First-Line Chemotherapy Regimens for Advanced and Metastatic Leiomyosarcoma: Doxorubicin vs. Gemcitabine—A Systematic Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Congratulations to the authors for providing a comprehensive review of first-line chemotherapy regimens utilized in the management of advanced leiomyosarcoma. Their conclusions support what has widely been noted in the sarcoma community, namely superiority of doxorubicin-based chemotherapy regimens over gemcitabine/docetaxel. It is incredibly helpful to have all available data supporting this impression reviewed in a singular manuscript.

Several of the studies specify soft tissue from uterine LMS in the patient cohort. Are the authors able to make any specific conclusions on one regimen vs another in this specific population, particularly given the interest in gemcitabine-based regimens in uterine tumors?

Author Response

Comment:

Congratulations to the authors for providing a comprehensive review of first-line chemotherapy regimens utilized in the management of advanced leiomyosarcoma. Their conclusions support what has widely been noted in the sarcoma community, namely superiority of doxorubicin-based chemotherapy regimens over gemcitabine/docetaxel. It is incredibly helpful to have all available data supporting this impression reviewed in a singular manuscript. Several of the studies specify soft tissue from uterine LMS in the patient cohort. Are the authors able to draw any specific conclusions on one regimen vs another in this specific population, particularly given interest in gemcitabine-based regimens in uterine tumors?

Response: We thank the reviewer for this important point. According to the studies included, outcomes stratified by uterine versus non-uterine LMS were reported inconsistently, and only a subset of studies (n=2) provided extractable, subtype-stratified efficacy outcomes. Most trials reported aggregate results for the overall cohort, limiting robust regimen-specific conclusions within uLMS alone. We therefore added a narrative subtype-focused synthesis and highlighted this limitation in the Discussion:
“Subtype-stratified (uLMS vs non-uLMS) outcomes were inconsistently reported.”

“…sample sizes across trials, particularly prospective studies, were small, reflecting the rarity of LMS but limiting statistical power and the ability to evaluate important subgroups such as uterine versus non-uterine LMS.”

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors your manuscript entitled First-Line Chemotherapy Regimens for Advanced and 2
Metastatic Leiomyosarcoma: A Systematic Review is of interst. However, several improvements are required to strengthen the methodological rigor, clarity of presentation, and balance of interpretation before the manuscript can be considered for acceptance. Kindly find the attached comments.

1. In abstract include why first-line selection in LMS remains unresolved despite decades of use.
2. Clarify whether this is a qualitative systematic review or whether any quantitative synthesis.
3. The results section selectively highlights LMS04, which may bias perception. Consider briefly acknowledging variability across study designs.
4. In conclusion discuss between randomized  retrospective.

5. In introduction emphasize on clinical decision-making dilemma faced by oncologists in choosing first-line therapy.
6. Discuss how this work differs from prior LMS reviews (e.g., newer phase III data, toxicity-focused synthesis).
7. Discuses why targeted therapies and immunotherapy are not the primary focus, despite growing interest.
8. The protocol registration number (e.g., PROSPERO) is not mentioned kindly add it.

1. In results add a summary table stratified by uLMS vs non-uLMS.
2. The toxicity data lacks contextual interpretation (e.g., clinical relevance of grade 3–4 events). Kindly include it
3. In discussion discuss cytotoxic efficacy, treatment tolerability and Patient selection factors separately for readers understanding.
4. The emerging role of immunotherapy is appropriately along with certain biomarker should be discussed more in detail.

13. In conclusion avoid repeating discussion points; instead, focus on outcomes for clinicians and researchers.

 

Author Response

1. Comment: In abstract include why first-line selection in LMS remains unresolved despite decades of use.

Response: Revised as suggested. We added a sentence in the abstract emphasizing that first-line selection remains unresolved due to limited comparative evidence and heterogeneity across studies: “Despite decades of clinical experience, first-line treatment selection in leiomyosarcoma remains unresolved due to the absence of direct comparative trials, heterogeneous study designs, and trade-offs between efficacy and toxicity.”

