Efficacy and safety of Xuebijing injection for radiation pneumonitis: A meta-analysis.

BACKGROUND: Currently, the treatment of radiation pneumonitis (RP) remains a clinical challenge. Although glucocorticoids are used for RP treatment, they have associated side effects. Xuebijing injection (XBJ) has been widely used for RP treatment in China, but so far no meta-analysis has evaluated its efficacy and safety.
METHODS: PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure, WANFANG database, SinoMED, and China Science and Technology J Database were searched for randomized controlled trials related to XBJ in RP treatment. Two researchers independently conducted literature screening, data extraction, and risk of bias assessment. The outcomes were synthesized and analyzed using the Cochrane Review Manager (RevMan 5.3) software, and a forest plot generated. RESULT: Eight articles met the eligibility criteria for further data extraction and meta-analysis. A total of 578 patients with RP participated in these studies, including 296 in the experimental group (XBJ+BT), and 282 in the control group (BT). The results of the meta-analysis revealed that compared to the BT group, XBJ+BT significantly increased the total effective rate (n = 578; RR = 1.45, 95% CI: 1.30 to 1.61, p<0.0001), and IL-10 expression (n = 296; MD = 17.62, 95% CI:13.95 to 21.29, p<0.00001), decreased interleukin-6 (IL-6) expression (n = 296; MD = -21.56, 95% CI:-27.37 to -15.76, p<0.00001), that of tumor necrosis factor alpha (n = 246; MD = -25.63, 95% CI:-30.77 to -20.50, p<0.00001), and that of C-reactive protein (n = 296; MD = -48.61, 95% CI:-56.49-40.73, p< 0.00001).
CONCLUSION: Based on our results, we do not recommend XBJ as an adjuvant treatment for RP. Further randomized controlled trials with rigorous design, strict implementation, and standard reporting are needed to further evaluate the efficacy and safety of XBJ for RP treatment. SYSTEMATIC REVIEW REGISTRATION: INPLASY registration number: INPLASY2020120037.

Introduction

Radiation therapy (RT) is traditionally regarded as a method for local tumor treatment [1]. It is estimated that 10–30% of patients with thoracic malignant tumors receiving radiation therapy develop radiation-induced lung injury (RILI) [2], which consists of two stages: radiation pneumonitis (RP) and radiation pulmonary fibrosis (RF). Once RF is reached, the condition is almost irreversible; therefore, the treatment of RP is particularly important. Patients with RILI may experience progressive dyspnea, worsening lung function, and respiratory failure, eventually leading to death [3]. Currently, clinical treatment is not required for asymptomatic RP. The treatment of symptomatic RP with CTCAE 4.0 grade ≥2 includes glucocorticoids, antibiotics, oxygen, symptomatic treatment, and mechanical ventilation support, if necessary [4]. However, a large dose of glucocorticoids can easily induce or aggravate infections, leading to osteoporosis, digestive and cardiovascular complications, and increased intraocular pressure [5, 6], which affect the patients’ quality of life.

In China, traditional Chinese medicine (TCM) treatment is under the guidance of unique Chinese medical theories, which has a history of thousands of years to prevent and treat diseases. TCM treatment, as one of complementary and alternative medicine (CAM), includes Chinese medicine decoction, Chinese patent medicine, traditional Chinese medicine (TCM) injection, acupuncture, Tai Chi and so on. In the treatment of RP, TCM treatment can also improve symptoms such as cough, wheezing, and fever, which has gradually attracted the researchers’ attention [7]. Xuebijing injection (XBJ) is one of TCM injections commonly used in clinical prescriptions in China. Its main components are Carthami flos, Radix paeoniae rubra, Angelicae sinensis radix, and Radix salviae chuanxiong [8]. These herbs can activate blood circulation, and resolve blood stasis, and detoxification, and are used to relieve fever, heart palpitations, wheezing, other stasis symptoms, and the toxic mutual syndrome caused by systemic inflammatory response syndrome [9, 10].

A number of randomized controlled trials (RCTs) have indicated that XBJ combined with basic treatment (BT) could be advantageous for RP treatment [11, 12]. However, there is a lack of reliable evidence-based medicine, and questions about its effectiveness and safety have not been accurately answered. Therefore, the main purpose of our meta-analysis was to: (1) evaluate the efficacy of XBJ in the treatment of RP compared with basic medical treatment methods and (2) evaluate the safety of the clinical use of XBJ.

