Safety Profile of Niraparib as Maintenance Therapy for Ovarian Cancer: A Systematic Review and Meta-Analysis
Round 1
Reviewer 1 Report
The paper needs revision to solve minor problems.
Author Response
We thank the reviewer for taking the time to review our paper and making suggestions. We apologize for all the misspellings. It is the journal’s submission platform that caused some of the errors, which were not made in the original article form. We addressed and corrected all the grammatical/vocabulary mistakes including the words separated by “- “ incorrectly.
Reviewer 2 Report
The manuscript is a very interesting review approaching niraparib safety profile. This topic has gained importance as PARP inhibitors have become a standard of care in ovarian cancer in maintenance treatment upfront and at recurrence. Due to this, it is very important, to generate data regarding this situation as patients are receiving this therapy frequently.
I will like to mark some general concepts first and then some specific things in order to improve the quality of the manuscript.
GENERAL CONCEPTS
- Systematic reviews should be registered at inception to help avoid unplanned duplication and to enable the comparison of reported review methods with what was planned in the protocol. The present manuscript has not described any registration at PROSPERO for example.
- Although no single recommendation is possible regarding what type of studies to include, the decision will depend primarily on the main focus of the research question, balancing the elements of the type of adverse effects of interest, rigor in searching, and time and resources available. Good data on a well-recognized, easily detectable adverse effect may potentially be available from randomized clinical studies. In contrast, information on new, rare, or long-term adverse effects is unlikely to be found in trial reports. Trial participants often differ from those given the intervention in everyday practice. Many RCTs set criteria that exclude patient groups who are potentially more likely to be harmed by adverse effects. Selecting only Phase 3 randomized trials may be generating bias in results.
SPECIFIC COMMENTS
- Multiple words are separated by "-" incorrectly.
- Exclusion criteria should be stated in the Eligibility criteria section
- In the Searching section authors state that Pubmed and Cochrane's databases were searched but then, Study selection, they refer to additional records on other search engines. This should be described in more detail in the Methods section.
- Study selection results should be in the Results section and not in the methods
- Risk of Bias analysis is described in methods and the table is presented in the Supplementary Material, but its never presented nor referenced in the manuscript
- Table 1 is very difficult to understand. It may be split into two tables, one regarding patient characteristics and the other related to adverse effects and treatment discontinuation data.
- Multiple of the subanalysis of adverse effects show a very high heterogeneity. This problem is not analyzed adequately by the authors.
- Both forest plot graphs are difficult to analyze. For readers to interpret data, a solution should be thought of.
Although it was initially designed for intervention Meta-analysis, I suggest authors evaluate their manuscript with the AMSTAR2 tool in order to improve certain details of their work.
Author Response
The manuscript is a very interesting review approaching niraparib safety profile. This topic has gained importance as PARP inhibitors have become a standard of care in ovarian cancer in maintenance treatment upfront and at recurrence. Due to this, it is very important, to generate data regarding this situation as patients are receiving this therapy frequently.
We thank the reviewer for describing the manuscript as of high interest.
GENERAL CONCEPTS
- Systematic reviews should be registered at inception to help avoid unplanned duplication and to enable the comparison of reported review methods with what was planned in the protocol. The present manuscript has not described any registration at PROSPERO for example.
We thank the reviewer for this observation. We totally agree with the fact that all reviews should be registered from the beginning at PROSPERO to avoid duplicates. We have now followed the procedure and received a registration number.
- Although no single recommendation is possible regarding what type of studies to include, the decision will depend primarily on the main focus of the research question, balancing the elements of the type of adverse effects of interest, rigor in searching, and time and resources available. Good data on a well-recognized, easily detectable adverse effect may potentially be available from randomized clinical studies. In contrast, information on new, rare, or long-term adverse effects is unlikely to be found in trial reports. Trial participants often differ from those given the intervention in everyday practice. Many RCTs set criteria that exclude patient groups who are potentially more likely to be harmed by adverse effects. Selecting only Phase 3 randomized trials may be generating bias in results.
