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Perioperative PD-1/PD-L1 inhibitors for resectable non-small cell lung cancer: A meta-analysis based on randomized controlled trials
PPI for resectable NSCLC
Huang Hai Conceptualization Data curation Formal analysis Investigation Methodology Project administration Resources Software Supervision Validation Visualization Writing – original draft Writing – review & editing
Li Lianyun Conceptualization Data curation Formal analysis
Tong Ling Conceptualization Data curation Formal analysis
Luo Houfu Conceptualization Data curation Formal analysis
Luo Huijing Conceptualization Data curation Formal analysis
https://orcid.org/0009-0003-3080-021X
Zhang Qimin Conceptualization Data curation Formal analysis Investigation Methodology Project administration Resources Software Supervision Validation Visualization Writing – original draft Writing – review & editing *
Department of Oncology, Taihe People’s Hospital, Taihe, China
Raza Afsheen Editor
Abu Dhabi University, UNITED ARAB EMIRATES
Competing Interests: The authors have declared that no competing interests exist.

* E-mail: thxrmyyzlk@163.com
23 9 2024
2024
19 9 e03108081 7 2024
4 9 2024
© 2024 Huang et al
2024
Huang et al
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Background

PD-1/PD-L1 inhibitors (PI) have shown promising results in both neoadjuvant and adjuvant therapies for resectable non-small cell lung cancer (NSCLC). However, substantial evidence from large-scale studies is still lacking for their use in the perioperative setting (neoadjuvant plus adjuvant). This meta-analysis aims to evaluate the integration of perioperative PI (PPI) with neoadjuvant chemotherapy for resectable NSCLC.

Methods

To identify appropriate randomized controlled trials (RCTs), we thoroughly explored six different databases. The primary endpoint was survival, while the secondary measures included pathological responses and adverse events (AEs).

Results

Six RCTs involving 2941 patients were included. The PPI group significantly improved overall survival (OS) (hazard ratio [HR]: 0.62 [0.51, 0.77]), event-free survival (EFS) (HR: 0.57 [0.51, 0.64]), pathological complete response (risk ratio [RR]: 5.81 [4.47, 7.57]), and major pathological response (RR: 2.60 [1.77, 3.82]). Benefits in EFS were seen across all subgroups. OS rates at 12–48 months and EFS rates at 6–48 months were higher in the PPI cohort. Furthermore, the advantages in OS and EFS increased with prolonged survival times. The PPI group also exhibited higher rates of surgery and R0 resections. However, the PPI group experienced more grade 3–5 AEs, serious AEs, and treatment discontinuations due to AEs.

Conclusions

The integration of perioperative PI with neoadjuvant chemotherapy can significantly improve survival and pathological responses for resectable NSCLC. However, the increased incidence of grade 3–5 AEs must be carefully evaluated.

The author(s) received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.
Data Availability

All relevant data are within the paper and its Supporting Information files.
==== Body
pmcIntroduction

Lung cancer remains a major cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases [1]. Among NSCLC patients, those with resectable disease present a unique opportunity for curative surgical intervention. However, the high recurrence rates following surgery underscore the need for effective perioperative treatment strategies [2]. Recently, PD-1/PD-L1 inhibitors (PI) have emerged as promising therapeutic options, transforming the treatment landscape for NSCLC [3]. Various studies have confirmed the efficacy of PI in both neoadjuvant and adjuvant settings [4, 5]. For instance, neoadjuvant therapy with PI has demonstrated a reduction in tumor burden and improved surgical outcomes by enhancing pathological responses [4]. Similarly, adjuvant therapy with these inhibitors has shown improved survival rates by targeting residual disease and preventing recurrence [5]. Pasqualotto et al.’s meta-analysis, based on seven RCTs, also confirmed the role of PI in both standalone neoadjuvant and adjuvant therapy for resectable NSCLC [6]. Despite these successes, significant controversies and gaps in evidence remain, particularly regarding the integration of these treatments into a comprehensive perioperative approach.

One of the primary controversies in this field involves the optimal timing and sequencing of PI in conjunction with chemotherapy [7]. While neoadjuvant chemotherapy has long been a standard to downstage tumors and eradicate micrometastases, the addition of PI in both the neoadjuvant and adjuvant settings (perioperative PI [PPI]) has not been thoroughly investigated in large sample meta-analyses. The hypothesis that combining chemotherapy with PI can elicit a stronger anti-tumor immune response is compelling [8–13]. Chemotherapy can cause immunogenic cell death, which potentially enhances the efficacy of PI by increasing tumor antigen presentation and T-cell infiltration. However, this theoretical synergy requires validation through rigorous clinical trials [14].

By pooling data from high-quality randomized controlled trials (RCTs), our analysis aims to provide a comprehensive assessment of the impact of PPI on key outcomes, including overall survival (OS), event-free survival (EFS), pathological response, and adverse events (AEs).

Materials and methods

Search strategy

MeSH terms such as “PD-1/PD-L1 (see S1 Table for details)”, “Chemotherapy”, “Lung cancer”, and “Randomized” were utilized. We thoroughly searched six databases, including PubMed, ScienceDirect, the Cochrane Library, Scopus, EMBASE, and Web of Science. The search period covered from inception to June 15, 2024 (S1 Table). Furthermore, the reference lists of the selected studies were scrutinized to identify additional eligible RCTs.