Methods

Protocol registration

The study protocol was registered on INPLASY (ID:INPLASY2020120037, https://inplasy.com/inplasy-2020-12-0037/)) and previously published [13]. This meta-analysis was implemented based on the Preferred Reporting Items for Systematic Review and Meta-analyses Statement (PRISMA) [14].

Eligibility criteria

Type of studies

Only RCTs associated with XBJ for RP treatment were included. Other studies, such as animal experiments, case reports, reviews, cohort studies, case-control studies, and commentaries were excluded.

Type of participants

Participants >18 years of age who were clinically, pathologically, or histologically diagnosed with RP were included. Participants with chronic bronchitis, chronic obstructive pulmonary disease, RF, acute infectious disease, severe heart disease, and KPS<60 were excluded. Gender, nationality, and ethnicity were not restricted.

Type of interventions

The interventions were divided into two groups: the control group (BT) and the experimental group (BT and XBJ, XBJ+BT). The former contained glucocorticoids along with bronchodilators, antibiotics, oxygen therapy, and respiratory support therapy when necessary. The latter included XBJ and the interventions in the control group. There were no restrictions on dosage, intervention time, or pharmaceutical provider.

Type of outcome

The primary outcome was the total effective rate, which equaled the ratio of patients cured and improved to the total number of patients [15]. The clinical efficacy evaluation includes cure, improvement and failure. Cure: all clinical symptoms disappeared and lung CT examination showed that pulmonary inflammation was completely absorbed; improvement: most of clinical symptoms disappeared and lung CT examination showed that pulmonary inflammation was partially absorbed but there were some fibrous shadows; failure: clinical symptoms did not disappear and lung CT examination showed that the pulmonary inflammation was not absorbed and extensive fibrous shadow distribution was seen and even respiratory failure occurred.

Secondary outcomes were inflammatory cytokines, including interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and the incidence of adverse events (AEs).

Search strategy

The following seven electronic databases were searched: PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), WANFANG database, SinoMED, and China Science and Technology J Database. The search time included from the beginning of these libraries to May 1, 2021. There were no language limitations. In addition, two clinical trial registry websites (http://www.chictr.org and http://www.clinicaltrials.gov) were also searched for unpublished clinical trials. The search keywords were: radiation pneumonitis, Xuebijing injection, and randomized controlled trial; for more details, see Table 1.

Table 1

Search strategy for PubMed.

Number	Search terms
#1	Radiation Pneumonitis[MESH]
#2	(Radiation Pneumonitides) OR (Pneumonitides, Radiation) OR (Pneumonia, Radiation) OR (Pneumonias, Radiation) OR (Radiation Pneumonias) OR (Pneumonitis, Radiation) OR (Radiation Pneumonia) OR (Fibrosis, Radiation) OR (Radiation Fibrosis) OR (Radiation induced lung injury) OR (Radiation induced pneumonitis)
#3	(XUEBIJING) OR (XUE-BI-JING) OR (XUEBIJING injection) OR (XUE-BI-JING injection)
#4	(Randomized Controlled Trials[Mesh])OR(Clinical Trials, Randomized) OR (Trials, Randomized Clinical) OR (Controlled Clinical Trials, Randomized) OR (RCT)
#5	#1 AND #2 AND #3 AND #4

Study selection

Two reviewers independently conducted the study selection process. Study titles were screened and duplicates eliminated using NOTEEXPRESS software (version 3.0). Then, abstracts and articles were carefully read, and studies not conforming to the eligibility criteria were removed. In case of disagreement during the process, a third reviewer helped with the evaluation.

Data extraction

Data were independently extracted from the preliminary articles screened by two reviewers. Any disagreement should be resolved in consultation with a third reviewer. The extracted data included the first author’s name, publication year, country, sample size, patient characteristics, intervention measures, primary and secondary outcomes, and adverse events. Missing data were obtained, if possible, by contacting the original author.

Risk of bias assessment

The “risk of bias assessment tool” of the Cochrane Handbook was applied to evaluate the risk of bias of the included articles [16]. Any objections were resolved through discussion or negotiation with a third reviewer. The assessment criteria were as follows: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other biases.