We thank the reviewer for his observation. Truth is that patients participating in trials have many discrepancies from what we see in everyday practice. However, our included studies are of high quality, encompassing a big number of patients receiving the same drug. Our purpose was to compare niraparib maintenance versus placebo, and therefore we chose to include only phase 3 RCTs.
SPECIFIC COMMENTS
- Multiple words are separated by "-" incorrectly.
We thank the reviewer for this comment, and we apologize for the misspellings. The journal’s submission platform causes some errors, that were not made in the original article form. We addressed and corrected all the grammatical/vocabulary errors including the words separated by “-“incorrectly.
- Exclusion criteria should be stated in the Eligibility criteria section
We thank the reviewer for this comment. We added the exclusion criteria in the eligibility criteria section, as follows:
“We excluded non comparative, non-randomized (e.g. case controls, cohorts or cross-sectional) and not written in english studies”
- In the Searching section authors state that Pubmed and Cochrane's databases were searched but then, Study selection, they refer to additional records on other search engines. This should be described in more detail in the Methods section.
We thank the reviewer for this comment. We included articles and studies from both PubMed and Cochrane database. By noting in the study selection section that “we identified 59 records on PubMed and 106 additional records on other search engines” we were referring to Cochrane. It is now clarified and written as follows:
“…we identified 59 records on PubMed and 106 additional records on Cochrane…”
- Study selection results should be in the Results section and not in the methods
We thank the reviewer for this clarification. Study selection section is now removed from the Methods section and placed in the Results section as advised.
- Risk of Bias analysis is described in methods and the table is presented in the Supplementary Material, but its never presented nor referenced in the manuscript
We thank the reviewer for this comment. Risk of bias is described in detail in the Methods section. Due to the limited number of figures and tables that can be included in the article main form, we chose to present the table in the Supplementary material.
- Table 1 is very difficult to understand. It may be split into two tables, one regarding patient characteristics and the other related to adverse effects and treatment discontinuation data.
We thank the reviewer for this observation. Since there was a difficulty for comprehending the table and the data, we only included the basic patients’ characteristics instead.
- Multiple of the subanalysis of adverse effects show a very high heterogeneity. This problem is not analyzed adequately by the authors.
We thank the reviewer for this comment. We are not sure on which subanalysis you’re referring to. If your comment focuses on the subanalysis of the NOVA trial, considering older patients here is the explanation as heterogeneity is concerned:
“Considering the NOVA subanalysis [16], for niraparib’s efficacy towards elderly patients, only 61 out of 553 total patients enrolled in the study who received niraparib were older than 70 years of age (n=14 germline BRCA mutated and n=47 non-germline BRCA mutated). This discrepancy may be due to the clinician bias against assigning elderly patients in clinical trials. In this subanalysis, 2/3 out of the total treatment discontinuations among elderly patients happened due to grade 1 or grade 2 adverse effects. This explains why physicians and researchers sometimes avoid conducting studies in-cluding a great number of elderly patients. Despite of all these, we strongly believe in the reliability of our study and the certainty around its results, since all RCTs included a large population size.”
- Both forest plot graphs are difficult to analyze. For readers to interpret data, a solution should be thought of.
We thank the reviewer for this comment. Truth is that both forest plots included many details for numerous adverse effects. We tried fixing the issue, by splitting the forests plots into two pages so that they can be easily readable.
- Although it was initially designed for intervention Meta-analysis, I suggest authors evaluate their manuscript with the AMSTAR2 tool in order to improve certain details of their work.
We thank the reviewer for this comment. It is true that Rob 2.0 tool and AMSTAR2 tool are both newest revisions. We chose the RoB 2.0 tool for our study since it is most suitable for randomized, parallel-group trials. Following authors’ uninanimous decision, we thought that the included trials of our meta-analysis were easier to be rated by the assessment of Rob 2.0 tool
Reviewer 3 Report
Thank you very much for giving me the chance to review this article.
