Trabectedin for L-Type Sarcoma: A Retrospective Multicenter Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have presented a retrospective study on trabectedin in advanced/metastatic L-type sarcomas. The limitations of the study include the retrospective nature. Prospective clinical trials of trabectedin in this study population has been conducted. The authors provide a comprehensive introduction, methods section, and discussion/conclusion. With respect to results, I have the following comments to consider for revision:

- In general, the results section could be restructured/organized to be more clear. For example, section 3.2, the authors include response data, which should be included in the below section. 

- In discussion of patients who achieved a CR, how many cycles did they receive?

- Consider showing survival for entire cohort as well as by histologic subtype for both ToTF and OS

- Table 2 is not necessary

- Curiously ToTF was longer for patients with dose reduction due to toxicity, yet survival reported in this study is shorter than other investigations. Can the authors comment on this?

- How were survival outcomes impacted by those who underwent local therapy for oligoprogression compared to those who did not?

Comments on the Quality of English Language

Recommend additional proof reading for editing and spelling corrections. Multiple spelling errors including drug names and anatomic locations. For example, trabectedin is often spelled trabectedine. 

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed

responses below and the corresponding revisions/corrections highlighted/in track changes in

the re-submitted files. 

-Comments 1: In general, the results section could be restructured/organized to be more clear. For example, section 3.2, the authors include response data, which should be included in the below section. 

-Response 1: The results section has been reorganized, and edits were made in line with your suggestions. We appreciate your input in improving our work's clarity. The name of section 3.2 has been changed to be more descriptive, including local treatments. Statements about patients who received an objective response were collected under the section of response of treatment. Treatment durations in patients with complete response were added. With the recommendation of Reviewer 2, the title "time of the treatment failure" was changed to "time to treatment failure", as it was thought to be a more appropriate expression.

-Comments 2: In discussion of patients who achieved a CR, how many cycles did they receive?

-Response 2: Patients who achieved complete responses received 6, 8, 16, and 34 cycles of trabectedin, respectively. Also found on page 4, results-section 3.3 and line 148.

-Comments 3: Consider showing survival for entire cohort as well as by histologic subtype for both ToTF and OS.

-Response 3: TTF and OS Kaplan-Meier curves for leiomyosarcoma and liposarcoma histological subtypes are included as figures 2 and 4.

-Comments 4: Table 2 is not necessary

-Response 4: Table 2 has been removed. The p-values of the multivariate analysis were added to the relevant sections in the time to treatment failure and overall survival sections.

-Comments 5: Curiously ToTF was longer for patients with dose reduction due to toxicity, yet survival reported in this study is shorter than other investigations. Can the authors comment on this?

-Response 5: In our study, the median overall survival (mOS) was 19 months for patients who underwent dose reduction due to toxicity (line 198). Although this duration is relatively long, it did not reach statistical significance. In the prospective Phase III study, the mOS was 14 months (1). When we examine large-scale real-life data, the mOS was 15 months in the YON-SAR study and 28 months in L-type sarcomas in the TrOBS study (2,3). A shorter survival duration was observed compared to the TrOBS study alone. Two other prospective studies also reported shorter survival compared to the survival of patients who underwent dose reduction due to toxicity in our study.

1) Demetri et al. J Clin Oncol doi: 10.1200/JCO.2015.62.4734. 

2) Grünwald et al. Cancers 2022,  doi: 10.3390/cancers14215234. 

3) Palmerini et al., Cancer 2021, . doi: 10.3390/cancers13051053

-Comments 6: How were survival outcomes impacted by those who underwent local therapy for oligoprogression compared to those who did not?

-Response 6: All patients receiving local treatment while trabectedin experienced oligo progression. However, we do not have information on the number of patients who developed oligo progression and did not receive local treatment. Local treatments were administered in multidisciplinary collaboration. Patients who experienced progression were not categorized as oligoprogression or overt progression during data collection.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors provided a retrospective multicenter review on the use of trabectedin in patients with L-type sarcomas over an ~8 year time period in Turkey to provide additional real world data on effectiveness and safety. The study involved 10 tertiary care centers across Turkey and involved 98 patients in total.

Comments:

1. I would suggest defining L-type sarcoma at first mention in the abstract. For example, line 21, "L-type sarcomas (liposarcoma and leiomyosarcoma)..."

2. Line 31, TToF should be ToTF to be consistent with original abbreviation

3. Line 34, p=0,002 should be 0.002 to be consistent with prior formatting of p-values.

4. Line 58 shows [6,]. Is there a reference missing or should it only be reference [6]?

5. The eligibility requirement (line 86-87) of at least 2 cycles of trabectedin is potentially problematic. It eliminates patients who may have come off early after 1 dose due to side effects/tolerability, which is, in part, one of the goals of the study. Inclusion of anyone who received at least 1 dose may have been a more appropriate inclusion criteria for safety. Perhaps consider limiting to at least 2 when consider ORR or OS but at least 1 when considering safety. How many more pts would have been included if at least 1 dose was the requirement?

6. Table 1. I would define age as years. For example, "Age, yrs (mean)"

7. Table 1. Histology. The following words are misspelled:  Leiomyosarcoma, Uterine and Non-uterine, Liposarcoma, Dedifferentiated, Well-differentiated and Trabectedin.

8. Under treatment exposure. For the patients who achieved CR, what was the duration of therapy for those patients? That would be of interest to the reader.

9. Line 154. p:0.39 should be p=0.39 to be consistent with prior formatting of p-values.

10. Section 3.4. All the TToFs in this section should be ToTF. (Personally, I would suggest one use the abbreviation TTF throughout the paper, instead of ToTF, and define it Time to Treatment Failure as opposed to Time of Treatment Failure). That is, in my opinion, a more accepted abbreviation.