Data analysis

Review Manager software (version 5.3) was used for data processing. The total effective rate was expressed as the risk ratio (RR) with a 95% confidence interval (95% CI). Inflammatory cytokines are shown as mean difference (MD) with 95% CI. The I2 value was applied to assess heterogeneity, and a fixed-effects model used if I 2 < 50%. If I2>50%, the random-effects model was employed, and the source of heterogeneity was explored by subgroup and sensitivity analyses. If >10 articles were included, a stratified analysis was conducted according to intervention measures and participants’ characteristics. In the sensitivity analysis, every study was deleted one-by-one to observe the impact on the overall results.

Publication bias

If there were >10 articles for analysis, a funnel plot was generated to evaluate publication bias [17].

Results

According to the search strategy, a total of 50 relevant articles were initially screened in seven electronic databases. After removing 35 duplicates using NOTEEXPRESS software, 15 articles remained. By carefully reading the abstracts and full texts, seven articles were removed for the following reasons: animal study (n = 1), wrong study design (n = 4), wrong participants (n = 1), and wrong outcomes (n = 1). Finally, eight articles [18-25] met the eligibility criteria for further data extraction and meta-analysis. Fig 1 illustrates the study selection process.

Fig 1

Flow chart of study selection process.

Study characteristics

Table 2 shows the characteristics of the eight RCTs included in this study. All of them were conducted in China, and all patients were Chinese. A total of 578 patients with RP participated in these studies, including 296 in the XBJ+BT group and 282 in the BT group. There were 334 male and 224 female patients with ages ranging from 45 to 60 years. Sample sizes varied from 48 to 140. In the BT group, the main treatment was hormonal, and antibiotics were administered in case of infection. Nutritional support, bronchodilators, and oxygen support were provided when necessary. Prednisone was reported in six articles [18–21, 23, 25], five [18–21, 23] of which were administered at 40–60 mg per day with an unknown administration route, while one [25] administered 30 mg orally three times per day. The XBJ dosage was 100 mL in six articles [18–21, 23, 25] and 50 mL in two [22, 24]. XBJ duration was 14 days in seven articles, but not in one study [24]. All studies reported the total effective rate. CRP, IL-6, and IL-10 were reported in five studies [18, 19, 21, 22, 25], and TNF-α in four [18, 19, 21, 22]. None of the eight studies reported adverse events.

Table 2

Study characteristics.

First Author	Publication Year	Country	Sample Size (X/B)	Gender (M/F)	Age (X/B)	Basic Treatment (BT)	Xue-Bi-Jing (XBJ+BT)	Dosage of XBJ	Duration of XBJ (days)	Outcomes	Adverse event report
Yang et al	2013	China	48 (25/23)	28/20	X:51.20±10.20B:50.20±9.50	prednisone (40-60mg/d)、antibiotics、oxygen therapy、bronchodilators、nutrition support、normal saline (placebo)	XBJ+BT	100mL, bid	14d	Total effective rate, CRP, IL-6、IL-10, TNF-α	No
Yang	2015	China	52 (26/26)	31/21	X:50.14±3.23B:52.36±3.35	prednisone (40-60mg/d)、antibiotics、oxygen therapy、bronchodilators、nutrition support	XBJ+BT	100mL, bid	14d	Total effective rate, CRP, IL-6、IL-10, TNF-α	No
Zhao	2016	China	140 (70/70)	68/72	X:48.10±3.54B:46.90±4.05	prednisone (40-60mg/d)、nutrition support、 oxygen therapy	XBJ+BT	100mL, bid	14d	Total effective rate	No
Zhai et al	2016	China	78 (39/39)	46/32	X:52.60±3.50B:50.80±3.20	glucocorticoid 、nutrition support 、 antibiotics、oxygen therapy、bronchodilators	XBJ+BT	50mL, bid	14d	Total effective rate, CRP, IL-6、IL-10, TNF-α, Temperature, WBC	No
Xu	2016	China	68 (34/34)	39/29	X:47.10±3.80B:47.20±3.60	prednisone (40-60mg/d)、antibiotics、oxygen therapy、bronchodilators、nutrition support	XBJ+BT	100mL, bid	14d	Total effective rate, CRP, IL-6、IL-10, TNF-α	No
Gu	2016	China	74 (37/37)	53/21	57.30±9.40	prednisone (40-60mg/d)、antibiotics、oxygen therapy、bronchodilators、nutrition support	XBJ+BT	100mL, bid	14d	Total effective rate, CD4、CD8、CD4/CD8	No
Shi	2017	China	50 (30/20)	30/20	X:52.60±1.80B:52.50±1.50	prednisone (30mg po tid)、oxygen therapy、antibiotics、nutrition support、normal saline (placebo)	XBJ+BT	100mL, bid	14d	Total effective rate, CRP, IL-6、IL-10	No
Kang et al	2017	China	68 (35/33)	39/29	X:55.70±4.30B:51.70±5.60	methylprednisolone sodium succinate (80-120mg ivgtt)、antibiotics	XBJ+BT	50mL, bid	-	Total effective rate, WBC, PLT, Neutrophil, HB	No