2. Comment: Clarify whether this is a qualitative systematic review or whether any quantitative synthesis.

Response: Revised as suggested. We clarified that this is a qualitative systematic review and that no meta-analysis was performed due to clinical and methodological heterogeneity:
“This study is a qualitative systematic review conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines; no quantitative meta-analysis was performed due to clinical and methodological heterogeneity.[15]”

3. Comment: The results section selectively highlights LMS04, which may bias perception. Consider briefly acknowledging variability across study designs.

Response: Revised as suggested. We added statements acknowledging variability across study designs (phase 2, phase 3, and retrospective cohorts) and the inherent limitations of cross-trial comparison: “While LMS04 provides the only LMS-specific prospective OS data, outcomes across studies varied substantially by design, population, and endpoints, underscoring the limitations of cross-trial comparison.”

4. Comment: In conclusion discuss between randomized retrospective.

Response: Revised as suggested. We incorporated explicit statements contrasting randomized evidence (internal validity) and retrospective evidence (real-world insight but selection bias):

“Importantly, the evidence base includes both randomized and retrospective data sources. Randomized trials offer higher internal validity and reduce confounding, but their strict eligibility criteria may limit generalizability. In contrast, retrospective studies provide real-world insights into regimen utilization and outcomes at the cost of selection bias and heterogeneity. This distinction is particularly relevant when interpreting outcomes across LMS04, GeDDiS, and retrospective cohorts such as D’Ambrosio et al”

 

5. Comment: In introduction emphasize clinical decision-making dilemma faced by oncologists in choosing first-line therapy.

Response: Revised as suggested. We added language highlighting the clinical dilemma of selecting first-line therapy in LMS, particularly given the lack of definitive comparative data:

“Due to the absence of head-to-head randomized trials, oncologists must individualize first-line treatment selection in advanced LMS based on indirect evidence, toxicity profiles, and patient-specific considerations rather than clear regimen superiority.”

6. Comment: Discuss how this work differs from prior LMS reviews (e.g., newer phase III data, toxicity-focused synthesis).

Response: Revised as suggested. We clarified the novelty of this review by emphasizing the inclusion of recent phase 3 evidence, the comparative synthesis of efficacy and toxicity, and the focus on first-line decision-making:

“Unlike prior reviews that examined LMS across multiple treatment lines or pooled heterogeneous STS populations, this review focuses exclusively on first-line systemic chemotherapy, incorporates newer phase III data such as LMS04, and provides a structured synthesis of efficacy and toxicity stratified within LMS subtypes.”

“This review focuses exclusively on first-line doxorubicin- and gemcitabine-based regimens, aiming to clarify comparative effectiveness and inform future treatment standards through a focused evaluation of available clinical data”

7. Comment: Discuss why targeted therapies and immunotherapy are not the primary focus, despite growing interest.

Response: Revised as suggested. We added a concise justification emphasizing that cytotoxic chemotherapy remains the first-line standard, while most targeted therapies and immunotherapy approaches remain later-line or investigational in LMS.

“Although targeted therapies and immunotherapy are areas of growing interest, cytotoxic chemotherapy remains the standard first-line approach in advanced LMS, with most novel agents evaluated in later-line or investigational settings.”

 

 

 

 

8. Comment: The protocol registration number (e.g., PROSPERO) is not mentioned, kindly add it.

Response: Revised as suggested. We added the PROSPERO registration number: PROSPERO CRD420261280028 in both the Methods and the abstract.

9. Comment: In results add a summary table stratified by uLMS vs non-uLMS.

Response: We appreciate this suggestion. However, subtype-stratified outcomes (uLMS vs non-uLMS) were not consistently reported across studies; only two studies provided extractable stratified efficacy outcomes. A pooled summary table would therefore be incomplete and potentially misleading. Instead, we incorporated an explicit narrative comparison of uLMS versus non-uLMS outcomes where data were available.

10. Comment:
    The toxicity data lacks contextual interpretation (e.g., clinical relevance of grade 3–4 events). Kindly include it.