1- I am not sure that the article can be considered as a systematic review as you summarised the results of only 3 CRTs.
2- Line 43, these approaches present with a cumulative increase in taxicities provoking more harm than good, is not a citation from the cited reference!! Actually Pignata et. al. concluded an opposite result.
3- Line 70, reference 7 is even wrong. Here the approval of Niraparib has to be cited.
4- Line 125, you talked about three reviewers and mentioned only two.
5- In figure 2., it looks like placebo has more side-effects than Niraparib, please review it. The text in this figure is even not readable!
6- Mentioning the results of Olaparib in discussion is not appropriate as your review is not about PARPIs but only about Niraparib.
7- there are a lot of typing mistakes. please correct them.
Author Response
1- I am not sure that the article can be considered as a systematic review as you summarised the results of only 3 CRTs.
We thank the reviewer for this comment. There is no minimum number of trials to be included in a systematic review. In addition, we strongly believe in article’s high impact since a big number of patients is included in the analysis. As for the meta-analysis, at least two studies are required to sum-up the data and provide new evidence in the current knowledge.
2- Line 43, these approaches present with a cumulative increase in taxicities provoking more harm than good, is not a citation from the cited reference!! Actually Pignata et. al. concluded an opposite result.
We thank the reviewer for this observation. We deleted the phrase “provoking more harm than good” and the new phrase is now “However, these approaches present with some toxicities”.
3- Line 70, reference 7 is even wrong. Here the approval of Niraparib has to be cited.
We thank the reviewer for this comment. The approval of niraparib was based on data from the NOVA trial of March 2017. The correct reference is now added.
4- Line 125, you talked about three reviewers and mentioned only two.
We thank the reviewer for this comment. We replaced the sentence and added the third reviewer that assessed the risk of bias of our study.
“Risk of bias assessment was performed independently by 3 reviewers (A.P., A.P.A., I.M.); disagreements were resolved by consensus.”
5- In figure 2., it looks like placebo has more side-effects than Niraparib, please review it. The text in this figure is even not readable!
We thank the reviewer for this comment. Our meta-analysis results proved that any grade adverse effects are commonest among patients treated with niraparib, and not with placebo; a result that it is clearly presented in both meta-analysis forest plots. More specifically, results of figure 2 are thouroughly explained one by one in the results section of our meta-analysis (see paragraph 3.3. Meta-Analysis of Any Grade and Grade 3 or 4 Adverse Effects). The only any grade side effects for all three studies that were mostly seen in patients treated with placebo included diarrhea, abdominal pain, back pain and abdominal distention. However, these results were not statistically significant. This is analyzed in the methods section.
6- Mentioning the results of Olaparib in discussion is not appropriate as your review is not about PARPIs but only about Niraparib.
We thank the reviewer for this comment. Our study’s purpose is indeed the safety profile of niraparib. However, we thought it was of great importance just to briefly mention one of the other FDA approved PARPi, in the discussion session, just to note the similarities that were observed in the tolerability and toxicity profile.
7- there are a lot of typing mistakes. please correct them.
We thank the reviewer for this comment, and we apologize for the misspellings. The journal’s submission platform causes the errors, that were not made in the original article form. We addressed and corrected all the gramatical/vocabulary errors including the words separated by “-“incorrectly.
Reviewer 4 Report
Review for article: Manuscript ID: curroncol-1441071
Safety Profile of Niraparib as Maintenance Therapy for Ovarian Cancer:
A Systematic Review and Meta-Analysis
Niraparib, is an anti-cancer medication (poly(ADP-ribose) polymerase (PARP)) used for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer. The most common side effects include nausea, thrombocytopenia, tiredness and anemia, weakness, constipation, vomiting, insomnia , headache, lack of appetite, diarrhea,
dyspnea, hypertension , back pain, dizziness, cough, joint pain, hot flushes and decrease in white blood cells.