11. Figure 1 Legend. Capitalize the T in treatment.

12. Line 178. p:0.2 should be p=0.2 to be consistent with prior formatting of p-values.

13. Table 3. Adverse, febrile and creatinine are misspelled.

14. Line 210. Trabectedin is misspelled

15. The conclusion made on line 39 regarding "use of local treatments simultaneous with trabectedin seems to be effective" seems to be potentially overreaching. Line 142 says that the most common local treatment was RT but there is no mention of whether it was given concurrently with trabectedin or not. Also, how many underwent surgery and what was the median time frame from last dose of trabectedin to surgery or from surgery to next dose of trabectedin? The manuscript is bit short on details here but only says in Discussion that "40% of patients underwent surgery as local treatment, trabectedin treatment was continued after surgery, and the toxicity profile was not different from that of the general population." It would seem this data should be presented more robustly in the results for both concurrent RT and in the peri-operative period.

16. Line 250 and 265. Trabectedin is misspelled.

17. Line 260. When it says "In the recent study", do you mean "In the present study"?

18. Line 294, the sentence is confusing as written. "In our study, patients who underwent dose reduction due to toxicity had a ToTF, OS was not statistically significant despite a numerical increase."

19. Line 325. Trabectedin is misspelled.

20. Line 333. Doxorubicin/Trabectedin is shown improved PFS but also has improved OS data that has been published. This could be added to the references.

Comments on the Quality of English Language

The manuscript is generally well-written. There are a number of misspellings and a few sentences that require revision as they are confusing to read.

Author Response

-Comments 1: I would suggest defining L-type sarcoma at first mention in the abstract. For example, line 21, "L-type sarcomas (liposarcoma and leiomyosarcoma)..."

-Response 1: The text has been updated based on your recommendation.

-Comments 2, 3 , 4, 7, 9, 11, 12, 13, 14, 16, 19: All comments are subject to spelling rules.

-Response  2, 3 , 4, 7, 9, 11, 12, 13, 14, 16, 19:  We have taken the liberty of correcting all typos. We sincerely apologize for any inconvenience caused by the oversight of such simple errors.

-Comments 5: The eligibility requirement (line 86-87) of at least 2 cycles of trabectedin is potentially problematic. It eliminates patients who may have come off early after 1 dose due to side effects/tolerability, which is, in part, one of the goals of the study. Inclusion of anyone who received at least 1 dose may have been a more appropriate inclusion criteria for safety. Perhaps consider limiting to at least 2 when consider ORR or OS but at least 1 when considering safety. How many more pts would have been included if at least 1 dose was the requirement?

-Response 5: In real life, the selection of patients for metastatic cancer treatment may not be as precise as in prospective randomized studies. For instance, patients with a life expectancy of less than 3 months may receive treatment based on patients and their physician's expectations. To ensure accurate evaluation of the drug's effectiveness and to eliminate inconsistencies in patient recruitment criteria, we included only those patients who received at least two cycles of trabectedin. The study was designed this way from the beginning, and we do not have the exact number of patients who started but discontinued or progressed due to drug toxicity after one cycle. These concerns have been mentioned in the study limitations section, line 366.

- Comments 6: Table 1. I would define age as years. For example, "Age, yrs (mean)"

-Response 6: The text has been updated based on your recommendation.

- Comments 8:  Under treatment exposure. For the patients who achieved CR, what was the duration of therapy for those patients? That would be of interest to the reader.

- Response 8: Patients who achieved complete responses received 6, 8, 16, and 34 cycles of trabectedin, respectively. Also found on page 4, results-section 3.3 and line 152.

- Comments 10:  Section 3.4. All the TToFs in this section should be ToTF. (Personally, I would suggest one use the abbreviation TTF throughout the paper, instead of ToTF, and define it Time to Treatment Failure as opposed to Time of Treatment Failure). That is, in my opinion, a more accepted abbreviation.

- Response 10: The text has been updated based on your recommendation.

-Comments 15: The conclusion made on line 39 regarding "use of local treatments simultaneous with trabectedin seems to be effective" seems to be potentially overreaching. Line 142 says that the most common local treatment was RT but there is no mention of whether it was given concurrently with trabectedin or not. Also, how many underwent surgery and what was the median time frame from last dose of trabectedin to surgery or from surgery to next dose of trabectedin? The manuscript is bit short on details here but only says in Discussion that "40% of patients underwent surgery as local treatment, trabectedin treatment was continued after surgery, and the toxicity profile was not different from that of the general population." It would seem this data should be presented more robustly in the results for both concurrent RT and in the peri-operative period.

-Response 15: The phrase "seems to be effective" in Line 39 has been changed to "can be." We understand that definitive statements should be avoided due to the small number of patients and the retrospective nature of the study. However, we want to highlight this as it is an important hypothesis and result of our study. We appreciate your continued input on improving the clarity of our work. Additional findings regarding the correlation between local treatment and trabectedin can be found on page 4, lines 142-145.

-Comments 17: Line 260. When it says "In the recent study", do you mean "In the present study"?

-Response 17: We intended to say, "In the present study." We have made the correction in line 304.

-Comments 18: Line 294, the sentence is confusing as written. "In our study, patients who underwent dose reduction due to toxicity had a ToTF, OS was not statistically significant despite a numerical increase."

-Response 18: We realized that the sentence lacked meaning. Thank you once more for your suggestion. We have revised the correct statement on page 10, line 339.

-Comments 20: Line 333. Doxorubicin/Trabectedin is shown improved PFS but also has improved OS data that has been published. This could be added to the references.

-Response 20: At the time of writing our study, the current article had not yet been published. Thank you for your attention. Re-edited on page 11, line 337.