Selection criteria

Inclusion criteria (PICOS):

Participants (P): resectable NSCLC.

Intervention (I) and control (C): PPI group (PPI plus neoadjuvant chemotherapy) versus Chemotherapy group (neoadjuvant chemotherapy).

Outcomes (O): survival, surgery condition, pathological response, and safety.

Study design (S): RCTs.

Exclusion criteria: animal experiments, reviews, meta-analyses, case reports, and studies missing key data.

Data extraction

Data included study characteristics (phase, period, etc.), patient demographics (sex, histologic classification, etc.), survival metrics (OS and EFS), survival rates (OS rate [OSR] and EFS rate [EFSR]), pathological responses (objective response rate [ORR], major pathologic response [MPR], etc.), and AEs (total, grade 3–5, etc.). Data were independently extracted by two researchers, and discrepancies were resolved through re-evaluation (S1 File).

Outcome assessments

The OSR and EFSR were analyzed at 6–48 months. Subgroup analyses of EFS were conducted according to age, sex, smoking status, Eastern Cooperative Oncology Group Performance Status (ECOG PS), race, geographic region, pathological stage, histologic classification, and PD-L1 TPS.

Quality assessment

We employed the Cochrane Risk Assessment Tool and the Jadad scale to evaluate the quality of RCTs, with the latter rating studies up to 5 points based on randomization, blinding, and participant inclusion, considering scores of 3 or more as high quality [15, 16]. The GRADE approach was used to assess the reliability of the results [17].

Statistical analysis

Review Manager 5.3, Stata 12.0 and SPSS 15.0 were used for data analysis. We employed hazard ratios (HR) for evaluating survival outcomes and risk ratios (RR) for dichotomous outcomes. Heterogeneity was assessed using the I2 statistic and the χ2 test. A fixed-effects model was selected when I2 was less than 50% or the P-value was above 0.1, indicating low heterogeneity; otherwise, a random-effects model was used. Funnel plots were used to assess publication bias. Statistical significance was defined as P < 0.05. (PROSPERO ID: CRD42024563648).

Results

Search results

Our meta-analysis incorporated RCTs involving 2941 patients: AEGEAN, CheckMate 77T, KEYNOTE-671, NADIM II, Neotorch, and RATIONALE-315 (Fig 1) [8–13]. Table 1 presents an overview of the baseline characteristics of these studies. Among these, three were global multicenter trials [8–10], two were conducted in China [12, 13], and one was based in Spain [11]. According to S1 Fig and S2 Table, all studies exhibited high quality. The GRADE approach was utilized to assess the quality of the results, which ranged from medium to high (S3 Table).

10.1371/journal.pone.0310808.g001 Fig 1 Flow chart.

10.1371/journal.pone.0310808.t001 Table 1 Baseline characteristics of the included studies.

Study	Phase	Period	Country	Groups	Patients	Sex (M/F)	Age (Mean, year)	ECOG PS	Histologic classification	TNM Stage	PD-1/PD-L1 type	Follow up (months)	
0	1	SCC	Non-SCC	II	IIIA	IIIB	
AEGEAN (NCT03800134)	Heymach 2023 [8]	III	2019.01–2022.04	Global multicenter	PPI	366	252/114	65	251	115	169	196	104	173	88	Durvalumab	34.0	
Chemotherapy	374	278/96	65	255	119	191	179	110	165	98	
CheckMate 77T (NCT04025879)	Cascone 2024 [9]	III	2019.11–2022.04	Global multicenter	PPI	229	167/62	66	147	82	116	113	81	146	Nivolumab	25.4	
Chemotherapy	232	160/72	66	141	91	118	114	81	149	
KEYNOTE-671 (NCT03425643)	Wakelee 2023 [10]	III	2018.04–2021.12	Global multicenter	PPI	397	279/118	63	253	144	226	171	118	217	62	Pembrolizumab	25.2	
Chemotherapy	400	284/116	64	246	154	173	227	121	225	54	
NADIM II (NCT03838159)	Provencio 2023 [11]	II	2019.06–2021.02	Spain	PPI	57	36/21	65	31	26	21	36	0	44	13	Nivolumab	26.1	
Chemotherapy	29	16/13	63	16	13	14	15	0	24	5	
Neotorch (NCT04158440)	Lu 2024 [12]	III	2020.03–2023.06	China	PPI	202	181/21	62	70	132	157	45	0	136	66	Toripalimab	18.3	
Chemotherapy	202	189/13	61	73	129	157	45	0	137	65	
RATIONALE-315 (NCT04379635)	Zhang 2023 [13]	III	2020.05–2023.08	China	PPI	226	205/21	62	143	83	179	45	93	133	0	Tislelizumab	22.0	
Chemotherapy	227	205/22	63	154	73	175	50	92	135	0	
Abbreviations: AE: Adverse event; ECOG PS: Eastern Cooperative Oncology Group Performance Status; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death 1 ligand 1; PPI: Perioperative PD-1/PD-L1 inhibitors; SCC: Squamous cell carcinoma; TNM: Tumor Node Metastasis.