The aim of this study is to perform a systematic review and a meta-analysis of randomised controlled trials, on the safety of the single agent niraparib, as the maintenance therapy in patients with platinum-sensitive epithelial ovarian cancer, compared with placebo.
I feel to addressed the following minor points:
Point 1: Line 4-5. It is: “Antonia Pagkali MD1, Ioannis Mamais, BEng, MEng, MS, PhD 2, Adamantios Michalinos, MD, MS, PhD1, Aris P. Agouridis, MD, PhD1” and it should be: “Antonia Pagkali MD1, Ioannis Mamais, BEng, MEng, MS, PhD2, Adamantios Michalinos, MD, MS, PhD1, Aris P. Agouridis, MD, PhD1”;
Point 2: Line 6-7. It is:
“1School of Medicine, European University Cyprus, Nicosia, Cyprus
2Department of Health Sciences School of Sciences, European University Cyprus, Nicosia, Cyprus”
and it should be: “ 1School of Medicine, European University Cyprus, Nicosia, Cyprus
2Department of Health Sciences School of Sciences, European University Cyprus, Nicosia, Cyprus”;
Point 3: Line 21. It is: “neutro-penia” and it should be: “neutropenia”;
Point 4: Line 24. It is: “on-ly” and it should be: “only”;
Point 5: Line 26. It is: “epi-sodes” and it should be: “episodes”;
Point 6: Line 38. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “cancers.1” with “cancers [1].”);
Point 7: Line 40. It is: “ treat-ment” and it should be: “treatment”;
Point 8: Line 40. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “treat-ment.2” with “treatment [2].”);
Point 9: Line 43. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “surgery.2” with “surgery [2].”);
Point 10: Line 43. It is: “Howev-er” and it should be: “However”;
Point 11: Line 44. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “more harm than good.2” with “more harm than good [2].”);
Point 12: Line 46. Replace “was bevacizumab,3, 4” with “was bevacizumab [3, 4]”);
Point 13: Line 49. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “thromboembolism and proteinuria.5” with “thromboembolism and proteinuria [5].”);
Point 14: Line 55. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “therapeutic option.6” with “therapeutic option [6].”);
Point 15: Line 57. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “disease progression.6” with “disease progression [6].”);
Point 16: Line 60. It is: “plati-num” and it should be: “platinum”;
Point 17: Line 60. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “chemotherapy.7” with “chemotherapy [7].”);
Point 18: Line 62. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “dysregulation.7” with “dysregulation [7].”);
Point 19: Line 63. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “mutations.7” with “mutations [7].”);
Point 20: Line 65. It is: “pre-serving” and it should be: “preserving”;
Point 21: Line 65. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “functioning cells.8” with “functioning cells [8].”);
Point 22: Line 66-67. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “cancer.8” with “cancer [8].”);
Point 23: Line 68. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “toxicities.8” with “toxicities [8].”);
Point 24: Line 69. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “quality of life (QoL).8” with “quality of life (QoL) [8].”);
Point 25: Line 71. It is: “tri-als” and it should be: “trials”;
Point 26: Line 72. It is: “plati-num” and it should be: “platinum”;
Point 27: Line 78. It is: “in-cluded” and it should be: “included”;
Point 28: Line 83. It is: “ran-domised” and it should be: “randomised”;
Point 29: Line 84. It is: “re-trieved” and it should be: “retrieved”;