Note: Basic Treatment: BT; X: XBJ+BT; B: BT; M: Male; F: Female; bid: two times a day; tid: three times a day; WBC: white blood cell; PLT: platelet; HB: hemoglobin.

Risk of bias

Five studies [19, 21, 23–25] declared random sequence generation, four [21, 23–25] of which used a random number table, and one [19] the sortition randomization method, so these had low risks. Two trials [18, 20] did not describe random sequence generation, so the risk of bias was regarded as high. Only one trial [22] mentioned a random method but did not describe how random sequences were generated, so the risk of bias was assessed as unclear. All studies had high risks because none described allocation concealment, nor the blinding method. For incomplete outcome data, all studies had a low risk of bias. For selective outcome reporting and other biases, there was no registered protocol or information from the authors, so the risks of bias of all studies were assessed as unclear. Fig 2 shows the risk of bias in all included studies.

Fig 2

The risk of bias of all included studies.

The red represents high risk; the green represents low risk; the yellow represents unclear risk.

Outcome

Primary outcome: Total effective rate

All studies did an objective assessment for RP by the clinical symptoms and the results of lung CT examination according to the clinical efficacy evaluation. The results of the meta-analysis revealed that compared with BT, XBJ+BT significantly increased the total effective rate (n = 578; RR = 1.45, 95% CI: 1.30 to 1.61, p<0.0001, Fig 3A) using the fixed-effects model (heterogeneity: χ2 = 0.95, I2 = 0%, p = 1.00).

Fig 3

A. Forest plot of total effective rate of meta-analysis of XBJ+BT group VS BT group. CI: confidence interval. Risk Ratio was the effect size. We made Mantel–Haenszel (M-H) fixed-effects. B. Forest plot of IL-6 expression of meta-analysis of XBJ+BT group VS BT group. CI: confidence interval. Mean Difference was the effect size. We made inverse variance (IV) fixed-effects. C. Forest plot of IL-10 expression of meta-analysis of XBJ+BT group VS BT group. CI: confidence interval. Mean Difference was the effect size. We made inverse variance (IV) fixed-effects. D. Forest plot of TNF-α expression of meta-analysis of XBJ+BT group VS BT group. CI: confidence interval. Mean Difference was the effect size. We made inverse variance (IV) fixed-effects. E. Forest plot of CRP expression of meta-analysis of XBJ+BT group VS BT group. CI: confidence interval. Mean Difference was the effect size. We made inverse variance (IV) fixed-effects.

Secondary outcomes

IL-6. IL-6 expression was reported in five studies [18, 19, 21, 22, 25]. The results showed that compared to BT, XBJ+BT significantly decreased the expression level of IL-6 (n = 296; MD = -21.56, 95% CI:-27.37 to -15.76, p<0.00001, Fig 3B) using the fixed-effects model (heterogeneity: χ2 = 0.06, I2 = 0%, p = 1.00).

IL-10. Five studies [18, 19, 21, 22, 25] evaluated IL-10 expression. The results of the fixed-effects (heterogeneity: χ2 = 0.32, I2 = 0%, p = 0.99) meta-analysis model showed that XBJ+BT significantly increased IL-10 expression in comparison to BT (n = 296; MD = 17.62, 95% CI:13.95 to 21.29, p<0.00001, Fig 3C).