Survival

In the PPI group, OS improved significantly, with an HR of 0.62 [0.51, 0.77] (Fig 2). Additionally, the OSR at 12 to 48 months was higher in this group (S2 Fig). The benefits in OSR became more evident as the survival time lengthened (Fig 3A and 3C).

10.1371/journal.pone.0310808.g002 Fig 2 Forest plots of overall survival and event-free survival associated with PPI versus chemotherapy.

10.1371/journal.pone.0310808.g003 Fig 3 Comparisons of OSR and EFSR.

(A) OSR at 6–48 months between the two groups; (B) EFSR at 6–48 months between the two groups; (C) trend of risk ratios in OSR; (D) trend of risk ratios in EFSR.

In the PPI group, EFS also improved significantly, with an HR of 0.57 [0.51, 0.64] (Fig 2). The EFSR at 6 to 48 months was higher in the PPI group (S3 Fig). The benefits in EFSR became more evident as the survival time lengthened (Fig 3B and 3D). The EFS advantage of the PPI group was consistent across all subgroups, particularly in the PD-L1 TPS > 50% subgroup (HR: 0.45 [0.35, 0.58]) (Table 2).

10.1371/journal.pone.0310808.t002 Table 2 Subgroup analysis of event-free survival.

Subgroups	Event-free survival	
Included studies	Patients	HR (95% CI)	I 2	P	
All patients	6	2941	0.57 [0.51, 0.65]	18%	<0.00001	
Age (year)						
    < 65	6	1631	0.55 [0.46, 0.65]	0%	<0.00001	
    > 65	6	1310	0.59 [0.49, 0.70]	0%	<0.00001	
Sex						
    Female	5	655	0.64 [0.49, 0.84]	26%	0.001	
    Male	5	2200	0.56 [0.48, 0.64]	29%	<0.00001	
Smoking status						
    Active smoker	4	535	0.52 [0.40, 0.70]	0%	<0.00001	
    Former smoker	5	2000	0.55 [0.44, 0.69]	54%	<0.00001	
    Non-smoker	6	406	0.62 [0.45, 0.87]	43%	0.006	
ECOG PS						
    0	4	1233	0.58 [0.48, 0.71]	0%	<0.00001	
    1	4	824	0.56 [0.44, 0.71]	48%	<0.00001	
Race category						
    White	2	536	0.53 [0.41, 0.68]	0%	<0.00001	
    Asian	4	1508	0.54 [0.45, 0.65]	27%	<0.00001	
    Others	3	1033	0.60 [0.49, 0.73]	35%	<0.00001	
Geographic region						
    Asia	4	1377	0.51 [0.42, 0.62]	5%	<0.00001	
    Europe	3	617	0.63 [0.48, 0.83]	0%	0.0008	
    North America	2	130	0.64 [0.34, 1.18]	0%	0.15	
Pathological stage (TNM)						
    II	4	798	0.66 [0.51, 0.86]	0%	0.002	
    III	6	2134	0.52 [0.45, 0.60]	0%	<0.00001	
Histologic classification						
    Nonsquamous	6	1291	0.62 [0.52, 0.74]	0%	<0.00001	
    Squamous	6	1641	0.53 [0.45, 0.63]	30%	<0.00001	
PD-L1 TPS						
    <1%	5	781	0.75 [0.60, 0.94]	0%	0.01	
    >1%	4	1071	0.47 [0.39, 0.58]	0%	<0.00001	
    1–49%	5	944	0.52 [0.37, 0.72]	54%	<0.00001	
    >50%	5	840	0.45 [0.35, 0.58]	37%	<0.00001	
Abbreviations: CI: Confidence interval; ECOG PS: Eastern Cooperative Oncology Group Performance Status; HR: Hazard ratio; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death 1 ligand 1; PPI: Perioperative PD-1/PD-L1 inhibitors; TNM: Tumor Node Metastasis; TPS: Tumor cell proportion score.

Pathological responses

The ORR (RR: 2.96 [2.06, 4.26]), pathological complete response (PCR) (RR: 5.81 [4.47, 7.57]), and MPR (RR: 2.60 [1.77, 3.82]) were greater in the PPI group (Fig 4).

10.1371/journal.pone.0310808.g004 Fig 4 Forest plots of pathological responses associated with PPI versus chemotherapy.

Surgery summary

In the PPI group, there was an increase in the rates of surgery (RR: 1.05 [1.01, 1.09]) and R0 resection (RR: 1.10 [1.05, 1.15]) (S4 Fig).

Safety

Overall, the PPI group had increased rates of grade 3–5 AEs (RR: 1.12 [1.04, 1.20]), serious AEs (RR: 1.34 [1.19, 1.51]), fatal AEs (RR: 1.64 [1.00, 2.68]), and discontinuations due to AEs (RR: 1.93 [1.54, 2.41]). The chemotherapy group showed a tendency for higher total AEs and dose interruptions due to AEs, but this was not statistically significant (Table 3 and S5 Fig).

10.1371/journal.pone.0310808.t003 Table 3 Summary of adverse events.