Point 30: Line 87. It is: “lan-guage” and it should be: “language”;
Point 31: Line 90. It is: “ni-raparib” and it should be: “niraparib”;
Point 32: Line 95. It is: “charac-teristics” and it should be: “characteristics”;
Point 33: Line 96. It is: “me-dian” and it should be: “median”;
Point 34: Line 97-98. It is: “admin-istration” and it should be: “administration”;
Point 35: Line 112. It is: “ini-tially” and it should be: “initially”;
Point 36: Line 120. It is: “alloca-tion” and it should be: “allocation”;
Point 37: Line 122. It is: “Accord-ing” and it should be: “According”;
Point 38: Line 126. It is: “by 3 reviewers (A.P., A.P.A.)” and it should be: “by 3 reviewers (A.P., A.P.A., and ? (you need to add a third person!)”;
Point 39: Line 126. It is: “disagree-ments” and it should be: “disagreements”;
Point 40: Line 133. It is: “anal-ysis” and it should be: “analysis”;
Point 41: Line 140. It is: “heteroge-neity” and it should be: “heterogeneity”;
Point 42: Line 144. It is: “anal-ysis” and it should be: “analysis”;
Point 43: Line 144. The period must be placed after the square brackets. A reference is made to this sentence. (Replace “in our analysis.10, 11” with “in our analysis [10,11].”);
Point 44: Line 147. Replace “In the NOVA trial,10” with “In the NOVA trial [10],”;
Point 45: Line 156. It is: “pe-riod” and it should be: “period”;
Point 46: Line 158. It is: “(200mg/day and 100 mg/day)” and it should be: “(200 mg/day and 100 mg/day)”;
Point 47: Line 162 – You need to write where the results are. What is the number of this drawing or table? Supplementary?
Point 48: Line 163. Replace “In the PRIMA study,11” with “In the PRIMA study [11],”;
Point 49: Line 165. It is: “ad-verse” and it should be: “adverse”;
Point 50: Line 166. It is: “popula-tion” and it should be: “population”;
Point 51: Line 171. It is: “300mg” and it should be: “300 mg”;
Point 52: Line 172. It is: “300mg/day” and it should be: “300 mg/day”;
Point 53: Line 173. It is: “indi-vidualized” and it should be: “individualized”;
Point 54: Line 174. It is: “either 300mg/day or 200mg/day” and it should be: “either 300 mg/day or 200 mg/day”;
Point 55: Line 175. It is: “300mg/day” and it should be: “300 mg/day”;
Point 56: Line 176. It is: “200mg/day” and it should be: “200 mg/day”;
Point 57: Line 176. It is: “<77kg” and it should be: “< 77 kg”;
Point 58: Line 177. It is: “<150,000μl” and it should be: “< 150,000 μl”;
Point 59: Line 178. It is: “treat-ment” and it should be: “treatment”;
Point 60: Line 180. It is: “de-creased” and it should be: “decreased”;
Point 61: Line 182. It is: “oc-curred” and it should be: “occurred”;
Point 61: Line 182 – You need to write where the results are. What is the number of this drawing or table? Supplementary?
Point 62: Line 185. It is: “ad-verse” and it should be: “adverse”;
Point 63: Line 190. It is: “neu-tropenia” and it should be: “neutropenia”;
Point 64: Line 191. It is: “300mg/day” and it should be: “300 mg/day”;
Point 65: Line 192. It is: “modifica-tion” and it should be: “modification”;
Point 66: Line 194. It is: “<77kg” and it should be: “< 77 kg”;
Point 67: Line 194. It is: “<150,000μl” and it should be: “< 150,000 μl”;
Point 68: Line 195. It is: “200mg/day” and it should be: “200 mg/day”;
Point 69: Line 196. It is: “>=150,000μl” and it should be: “>= 150,000 μl”;
Point 70: Line 196. It is: “300mg/day” and it should be: “300 mg/day”;
Point 71: Line 199. It is: “oc-curred” and it should be: “occurred”;
Point 72: Line 201 – You need to write where the results are. What is the number of this drawing or table? Supplementary?