TNF-α. Four trials [18, 19, 21, 22] analyzed TNF-α levels. In contrast to BT, the fixed-effects model (heterogeneity: χ2 = 0.09, I2 = 0%, p = 0.99) showed a significant decrease of TNF-α expression in XBJ+BT (n = 246; MD = -25.63, 95% CI:-30.77 to -20.50, p<0.00001, Fig 3D).

CRP. Five trials [18, 19, 21, 22, 25] assessed CRP expression. Compared with BT, the level of CRP was significantly decreased in XBJ+BJ (n = 296; MD = − -48.61, 95% CI: − -56.49, − -40.73, p<0.00001, Fig 3E), without significant heterogeneity (χ2 = 0.03, I2 = 0%, p = 1.00).

AEs. As none of these trials reported AEs, we could not perform this meta-analysis.

Publication bias. Because there were less than10 articles for meta-analysis, a funnel plot to evaluate publication bias was not generated. In order to evaluate publication bias more accurately, egger test, a quantitative analysis method was performed by stata software (Version 15). The results showed that p-value was equal to 0.845, indicating that the risk of publication bias was low.

Discussion

XBJ is a TCM injection that was approved by the State Food and Drug Administration (China FDA) in 2004 and is mainly used in systemic inflammatory response syndrome and sepsis in China. XBJ is a combination of Carthamus tinctorius flowers (Honghua in Chinese), Paeonia lactiflora roots (Chishao), Ligusticum chuanxiong rhizomes (Chuanxiong), Angelica sinensis roots (Danggui), and Salvia miltiorrhiza roots (Danshen). The main components of XBJ detected by ultra-high performance liquid chromatography include Hydroxysafflor yellow A, Oxypaeoniflorin, Senkyunolide I and Benzoylpaeoniflorin [26]. Studies have shown that XBJ mainly inhibits the activation of inflammatory pathways by inhibiting TNF-α, IL-1, IL-6, IL-8, IL-17 and PAR-1 and improves coagulation dysfunction in sepsis [27-29]. There is evidence that XBJ has high safety, mild adverse reactions and good outcomes when used reasonably in clinical practice [30].

To the best of our knowledge, this is the first meta-analysis of RCTs on XBJ for the treatment of RP. In this study, eight RCTs were screened and included in the quantitative synthesis, with a total of 578 participants, including 296 in the XBJ+BT group and 282 in the BT group. Based on current clinical evidence, the results of this meta-analysis indicate that XBJ+BT significantly increased the total effective rate, IL-10, and decreased IL-6, TNF-α, and CRP levels compared to BT. Since no AEs were reported in any trials, the safety of XBJ for RP treatment remains unclear. Furthermore, according to these RCTs, the recommended XBJ dosage was 100 mL for 14 days, and the prednisone dosage 40–60 mg per day for 14 days.

TNF-α is a cytokine that initiates inflammatory responses. Research [31] suggests that TNF-α is involved in the formation of RP and early reduction of TNF-α level can alleviate RP. IL-6 is a inflammatory factor secreted by Th2 cells. Current study suggests that the expression of IL-6 in the serum of patients with RP is significantly increased, which can be used as a predictive indicator for RP [32]. It has been reported that concentration of CRP is a very sensitive and effective indicator for judging the occurrence, development and prognosis of patients with RP [33]. IL-10 is known as cytokine synthesis inhibitor. IL-10 can inhibit the expression of inflammatory factors such as TNF, IL-6, and IL-1 through activated macrophages. As the most important anti-inflammatory cytokine in the body, its early expression in RP acts as a negative feedback to inhibit the occurrence of RP [34]. Our results showed that XBJ+BT significantly decreased pro-inflammatory factors such as IL-6, TNF-α and CRP levels and increased anti-inflammatory cytokine IL-10 to alleviate RP compared to BT.

For heterogeneity, we conducted forest plot from which we may find that the heterogeneity was low as I2 value < 50%. Nonetheless, for the degree of heterogeneity of each study, sensitivity analysis as well as changing the model was also implemented to evaluate in depth. First of all, each study was removed one by one to estimate whether the results could have been affected. The results showed that I2 was less than 50% for any one study, suggesting that the heterogeneity of each study was low. Then, the fixed-effects model was changed to the random-effects model and the p-value was consistent and without apparent fluctuation, suggesting that the heterogeneity of each study was low. So we believed that this analysis confirmed the stability of our results.

