate (ORR) achieved through dual-regimen chemotherapy, specifically anthracycline combined with alkylating therapy, when employed as a first-line treatment. Additionally, dual-therapy regimens, involving anthracycline plus alkylating or antimetabolite therapy plus taxane, as well as protein kinase inhibitors (PKIs), demonstrated substantial increases in the disease control rate (DCR) for patients with late-stage FIGO III-IVb uterine leiomyosarcoma.
Moreover, the study underscored the significance of disease evaluation tools such as computed tomography (CT) and magnetic resonance imaging (MRI) for effective disease surveillance. Neoadjuvant chemotherapy (NACT) post-surgery emerged as a promising treatment strategy for advanced uLMS, and localized chemoradiotherapy exhibited benefits as a second-line therapy. Importantly, the study indicated that a history of NACT and prior radiotherapy correlated with improved prognosis.
Various treatment approaches were analyzed, including alkylating agents like doxorubicin and rituximab, and the study highlighted their potential efficacy in monotherapy or combination therapy. Gemcitabine combined with docetaxel, aromatase inhibitors like letrozole, and PKIs as second-line monotherapies also demonstrated positive effects.
However, the study acknowledged some limitations, such as language restrictions and potential confounders in single-arm clinical trials. Despite these limitations, the study provides crucial insights into potential treatment strategies for advanced uterine leiomyosarcoma, emphasizing the need for large-scale, prospective, multi-institutional trials to deepen understanding and establish standardized practices.
In conclusion, this pioneering study offers a comprehensive evaluation of systemic therapeutic approaches for advanced uterine leiomyosarcoma, shedding light on effective treatment regimens and emphasizing the importance of further research and clinical trials to refine and establish evidence-based practices.
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