Point 73: Line 203. Replace “Adverse effects were recorded in 3/3 studies10, 11,12” with “Adverse effects were recorded in 3/3 studies [10,11,12]”;
Point 74: Line 213. It is: “ad-verse” and it should be: “adverse”;
Point 75: Line 219. It is: “pa-tients” and it should be: “patients”;
Point 76: Line 221. It is: “(RR, 2.48; 95% CI, 1.52 to 2.89, p=0.0003)” and it should be: “(RR, 2.48; 95% CI, 1.52 to 4.05, p=0.0003)”;
Point 77: Line 222. It is: “nasopharyngi-tis” and it should be: “nasopharyngitis”;
Point 78: Line 224. I would add (Figure 2) at the end for better reader's tracking of the results. Figure 2 includes the data shown on lines 203-224;
Point 79: Figure 2 and Figure 3 are written in a very small font.If we read on the computer it is ok, if we print it it reads very badly.
Point 80: Line 237. It is: “ab-dominal” and it should be: “abdominal”;
Point 81: Line 250. I would add (Figure 3) at the end for better reader's tracking of the results. Figure 3 includes the data shown on lines 229-250;
Point 82: Line 253. It is: “place-bo” and it should be: “placebo”;
Point 83: Line 254. It is: “ni-raparib’s” and it should be: “niraparib’s”;
Point 84: Line 258. Replace “olaparib12-14 and rucaparib,15 are” with “olaparib [12-14] and rucaparib [15] are”;
Point 85: Line 264. Replace “In the retrospective analysis21” with “In the retrospective analysis [21]”;
Point 86: Line 265. It is: “<77kg” and it should be: “< 77 kg”;
Point 87: Line 266. It is: “<150,000μl” and it should be: “< 150,000 μl”;
Point 88: Line 266. It is: “pa-tients” and it should be: “patients”;
Point 89: Line 267. It is: “treatment efficacy21” and it should be: “treatment efficacy [21]”;
Point 90: Line 268. It is: “sub-analysis21” and it should be: “subanalysis [21]”;
Point 91: Line 270. It is: “200mg/day” and it should be: “200 mg/day”;
Point 92: Line 271. It is: “in-cluded” and it should be: “included”;
Point 93: Line 273. It is: “200mg/day” and it should be: “200 mg/day”;
Point 94: Line 275. It is: “300mg/day” and it should be: “300 mg/day”;
Point 95: Line 276. It is: “200mg/day” and it should be: “200 mg/day”;
Point 96: Line 276. It is: “300mg/day” and it should be: “300 mg/day”;
Point 97: Line 277. It is: “200mg/day” and it should be: “200 mg/day”;
Point 98: Line 278. It is: “ei-ther” and it should be: “either”;
Point 99: Line 279. It is: “200mg/day or 100mg/day” and it should be: “200 mg/day or 100 mg/day”;
Point 100: Line 280. It is: “pa-tients” and it should be: “patients”;
Point 101: Line 280. It is: “300mg/day” and it should be: “300 mg/day”;
Point 102: Line 282. It is: “300mg/day” and it should be: “300 mg/day”;
Point 103: Line 282. It is: “in-dividualized” and it should be: “individualized”;
Point 104: Line 283. It is: “200mg/day” and it should be: “200 mg/day”;
Point 105: Line 283. It is: “bod-yweight” and it should be: “bodyweight”;
Point 106: Line 287. It is: “ni-raparib” and it should be: “niraparib”;
Point 107: Line 296. It is: “re-duced” and it should be: “reduced”;
Point 108: Line 299. It is: “re-duced” and it should be: “reduced”;
Point 109: Line 303. It is: “A sub-analysis16” and it should be: “A subanalysis [16]”;
Point 110: Line 305. It is: “sub-analysis” and it should be: “subanalysis”;
Point 111: Line 306. It is: “mainte-nance” and it should be: “maintenance”;
Point 112: Line 308. The period must be placed after the square brackets. A reference is made to this sentence. It is: “the younger population.16” and it should be: “the younger population [16].”;
Point 113: Line 310. The period must be placed after the square brackets. A reference is made to this sentence. It is: “the younger population.17” and it should be: “the younger population [17].”;