Limitations

There were some limitations to this study. It is well known that in CAM clinical trials, poor methodological quality exists [35]. All trials had a high risk of bias. None of the included studies described how allocation concealment was performed, whether blinding was implemented, and what kind of blinding method was employed. In terms of reporting bias, whether there was reporting bias was not clear because no protocol or information could be found for reference. As a result, all trials were of low quality. Even after conducting the meta-analysis, the results were not convincing.

Despite a comprehensive search of seven English and Chinese databases, including PubMed and CNKI, as well as clinical trial registries, there may be studies meeting the inclusion criteria that were not included. In addition, the eight included trials were all written in Chinese, so it was difficult to avoid the possibility of selective bias.

Moreover, the occurrence of AEs during the TCM treatment process should be paid close attention to. AEs caused by TCM injections have also been reported. In this study, we considered the occurrence of AEs as a secondary outcome, but unfortunately, none of the eight included trials clearly showed whether AEs occurred or not.

Conclusion

Based on the present results, we do not recommend XBJ as an adjuvant treatment for RP. However, we think that XBJ has the potential as an adjuvant treatment for RP. Therefore, future randomized controlled trials with rigorous design, strict implementation, and standard reporting are be needed to further evaluate the efficacy and safety of XBJ in the adjuvant treatment of RP.

PRISMA 2009 checklist.

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INPLASY protocol.

The Efficacy and Safety of Xuebijing Injection in the Treatment of Radiation Pneumonitis: A Protocol for Systematic Review and Meta-Analysis.

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24 Feb 2022

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Reviewer #1: thorough review of the literature. data and analysis sound.

appreciate the authors despite the favorable data to realize that the limitations of the current literature.

conclusion drawn from meta analysis is sound

Reviewer #2: This manuscript is easily readable, concise, and well-written. However, as you stated in Limitations section, all trials which included in this meta-analysis had a high risk of bias. None of the included studies described how allocation concealment was performed, whether blinding was implemented, and what kind of blinding method was employed. In terms of reporting bias, whether there was reporting bias was not clear because no protocol or information could be found for references. As a result, all trials were of low quality. Therefore, we cannot acquire any meaningful conclusions from these trials. You should conduct the meta-analysis with high quality trials. If there is no high quality trials in certain clinical field, there is no point to carry out the meta-analysis. Conclusions of this study has no credibility.

Reviewer #3: The manuscript submitted by the authors describe about the metaanalysis of 8 studies describing an agent Xuibijing as a radiation protector against radiation pneumonitis.

The authors have only taken randomised clinical trial for the purpose of metananalysis and have omitted studies which were preclinical in nature and studies which were retrospective.

The authors have followed the PRISMA guidelines for the metaanalysis and have properly done the risk bias assessment of all the studies as represented by the traffic light plot.

The authors have used appropriate statististical tests for analysing the data from the RCT’s.

Although the forest plots show a favourable response with the use of the experimental drug in terms of various diagnostic metrics, even then the authors do not recommend the use of the agent in question for radiation pneumonits.

The manuscript is well written and adheres strictly to the guidelines for reporting meta-analysis. Even though the metaanalysis can be termed as negative against the use of the experimental agent, I would still recommend the publication of the study after major modifications.

Comments

1. The authors in the discussion section need to elaborate a bit more on this agent as its mechanism of action, its pharmacology, kinetics and its toxicities have not been extensively reported given that it is a Chinese medicine and the readers outside China will not have much knowledge about it.

2. What is a bit surprising to me is that the clinical end points and majority of the biological markers (inflammatory cytokines) showed an improvement on the use of combination of the experimental drug + conventional therapy as opposed to the conventional therapy alone except for IL10 which is a proinflammatory cytokine which showed an increased levels which is a bit counterintuitive? An explanation needs to b e give regarding this phenomenon in the discussion section.

3. In the methodology section: the authors should write in detail if any of the studies did an objective assessment for radiation pneumonitis.