Adverse events	PPI	Chemotherapy	Risk ratio [95% CI]	P	
Event/total	%	Event/total	%	
Total adverse events	1467/1477	99.32%	1431/1464	97.75%	1.01 [0.99, 1.02]	0.31	
Grade 3–5 adverse events	759/1477	51.39%	682/1464	46.58%	1.12 [1.04, 1.20]	0.003	
Serious adverse events	434/1420	30.56%	328/1435	22.86%	1.34 [1.19, 1.51]	< 0.00001	
Fatal adverse events	39/1420	2.75%	24/1435	1.67%	1.64 [1.00, 2.68]	0.05	
Discontinuation due to adverse events	202/1420	14.23%	106/1435	7.39%	1.93 [1.54, 2.41]	< 0.00001	
Dose interruption due to adverse events	145/428	33.88%	102/429	23.78%	1.50 [0.93, 2.42]	0.09	
Abbreviations: CI: confidence interval; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death 1 ligand 1; PPI: Perioperative PD-1/PD-L1 inhibitors.

For any grade AEs, the PPI group experienced more instances of increased AST, constipation, fatigue, cough, increased ALT, hypothyroidism, rash, pruritus, pneumonitis, hyperthyroidism, and thyroiditis (Table 4 and S4 Table).

10.1371/journal.pone.0310808.t004 Table 4 Any grade adverse events (incidence rate > 10% in the PPI group).

Adverse events	PPI	Chemotherapy	Risk ratio [95% CI]	P	
Event/total	%	Event/total	%	
Anemia	565/1477	38.25%	542/1464	37.02%	1.05 [0.96, 1.14]	0.34	
Neutrophil count decreased	443/1218	36.37%	419/1233	33.98%	1.07 [0.97, 1.17]	0.18	
Nausea	481/1420	33.87%	477/1435	33.24%	1.02 [0.92, 1.13]	0.72	
Neutropenia	182/568	32.04%	177/576	30.73%	1.04 [0.88, 1.22]	0.66	
AST increased	117/428	27.34%	78/429	18.18%	1.50 [1.17, 1.94]	0.002	
White blood cell count decreased	312/1191	26.20%	304/1203	25.27%	1.03 [0.92, 1.17]	0.6	
Leukopenia	144/568	25.35%	127/576	22.05%	1.14 [0.95, 1.37]	0.16	
Constipation	297/1194	24.87%	245/1208	20.28%	1.23 [1.06, 1.42]	0.007	
Alopecia	336/1477	22.75%	344/1464	23.50%	0.96 [0.85, 1.09]	0.52	
Fatigue	282/1251	22.54%	225/1237	18.19%	1.20 [1.03, 1.40]	0.02	
Arrhythmia	58/259	22.39%	53/231	22.94%	1.07 [0.78, 1.48]	0.66	
Decreased appetite	255/1191	21.41%	232/1203	19.29%	1.14 [0.85, 1.52]	0.4	
Peripheral sensory neuropathy	49/259	18.92%	39/231	16.88%	1.06 [0.73, 1.54]	0.76	
Cough	101/599	16.86%	74/602	12.29%	1.37 [1.05, 1.79]	0.02	
ALT increased	207/1248	16.59%	139/1232	11.28%	1.49 [1.23, 1.81]	< 0.0001	
Vomiting	149/965	15.44%	126/976	12.91%	1.19 [0.96, 1.49]	0.11	
Platelet count decreased	148/989	14.96%	154/1001	15.38%	0.97 [0.79, 1.19]	0.77	
Thrombocytopenia	78/568	13.73%	74/576	12.85%	1.06 [0.80, 1.42]	0.68	
Asthenia	93/763	12.19%	109/774	14.08%	0.87 [0.67, 1.12]	0.27	
Procedural pain	70/599	11.69%	71/602	11.79%	0.99 [0.73, 1.35]	0.96	
Incision site pain	111/965	11.50%	99/976	10.14%	1.13 [0.88, 1.46]	0.33	
Hypothyroidism	161/1477	10.90%	28/1464	1.91%	5.66 [3.83, 8.36]	< 0.00001	
Insomnia	61/568	10.74%	58/576	10.07%	1.07 [0.76, 1.50]	0.7	
Diarrhea	133/1251	10.63%	112/1237	9.05%	1.28 [0.85, 1.93]	0.24	
Rash	133/1251	10.63%	63/1237	5.09%	2.08 [1.57, 2.77]	< 0.00001	
Pneumonia	67/656	10.21%	63/631	9.98%	1.04 [0.76, 1.43]	0.78	
Abbreviations: ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; CI: confidence interval; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death 1 ligand 1; PPI: Perioperative PD-1/PD-L1 inhibitors.

For grade 3–5 AEs, the PPI group experienced more instances of pneumonitis and rash. The top 5 grade 3–5 AEs in the PPI group were decreased neutrophil count (23.15%), neutropenia (18.31%), leukopenia (6.87%), anemia (6.23%), and decreased white blood cell count (5.79%) (Table 5 and S5 Table).

10.1371/journal.pone.0310808.t005 Table 5 Grade 3–5 adverse events (incidence rate > 1% in the PPI group).