Point 114: Line 313. It is: “ad-vantageous” and it should be: “advantageous”;
Point 115: Line 315. It is: “due to comorbidities.18 As for the sub-analysis of the NOVA trial,19 focusing” and it should be: “due to comorbidities [18]. As for the subanalysis of the NOVA trial [19], focusing”;
Point 116: Line 316. It is: “sub-analysis” and it should be: “subanalysis”;
Point 117: Line 317. It is: “ad-versely” and it should be: “adversely”;
Point 118: Line 319. It is: “can-cer” and it should be: “cancer”;
Point 119: Line 320. It is: “question-naire” and it should be: “questionnaire”;
Point 120: Line 321. It is: “questionnaires.19” and it should be: “questionnaires [19].”;
Point 121: Line 324. It is: “side effects.20” and it should be: “side effects [20].”;
Point 122: Line 331. It is: “disten-tion” and it should be: “distention”;
Point 123: Line 332. It is: “statis-tically” and it should be: “statistically”;
Point 124: Line 336. It is: “ther-apy” and it should be: “therapy”;
Point 124: Line 344. It is: “The meta-analysis of Guo et al.22” and it should be: “The meta-analysis of Guo et al. [22]”;
Point 125: Line 346-347. It is: “by Ruiz-Schutz et al.23” and it should be: “by Ruiz-Schutz et al. [23]”;
Point 126: Line 347. It is: “com-pared” and it should be: “compared”;
Point 127: Line 349. It is: “Another recent meta-analysis of Zhou et al.24” and it should be: “Another recent meta-analysis of Zhou et al. [24]”;
Point 128: Line 351. It is: “demon-strated” and it should be: “demonstrated”;
Point 137: Line 354. It is: “meta-analysis by Liu et al.25” and it should be: “meta-analysis by Liu et al. [25]”;
Point 129: Line 355. It is: “nau-sea” and it should be: “nausea”;
Point 130: Line 356. It is: “olaparib administration.8” and it should be: “olaparib administration [8].”;
Point 131: Line 358. It is: “statis-tically” and it should be: “statistically”;
Point 132: Line 363. It is: “homolo-gous” and it should be: “homologous”;
Point 133: Line 367. It is: “the NOVA sub-analysis16” and it should be: “the NOVA sub-analysis [16]”;
Point 134: Line 374. It is: “sub-analysis” and it should be: “subanalysis”;
Point 135: Line 381. It is: “servational study26, with a total of 153 pa-tients diagnosed” and it should be: “servational study [26], with a total of 153 patients diagnosed”;
Point 136: Line 384. It is: “200mg/day” and it should be: “200 mg/day”;
Point 137: Line 385. It is: “300mg/day” and it should be: “300 mg/day”;
Point 138: Line 388. It is: “200mg/day” and it should be: “200 mg/day”;
Point 139: Line 389. It is: “300mg/day” and it should be: “300 mg/day”;
Point 149: Line 398. It is: “pa-tient” and it should be: “patient”;
Point 140: Line 398-399. It is: “analysis28” and it should be: “analysis [28]”;
Point 141: Line 401. It is: “>=77kg” and it should be: “>=77 kg”;
Point 142: Line 401. It is: “>=150,000μl” and it should be: “>= 150,000 μl”;
Point 143: Line 403. It is: 300mg/day and 200mg/day” and it should be: “300 mg/day and 200 mg/day”;
Point 144: Line 404. It is: that ni-raparib 200mg/day” and it should be: “that niraparib 200 mg/day”;
Point 145: Line 412. It is: com-bination with bevacizumab28, 29 and” and it should be: “combination with bevacizumab [28, 29] and”;
Point 146: Line 413. It is: with pembrolizumab30.” and it should be: “with pembrolizumab [30].”;
Point 147: Line 416. It is: man-ageable” and it should be: “manageable”;
Point 148: Line 419. It is: ad-ministration” and it should be: “administration”;
Point 149: Please standardize and analyze the literature. Note positions 3, 12 (there is a free position), 26 (there is also a free position).