4. The authors have shown in their forest plots the results of the RCT’s favouring the use of xuibijing against RP as none of the plots were straddling the unity line. However, based on the limitation s of the RCT’s, the authors in their concluding remarks have not recommended the use of this agent against RP. I would expect the authors to clearly annotate the forest plots and expand the legends of figure 3. I would also want the authors to clearly mention the diagnostic metrics they used in the forest plots.(was it the Hazard ratio or the odds ratio?)

5. The authors also mention that none of the studies mentioned anything about AE’s & SAE’s in the limitation of the studies. In this last paragraph, the authors mention about TCM injection. The authors write in detail what TCM stands for as it has not been mentioned previously in the manuscript.

6. The authors mentioned that they did not do a funnel plot as the number of studies were less than 10. However, it will be worthwhile to do the HSROC curves to depict the extent of heterogeinity of each study.

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Reviewer #3: No

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Submitted filename: PLOS one review _JSG.docx

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30 Apr 2022

Dear Editors and Reviewers,

Thanks very much for taking your time to review this manuscript. We really appreciate all your comments and suggestions!These suggestions have enabled us to improve our work. The comments are reproduced and our responses are given directly afterward in a different color (in blue). We would like also to thank you for allowing us to resubmit a revised copy of the manuscript.

Suggestions from reviewers:

Reviewer #1: thorough review of the literature. data and analysis sound.appreciate the authors despite the favorable data to realize that the limitations of the current literature.conclusion drawn from meta analysis is sound

Reply to reviewer #1: We appreciate your careful review and approval of our manuscript.

Reviewer #2: This manuscript is easily readable, concise, and well-written. However, as you stated in Limitations section, all trials which included in this meta-analysis had a high risk of bias. None of the included studies described how allocation concealment was performed, whether blinding was implemented, and what kind of blinding method was employed. In terms of reporting bias, whether there was reporting bias was not clear because no protocol or information could be found for references. As a result, all trials were of low quality. Therefore, we cannot acquire any meaningful conclusions from these trials. You should conduct the meta-analysis with high quality trials. If there is no high quality trials in certain clinical field, there is no point to carry out the meta-analysis. Conclusions of this study has no credibility.

Reply to reviewer #2: Thank you for your support of our manuscript. We agree with you that all of the trials you mentioned have a high risk of bias. We followed the PRISMA guidelines for the meta-analysis and have rigorously performed the risk bias assessment of all the trial. It is for this reason that we do not recommend XBJ as a treatment for RP, despite the good results shown by the forest plot. We are also concerned that the conclusions drawn are inaccurate due to the high risk of bias. But we think this article is still relevant.The first is that based on the rigorous process of evaluation, we do not recommend XBJ for RP treatment. Second, due to the lack of more effective drugs with less side effects to treat RP, XBJ has still some potential in the treatment of RP. Third, this paper provides some ideas and references for more rigorous clinical trials in the future, so as to obtain high-quality clinical evidence.

Reviewer #3: The manuscript submitted by the authors describe about the metaanalysis of 8 studies describing an agent Xuibijing as a radiation protector against radiation pneumonitis.

The authors have only taken randomised clinical trial for the purpose of metananalysis and have omitted studies which were preclinical in nature and studies which were retrospective.

The authors have followed the PRISMA guidelines for the metaanalysis and have properly done the risk bias assessment of all the studies as represented by the traffic light plot.

The authors have used appropriate statististical tests for analysing the data from the RCT’s.

Although the forest plots show a favourable response with the use of the experimental drug in terms of various diagnostic metrics, even then the authors do not recommend the use of the agent in question for radiation pneumonits.

The manuscript is well written and adheres strictly to the guidelines for reporting meta-analysis. Even though the metaanalysis can be termed as negative against the use of the experimental agent, I would still recommend the publication of the study after major modifications.

Reply to reviewer #3: Thank you for your patience in reviewing our manuscript and itemizing key points in our manuscript. We will revise according to the comments in order to improve our manuscript and meet the requirements of the journal.

Comments to the author

1. The authors in the discussion section need to elaborate a bit more on this agent as its mechanism of action, its pharmacology, kinetics and its toxicities have not been extensively reported given that it is a Chinese medicine and the readers outside China will not have much knowledge about it.

Answer: Sure. We added more information about XBJ in the discussion part to let researchers and readers better know XBJ.