Adverse events	PPI	Chemotherapy	Risk ratio [95% CI]	P	
Event/total	%	Event/total	%	
Neutrophil count decreased	282/1218	23.15%	270/1233	21.90%	1.05 [0.92, 1.20]	0.44	
Neutropenia	104/568	18.31%	98/576	17.01%	1.07 [0.84, 1.36]	0.58	
Leukopenia	39/568	6.87%	28/576	0.05	1.27 [0.53, 3.03]	0.59	
Anemia	92/1477	6.23%	87/1464	0.06	1.07 [0.80, 1.42]	0.65	
White blood cell count decreased	69/1191	5.79%	67/1203	5.57%	1.04 [0.75, 1.43]	0.82	
Pneumonia	33/599	5.51%	29/602	4.82%	1.14 [0.71, 1.84]	0.59	
Thrombocytopenia	20/568	3.52%	16/576	0.03	1.26 [0.66, 2.41]	0.48	
Platelet count decreased	32/989	3.24%	42/1001	4.20%	0.77 [0.49, 1.21]	0.26	
Pneumonitis	16/828	1.93%	5/834	0.60%	3.22 [1.19, 8.74]	0.02	
Hyperglycemia	6/431	1.39%	1/434	0.23%	6.00 [0.73, 49.39]	0.10	
Vomiting	11/965	1.14%	5/976	0.51%	2.12 [0.77, 5.84]	0.15	
ALT increased	13/1248	1.04%	5/1232	0.41%	2.62 [0.94, 7.33]	0.07	
Abbreviations: ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; CI: confidence interval; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death 1 ligand 1; PPI: Perioperative PD-1/PD-L1 inhibitors.

Sensitivity analysis

Sensitivity analyses were performed for EFS (former smokers), EFSR at 12 months, and MPR. These analyses revealed that the overall reliability of the findings remained intact when any single study was excluded (S6 Fig).

Publication bias

The symmetry observed in funnel plots for survival, EFSR, pathological responses, and the safety summary indicated an acceptable level of publication bias (Fig 5).

10.1371/journal.pone.0310808.g005 Fig 5 Funnel plots of survival (A), EFSR (B), pathological responses (C), and safety summary (D).

Discussion

Various studies have established the efficacy of PI in both neoadjuvant and adjuvant settings [4, 5]. This finding was also corroborated by Pasqualotto et al.’s meta-analysis [6]. However, there is still a lack of large-sample evidence-based medical data for their use in the perioperative setting (neoadjuvant plus adjuvant). Our meta-analysis provides robust evidence supporting the combination of PPI with neoadjuvant chemotherapy for resectable NSCLC. The findings demonstrate significant improvements in OS and EFS, as well as enhanced pathological responses. However, the increased rates of AEs highlight the need for careful patient selection and management strategies to mitigate potential risks.

The pooled data from six RCTs show that the PPI group significantly improves OS and EFS for resectable NSCLC. This benefit was consistent across various subgroups, particularly in patients with a PD-L1 TPS greater than 50%, suggesting that higher PD-L1 expression may predict better responses to PI. These findings are corroborated by recent studies. For example, Forde et al. demonstrated that neoadjuvant nivolumab combined with chemotherapy significantly enhanced PCR and MPR compared to chemotherapy alone, ultimately translating into better survival outcomes [4]. Similarly, Provencio et al. indicated that perioperative PI significantly enhance survival rates in resectable NSCLC [18]. Furthermore, Efil et al. highlighted that the integration of immunotherapy in the perioperative setting leads to a substantial increase in OS and EFS, reinforcing the survival benefit observed in this meta-analysis [19]. The combined effect of chemotherapy and immunotherapy boosts tumor antigen presentation and fosters a stronger anti-tumor immune response [20, 21].

Our analysis also revealed that the PPI regimen significantly increased the rates of PCR and MPR. The RRs for PCR and MPR were 5.81 and 2.60, respectively, indicating that a greater proportion of patients achieved complete or near-complete eradication of their tumors. This is a critical finding, as pathological response has been associated with improved long-term outcomes in NSCLC. Pathological response serves as an important surrogate marker for survival in cancer treatment. Achieving a higher rate of PCR or MPR suggests that the combination therapy is effective in substantially reducing tumor burden, which is likely to translate into lower recurrence rates and better survival outcomes. This is supported by the NADIM trial, which showed that patients achieving PCR with neoadjuvant nivolumab and chemotherapy had significantly better EFS and OS than those who did not achieve PCR [18]. Recent studies have further validated these findings. For instance, the CheckMate 816 trial reported that neoadjuvant nivolumab plus chemotherapy led to a significant increase in MPR and PCR rates, compared to chemotherapy alone, which is consistent with our results [22]. Additionally, Gadgeel et al. highlighted that the enhanced pathological responses observed with the perioperative PPI approach can be attributed to the synergistic effects of chemotherapy and immunotherapy, which enhance tumor antigen presentation and T-cell activation [23].