Response: Revised as suggested. We added contextual interpretation emphasizing how myelosuppression, thrombocytopenia, transaminitis, and dose reductions influence regimen selection and deliverability in practice:

“Grade 3–4 hematologic toxicities frequently necessitated dose reductions or treatment discontinuation, limiting real-world feasibility despite observed efficacy.”
“These studies made it evident that there are relevant toxicities associated with ifosfamide; thus, the drug should be used with caution when treating patients with LMS”
“Although the combination therapy yielded more adverse events, the time to second disease progression was longer (26 months vs 13 months), making it more active against LMS (HR 0.46).[20,29]”.

 

 

 

 

 

 

 

11. Comment: In discussion discuss cytotoxic efficacy, treatment tolerability and patient selection factors separately for readers understanding.

Response: Revised as suggested. The Discussion was restructured into three explicit components: (I) cytotoxic efficacy; (II) treatment tolerability; and (III) patient selection.

12. Comment: The emerging role of immunotherapy is appropriate along with certain biomarkers that should be discussed in more detail.

Response: Revised as suggested. We expanded the immunotherapy discussion and explicitly stated that while immunotherapy has limited activity in unselected LMS, biomarker-enriched strategies may identify subsets more likely to benefit.

“While immunotherapy has shown limited activity in unselected LMS, emerging data suggests that biomarker-enriched strategies may better identify subsets more likely to derive benefit, warranting further investigation in prospective trials”

13. Comment: In conclusion avoid repeating discussion points; instead, focus on outcomes for clinicians and researchers.

Response: Revised as suggested. We revised the conclusion to explicitly state:

• For clinicians: what should be done now
• For researchers: what should be prioritized next

“Although these findings reflect meaningful therapeutic progress, For clinicians, doxorubicin-based therapy should remain the reference first-line option, with gemcitabine-based regimens reserved for selected patients who are unfit for anthracyclines or in whom cumulative cardiotoxicity is a concern. the current evidence base is still constrained by small sample sizes, heterogeneous study populations, and the persistent absence of adequately powered, LMS-specific randomized trials.”

 

“Urgent priorities include adequately powered LMS-specific randomized trials, uterine-stratified analyses, and biomarker-driven approaches.”

 

“Future research should also explore the potential of immunotherapy combinations, molecularly informed patient selection, and novel biomarker-driven strategies. Together, these efforts will be essential for establishing a clearer, more effective, and more personalized first-line standard of care for patients with leiomyosarcoma. Together, these efforts are essential to refine first-line standards of care and enable more personalized treatment selection for patients with leiomyosarcoma.

Reviewer 3 Report

Comments and Suggestions for Authors

The topic of first-line systemic therapy for advanced leiomyosarcoma is timely, clinically relevant, and well-suited for a review article. Given the ongoing uncertainty regarding optimal treatment strategies and the heterogeneity of available data, a focused synthesis of the evidence in this area is of clear value to the sarcoma community. That said, the authors are encouraged to carefully and thoughtfully address the following points outlined below, as they are essential to ensuring the methodological rigor, completeness, and interpretability of the review.

In Section 2.1 (Research Strategy), the authors state that the literature search was conducted using controlled vocabulary (MeSH and Emtree) and natural language terms specifically for leiomyosarcoma, doxorubicin, and gemcitabine, with the following search string: “leiomyosarcoma” AND (“gemcitabine” OR “doxorubicin” OR “adriamycin”).

However, this search strategy appears overly restrictive and is not well aligned with the stated objective of the review, namely “First-Line Chemotherapy Regimens for Advanced and Metastatic Leiomyosarcoma.” By limiting the search terms to predefined agents at the outset, the strategy risks introducing selection bias and may fail to comprehensively capture the full spectrum of first-line systemic chemotherapy regimens evaluated in advanced or metastatic leiomyosarcoma.