2. What is a bit surprising to me is that the clinical end points and majority of the biological markers (inflammatory cytokines) showed an improvement on the use of combination of the experimental drug + conventional therapy as opposed to the conventional therapy alone except for IL10 which is a proinflammatory cytokine which showed an increased levels which is a bit counterintuitive? An explanation needs to b e give regarding this phenomenon in the discussion section.

Answer: Thank you for pointing this phenomenon out. Let us explain this phenomenon. IL-10 is known as cytokine synthesis inhibitor. IL-10 can inhibit the expression of inflammatory factors such as TNF, IL-6, and IL-1 through activated macrophages. As the most important anti-inflammatory cytokine in the body, its early expression in RP acts as a negative feedback to inhibit the occurrence of RP. So, IL-10 is a kind of anti-inflammatory cytokines which is different from other pro-inflammatory factors such as IL-6, TNF and IL-1, etc. XBJ+BT significantly decreased pro-inflammatory factors such as IL-6, TNF-α and CRP levels and increased anti-inflammatory cytokine IL-10 to alleviate RP compared to BT.

3. In the methodology section: the authors should write in detail if any of the studies did an objective assessment for radiation pneumonitis.

Answer: Thank you for mentioning this key point. We added the clinical efficacy evaluation in ‘the type of outcome’ part. We also mentioned that all studies did an objective assessment for RP by the clinical symptoms and the results of lung CT examination according to the clinical efficacy evaluation in the ‘outcome’ part.

4. The authors have shown in their forest plots the results of the RCT’s favouring the use of xuibijing against RP as none of the plots were straddling the unity line. However, based on the limitation s of the RCT’s, the authors in their concluding remarks have not recommended the use of this agent against RP. I would expect the authors to clearly annotate the forest plots and expand the legends of figure 3. I would also want the authors to clearly mention the diagnostic metrics they used in the forest plots.(was it the Hazard ratio or the odds ratio?)

Answer: Thank you for your attention to the details of the forest plot. We apologized for not annotating the forest plot clearly. We re-annotated the forest plot and expanded the legend of Figure 3. For the total effective rate，risk ratio (RR) was used as effect size. For cytokines or inflammatory factors，mean difference (MD) was the effect size.

5. The authors also mention that none of the studies mentioned anything about AE’s & SAE’s in the limitation of the studies. In this last paragraph, the authors mention about TCM injection. The authors write in detail what TCM stands for as it has not been mentioned previously in the manuscript.

Answer: Sure. We explained what was TCM in detail so that readers may clearly understand the meaning of TCM.

6. The authors mentioned that they did not do a funnel plot as the number of studies were less than However, it will be worthwhile to do the HSROC curves to depict the extent of heterogeinity of each study.

Answer: Thank you for raising this method to address the heterogeneity. We have been thinking about this issue for a long time and have also consulted related paper. We suspect that the editors need us to discuss the heterogeneity of each study. The HSROC curve seems to be used to evaluate the sensitivity and specificity of diagnostic indicators. We have consulted a large number of literature, but unfortunately, we couldn't figure out how to use the HSROC curve to describe the heterogeneity of each study. So we tried to take the following two approaches instead if it is feasible. For heterogeneity, we conducted forest plot from which we may find that the heterogeneity was low as I² value < 50 %. Nonetheless, for the degree of heterogeneity of each study, sensitivity analysis as well as changing the model was also implemented to evaluate in depth. With both methods, the heterogeneity of the studies was low. So we believed that this analysis confirmed the stability of our results.What's more, in order to evaluate publication bias more accurately, egger test, a quantitative analysis method was performed by stata software (Version 15). The results showed that p-value was equal to 0.845, indicating that the risk of publication bias was low.

If our understanding of this issue deviates from your ideas, we hope that the editors and reviewers will give us another chance to revise this to improve the manuscript. Thanks again.

Submitted filename: Response to Reviewers.docx

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10 May 2022

Efficacy and Safety of Xuebijing Injection for Radiation Pneumonitis: A Meta-Analysis

PONE-D-21-23587R1

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23 May 2022

PONE-D-21-23587R1

Efficacy and Safety of Xuebijing Injection for Radiation Pneumonitis: A Meta-Analysis

Dear Dr. Hou:

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