Despite the efficacy benefits, the higher incidence of grade 3–5 AEs raises concerns about the safety of the PPI regimen. Common severe AEs included pneumonitis and rash, which require vigilant monitoring and management. These findings underscore the need for balancing the potential benefits of PPIs with their associated risks. The safety profile of PI has been well-documented, with immune-related adverse events (irAEs) being a notable concern. These irAEs result from the activation of the immune system against normal tissues, leading to a range of inflammatory conditions that can affect various organs, including the lungs, liver, skin, and endocrine glands [24]. In the context of perioperative treatment, the risk of irAEs must be carefully weighed against the potential survival benefits, especially since these events can greatly affect the patient’s compliance with treatment and overall quality of life [25, 26].

In clinical practice, managing the safety concerns associated with PPIs involves several strategies. Early identification and prompt management of irAEs are crucial to minimizing their severity and preventing long-term complications. This requires regular monitoring of patients, educating them about the potential signs and symptoms of irAEs, and having a clear management plan in place that includes the use of immunosuppressive agents such as corticosteroids when necessary [27]. Furthermore, patient selection is critical to optimizing the safety and efficacy of perioperative PPIs. Identifying biomarkers that can predict response to therapy and the likelihood of developing severe irAEs can help tailor treatment to individual patients, thereby maximizing the therapeutic benefits while minimizing risks. For example, PD-L1 expression levels and other immune-related biomarkers have been investigated as potential predictors of response to PI [28, 29]. The use of these biomarkers can significantly improve the safety profile and efficacy of the treatment regimen [30, 31].

Our study has some limitations. First, restricting the review to English-language publications may have caused language bias. Second, the inclusion of RCTs that were not all phase 3 trials could influence the robustness of the outcomes. Third, the unavailability of individual patient data precluded a detailed meta-analysis, which may have limited the clinical relevance of the findings.

Conclusion

The PPI group offers significant survival and pathological response benefits for resectable NSCLC. The survival advantages were confirmed across all subgroups and increased with longer survival times. However, the increased risk of severe AEs necessitates careful patient management and further investigation to optimize treatment protocols. Future studies should focus on improving patient selection criteria, developing methods to minimize AEs, and examining the long-term outcomes of this treatment on survival and safety.

Supporting information

S1 Checklist PRISMA 2020 checklist.

(DOCX)

S1 Fig Cochrane risk assessment.

(TIF)

S2 Fig Forest plots of OSR at 12–48 months associated with PPI versus chemotherapy.

(TIF)

S3 Fig Forest plots of EFSR at 6–48 months associated with PPI versus chemotherapy.

(TIF)

S4 Fig Forest plots of surgery summary associated with PPI versus chemotherapy.

(TIF)

S5 Fig Forest plots of safety summary associated with PPI versus chemotherapy.

(TIF)

S6 Fig Sensitivity analysis of EFS (Smoking status—Former smoker) (A), EFSR-12m (B), and MPR (C).

(TIF)

S1 Table Search strategy.

(DOCX)

S2 Table Methodological quality assessments (Jadad scale) of the included studies.

(DOC)

S3 Table GRADE quality assessment by therapeutic strategy and study design for the outcomes.

(DOC)

S4 Table Any grade adverse events (all).

(DOC)

S5 Table Grade 3–5 adverse events (all).

(DOC)

S1 File Extract data details.

(XLSX)

The authors thank professor Wenxiong Zhang, MD (Department of Thoracic Surgery, The second affiliated hospital of Nanchang University) for his data collection and statistical advice.

Abbreviations

AE Adverse event

ALT Alanine aminotransferase

AST Aspartate aminotransferase

CI Confidence interval

CR Complete response

DCR Disease control rate

ECOG PS Eastern Cooperative Oncology Group Performance Status

EFS Event-free survival

EFSR Event-free survival rate

GRADE Grading of Recommendations, Assessment, Development, and Evaluation

HR Hazard ratio

irAEs Immune-related adverse events

M/F Male/Female

MPR Major pathologic response

PCR Pathological complete response

ORR Objective response rate

OS Overall survival

OSR Overall survival rate

PD-1 Programmed cell death protein 1

PD-L1 Programmed cell death 1 ligand 1

PICOS Participants, Intervention, Control, Outcomes, Study design

PI PD-1/PD-L1 inhibitors

PPI Perioperative PD-1/PD-L1 inhibitors

PR Partial response

PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCT Randomized controlled trial

RR Risk ratio

SCC Squamous cell carcinoma

SD Stable disease

TNM Tumor Node Metastasis

TPS Tumor cell proportion score

TRAEs Treatment-related adverse events

10.1371/journal.pone.0310808.r001
Decision Letter 0
Raza Afsheen Academic Editor
© 2024 Afsheen Raza
2024
Afsheen Raza
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version0
13 Aug 2024

PONE-D-24-26934Perioperative PD-1/PD-L1 inhibitors for resectable non-small cell lung cancer: a meta-analysis based on randomized controlled trialsPLOS ONE

Dear Dr. Zhang,

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: I would like to thank the authors for their submission. After carefully reviewing the manuscript, I have some concerns that need to be addressed.

Firstly, there is a previously published meta-analysis on this specific topic that presents very similar results to those found by the authors. This earlier meta-analysis was published in Cancers last year and covers the same variables and timeframes discussed in this study.

Furthermore, the authors did not cite this existing meta-analysis in their manuscript, which is a significant oversight. Proper citation of relevant literature is essential to contextualize the new research within the existing body of knowledge.