The meta-analysis is performed correctly.
The authors put a lot of work into writing and analyzing it.
Author Response
We thank the reviewer for his kind words and for taking the time to address the following issues, line by line. We apologize for all the misspellings. It is the journal’s submission platform that caused some of the mistakes, which were not made in the original article form. We addressed and corrected all the grammatical/vocabulary errors including the words separated by “-“incorrectly. In addition, both forest plots included many details for numerous adverse effects. We tried fixing the issue, since figures were not readable, by splitting the forests plots into two pages so that they can be better seen. In addition, line 315 is now “Risk of bias assessment was performed independently by 3 reviewers (A.P., A.P.A., I.M.)”, since we forgot to mention the third person that performed the risk of bias. Moreover, considering the references, all the periods are placed after the brackets. References at the references’ section are now corrected
We also made the following corrections
Line 536 It is now “(RR, 2.48; 95% CI, 1.52 to 4.05, p=0.0003)” instead of “(RR, 2.48; 95% CI, 1.52 to 2.89, p=0.0003)”
Line 539 We now added the reference (Figure 2) for better reader’s tracking of the results.
Line 576 We now added the reference (Figure 3) for better reader’s tracking of the results.
Round 2
Reviewer 2 Report
The authors have addressed most of the points suggested in the first review.
Nevertheless, there are some important aspects still missing.
- Prospero registration number should be stated in the manuscript.
- The reasons why not including other studies not Phase 3 randomized trials should be described in the manuscript according to AMSTAR2 tool.
- Risk of bias assessment results should be included in the result section. At least with a reference to the Supplementary section.
- Multiple of the analysis of Adverse effects present High heterogeneity. For example: Anemia I2 84%, Thrombocytopenia I2 96%, Neutropenia I2 93%. This type of heterogeneity has to be addressed in order to adequately interpret results.
Author Response
Thank you again for your comments and suggestions.
1. Prospero registration is now included in the manuscript, as advised.
Line 87: " The protocol was registered with the international prospective register of systematic reviews (PROSPERO), in accordance with PRISMA-P guidelines (PROSPERO CRD42021286446)."
2. AMSTAR2 tool was also included in our study, as advised.
Line 121: "According to the ARMSTAR2 tool [10], in order to appraise this systematic review of randomised controlled clinical trials, our study was identified as a high-quality review paper. "
3. Risk of bias, with a reference to the supplementary figure, is now included in the results section.
Line 144: "The study is categorized as low risk of bias, implying confidence that results represent true treatment and adverse effects. Findings are likely to be reliable, since no major or minor sources of bias are likely to influence our results, supporting our conclusions by evidence (Supplementary Figure 1)."
4. Since many of "any grade" adverse effects present high heterogeneity, we agree with the fact that they need to be included in our discussion section.
Line 352: "What needs to be addressed is the fact that numerous any grade adverse effects of our analysis present with high heterogeneity, such as anemia (I2 84%, p=0.002), thrombocytopenia (I2 96%, p=0.00001), neutropenia (I2 93%, p<0.00001), decreased apetite (I2 77%, p=0.04), and back pain (I2 73%, p=0.05). Due to this heterogeneity, we opted to use the random effect model, that calculates more conservatively confidence intervals, rather than the fixed effect model does. This high heterogeneity is attributed mainly to the clinical differences between Caucasian and Asian population and earlier termination of the NORA[13] trial. "
Reviewer 3 Report
Thank you for considering all the reviewers points.
Author Response
We thank you for the time you allocated to review our paper.
Round 3
Reviewer 2 Report
Changes have been done.