For a systematic review intended to identify and compare first-line chemotherapy regimens, the search strategy should be broader and concept-driven rather than drug-specific, incorporating general treatment-related terms such as “chemotherapy,” “systemic therapy,” or “drug therapy” in combination with leiomyosarcoma. This approach would better ensure the identification of all relevant studies, including those evaluating regimens not explicitly centered on doxorubicin or gemcitabine, as well as emerging or less commonly used first-line approaches.

Therefore, a revision of the search strategy and a repeat of the literature search are warranted to ensure methodological rigor, completeness, and consistency with the review's stated aims. The revised search strategy should be clearly described and, ideally, presented in sufficient detail (e.g., as a supplementary appendix) to allow reproducibility.

Author Response

Comment:
The search strategy appears overly restrictive… A revision of the search strategy and repeat of the literature search are warranted.

Response:
We thank the reviewer for this important methodological observation. We acknowledge that a broader concept-driven strategy would be necessary for a comprehensive review of all systemic options in LMS. Our intent was to conduct a focused systematic review comparing first-line regimens containing doxorubicin and/or gemcitabine, given that these agents represent the most used cytotoxic backbones in advanced LMS. To avoid any misunderstanding, we revised the manuscript title and clarified throughout the Methods/Introduction that the scope of this review is limited to doxorubicin- and gemcitabine-based regimens. We also addressed other emerging approaches (including targeted therapies and immunotherapy) within the Discussion for contextual completeness.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

All the reviewer comments have been addressed in a clear and scientifically . The revisions have significantly improved the clarity, balance, and overall quality of the manuscript. In view of the satisfactory responses and the comprehensive incorporation of the suggested corrections, I recommend that the manuscript be accepted in its current form.

Author Response

Comment 1: All the reviewer comments have been addressed in a clear and scientifically. The revisions have significantly improved the clarity, balance, and overall quality of the manuscript. In view of the satisfactory responses and the comprehensive incorporation of the suggested corrections, I recommend that the manuscript be accepted in its current form.

Response 1: Thank you for reviewing the manuscript on behalf of the co-authors. 

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript has improved considerably in the current revision, and I find the overall content to be satisfactory.

One point that would benefit from clarification concerns a discrepancy between the manuscript's Methods section and the full protocol registered in PROSPERO (CRD420261280028). In the manuscript, the search strategy is described as “‘leiomyosarcoma’ AND (‘gemcitabine’ OR ‘doxorubicin’ OR ‘adriamycin’),” whereas the PROSPERO protocol outlines a broader, concept-driven search approach incorporating terms related to chemotherapy, systemic therapy, and drug therapy, with a representative strategy of “‘leiomyosarcoma’ AND (‘chemotherapy’ OR ‘systemic therapy’ OR ‘drug therapy’).”

It would be helpful to clarify which search strategy was ultimately used and to align the descriptions in the manuscript and the registered protocol accordingly to ensure transparency and methodological consistency.

Author Response

Comment 1: 

One point that would benefit from clarification concerns a discrepancy between the manuscript's Methods section and the full protocol registered in PROSPERO (CRD420261280028). In the manuscript, the search strategy is described as “‘leiomyosarcoma’ AND (‘gemcitabine’ OR ‘doxorubicin’ OR ‘adriamycin’),” whereas the PROSPERO protocol outlines a broader, concept-driven search approach incorporating terms related to chemotherapy, systemic therapy, and drug therapy, with a representative strategy of “‘leiomyosarcoma’ AND (‘chemotherapy’ OR ‘systemic therapy’ OR ‘drug therapy’).”

It would be helpful to clarify which search strategy was ultimately used and to align the descriptions in the manuscript and the registered protocol accordingly to ensure transparency and methodological consistency.

Response 1: 

Dear Reviewer,

We appreciate your response and clarification regarding this matter. The strategy string, following its adaptation based on reviewer comments, was correctly updated in the manuscript but had not yet been reflected in the PROSPERO Protocol. Please refer to version 2.0 of the updated protocol, where you can download the PDF containing the appropriate MeSH terms as referenced in the manuscript.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420261280028 

We are grateful for your precision and thorough review of this issue.

Best regards, 
On behalf of all co-authors