Given that the new research does not present a substantial difference in methods, data, or conclusions compared to the existing meta-analysis, the publication of this manuscript may not add significant value to the current scientific literature. While replication of studies is important, the lack of new insights or innovative approaches makes it difficult to justify publication at this time.

I recommend that the authors consider incorporating a citation of the existing meta-analysis from Cancers and justify the unique contributions or advancements their study provides. If the authors can demonstrate a significant advancement or new perspective beyond what has already been published, it would strengthen the case for publication.

In summary, due to the redundancy of the results with the already published meta-analysis and the failure to cite this key work, I do not recommend the publication of this manuscript in the journal unless the authors address these issues and provide a clearer justification of the study's relevance.

Reviewer #2: Thank you for the opportunity to review this work. This systematic review and meta-analysis focus on neoadjuvant treatment with PD-1/PD-L1 inhibitors for resectable non-small cell lung cancer (NSCLC). The authors included six randomized controlled trials (RCTs) involving 2,941 patients. The PD-1/PD-L1 inhibitor group showed significant improvement in overall survival (OS) with a hazard ratio (HR) of 0.62 [95% CI: 0.51, 0.77], event-free survival (EFS) with an HR of 0.57 [95% CI: 0.51, 0.64], pathological complete response with a risk ratio (RR) of 5.81 [95% CI: 4.47, 7.57], and major pathological response with an RR of 2.60 [95% CI: 1.77, 3.82]. Benefits in EFS were observed across all subgroups.

This is a valuable article, and the results are consistent with existing literature. However, there are important errors in its execution, and major revisions are requested.

A previous meta-analysis on the same theme has been published:

Pasqualotto E, Moraes FCA, Chavez MP, Souza MEC, Rodrigues ALSO, Ferreira ROM, Lopes LM, Almeida AM, Fernandes MR, Santos NPCD. PD-1/PD-L1 Inhibitors plus Chemotherapy Versus Chemotherapy Alone for Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cancers (Basel). 2023 Oct 26;15(21):5143. doi: 10.3390/cancers15215143. PMID: 37958317; PMCID: PMC10648147.

The authors did not cite this article, and it is doubtful that it was not found during their screening process. Please cite this work and consider mentioning that your article is an updated meta-analysis. Cite Pasqualotto et al. and describe how your meta-analysis differs from the one currently published in the introduction.

Please make an Excel spreadsheet with the complete data extraction available. Additionally, describe in your methods how you created Figure 3 and provide the script for its execution in your supplementary material.

**********

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10.1371/journal.pone.0310808.r002
Author response to Decision Letter 0
Submission Version1
16 Aug 2024

Dear Editor and Reviewers:

Thank you for your letter and for the comments concerning our manuscript entitled “Perioperative PD-1/PD-L1 inhibitors for resectable non-small cell lung cancer: a meta-analysis based on randomized controlled trials” (ID: PONE-D-24-26934). All of the comments were valuable and very helpful for revising and improving our paper, as well guiding future research. We studied the comments carefully and made corrections that we hope make the paper satisfactory. The revised portions are marked in red in the paper. The main corrections in the paper and the responses to the editors’ comments are as follows:

Responses to the reviewer’s comments:

Reviewer #1:

Comment 1: I would like to thank the authors for their submission. After carefully reviewing the manuscript, I have some concerns that need to be addressed.

Firstly, there is a previously published meta-analysis on this specific topic that presents very similar results to those found by the authors. This earlier meta-analysis was published in Cancers last year and covers the same variables and timeframes discussed in this study.

Furthermore, the authors did not cite this existing meta-analysis in their manuscript, which is a significant oversight. Proper citation of relevant literature is essential to contextualize the new research within the existing body of knowledge.

Given that the new research does not present a substantial difference in methods, data, or conclusions compared to the existing meta-analysis, the publication of this manuscript may not add significant value to the current scientific literature. While replication of studies is important, the lack of new insights or innovative approaches makes it difficult to justify publication at this time.

I recommend that the authors consider incorporating a citation of the existing meta-analysis from Cancers and justify the unique contributions or advancements their study provides. If the authors can demonstrate a significant advancement or new perspective beyond what has already been published, it would strengthen the case for publication.

In summary, due to the redundancy of the results with the already published meta-analysis and the failure to cite this key work, I do not recommend the publication of this manuscript in the journal unless the authors address these issues and provide a clearer justification of the study's relevance.

Response: We sincerely apologize for the oversight in not citing the meta-analysis by Pasqualotto et al., which was published in Cancers and covers a similar topic. This omission was unintentional, and we appreciate you bringing this to our attention. We have now thoroughly reviewed the work by Pasqualotto et al. and have included a citation in our revised manuscript. We acknowledge the importance of situating our research within the context of existing literature and have made the necessary adjustments to our introduction and discussion sections to reflect this.

Clarification of Novelty and Contribution

Although our meta-analysis and that of Pasqualotto et al. may seem similar in title, the content of our studies is entirely different. The study by Pasqualotto et al. primarily compares neoadjuvant therapy with PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone and adjuvant therapy with PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone for resectable non-small cell lung cancer (NSCLC). This paper included seven RCTs (IMpower010, KEYNOTE-091, CheckMate 816, KEYNOTE-671, NADIM II, NEOTORCH, and TD-FOREKNOW).

• Two of these RCTs (CheckMate 816 and TD-FOREKNOW) focused solely on neoadjuvant therapy.

• Two RCTs (IMpower010 and KEYNOTE-091) were limited to adjuvant therapy.

• The remaining three RCTs (NADIM II, KEYNOTE-671, and NEOTORCH) involved perioperative use (neoadjuvant plus adjuvant) of PD-1/PD-L1 inhibitors.

Moreover, the paper's analysis only conducted separate subgroup survival analyses for neoadjuvant and adjuvant therapies, without an isolated analysis (survival and adverse effects) for perioperative use of PD-1/PD-L1 inhibitors. While PD-1/PD-L1 inhibitors (PI) have shown promising results in both neoadjuvant and adjuvant settings for resectable NSCLC, robust evidence from large-scale studies on their use in the perioperative setting (neoadjuvant plus adjuvant) is still lacking. Given that there have been several meta-analyses on neoadjuvant and adjuvant therapy alone, including the aforementioned study by Pasqualotto et al., these were not the focus of our research.

While PD-1/PD-L1 inhibitors have demonstrated their benefits in both standalone neoadjuvant and adjuvant therapies, this does not necessarily imply that their use in a perioperative setting will offer the same advantages. Therefore, our meta-analysis primarily compares the PPI group (neoadjuvant PD-1/PD-L1 inhibitors plus chemotherapy followed by adjuvant PD-1/PD-L1 inhibitors post-surgery) versus the Chemotherapy group (neoadjuvant chemotherapy alone). Our study includes six RCTs (AEGEAN, CheckMate 77T, KEYNOTE-671, NADIM II, Neotorch, and RATIONALE-315).

• Three of these RCTs (NADIM II, KEYNOTE-671, and NEOTORCH) overlap with those analyzed by Pasqualotto et al.

• The remaining three RCTs (AEGEAN, CheckMate 77T, and RATIONALE-315) are more recent studies published within the past year.

Thus, while our study shares a similar title with Pasqualotto et al.’s, it is fundamentally a different meta-analysis. Furthermore, our subgroup analysis and complication analysis are more detailed than those in Pasqualotto et al.’s study. We have conducted detailed subgroup analyses based on factors such as PD-L1 expression levels, tumor stage, and other relevant biomarkers, which were not extensively covered in the previous meta-analysis. These analyses offer insights into how different patient populations may respond to these therapies, potentially guiding more personalized treatment strategies.

Justification for Publication:

We understand the importance of ensuring that new research adds significant value to the existing body of knowledge. By incorporating the latest data and focusing on the perioperative approach, we believe our meta-analysis provides new insights that can help guide clinical practice and future research in the treatment of resectable NSCLC. We hope that the revisions we have made to the manuscript demonstrate the relevance and importance of our findings.

Once again, we sincerely appreciate your feedback and the opportunity to improve our manuscript. We have made the necessary revisions to address your concerns and believe that these changes strengthen the overall quality and contribution of our work. We look forward to your further comments and hope that our revised manuscript meets your expectations.

Reviewer #2:

Comment 1: Thank you for the opportunity to review this work. This systematic review and meta-analysis focus on neoadjuvant treatment with PD-1/PD-L1 inhibitors for resectable non-small cell lung cancer (NSCLC). The authors included six randomized controlled trials (RCTs) involving 2,941 patients. The PD-1/PD-L1 inhibitor group showed significant improvement in overall survival (OS) with a hazard ratio (HR) of 0.62 [95% CI: 0.51, 0.77], event-free survival (EFS) with an HR of 0.57 [95% CI: 0.51, 0.64], pathological complete response with a risk ratio (RR) of 5.81 [95% CI: 4.47, 7.57], and major pathological response with an RR of 2.60 [95% CI: 1.77, 3.82]. Benefits in EFS were observed across all subgroups.

This is a valuable article, and the results are consistent with existing literature. However, there are important errors in its execution, and major revisions are requested.

A previous meta-analysis on the same theme has been published:

Pasqualotto E, Moraes FCA, Chavez MP, Souza MEC, Rodrigues ALSO, Ferreira ROM, Lopes LM, Almeida AM, Fernandes MR, Santos NPCD. PD-1/PD-L1 Inhibitors plus Chemotherapy Versus Chemotherapy Alone for Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cancers (Basel). 2023 Oct 26;15(21):5143. doi: 10.3390/cancers15215143. PMID: 37958317; PMCID: PMC10648147.

The authors did not cite this article, and it is doubtful that it was not found during their screening process. Please cite this work and consider mentioning that your article is an updated meta-analysis. Cite Pasqualotto et al. and describe how your meta-analysis differs from the one currently published in the introduction.

Response: We sincerely apologize for the oversight in not citing the meta-analysis by Pasqualotto et al., which was published in Cancers and covers a similar topic. This omission was unintentional, and we appreciate you bringing this to our attention. We have now thoroughly reviewed the work by Pasqualotto et al. and have included a citation in our revised manuscript. We acknowledge the importance of situating our research within the context of existing literature and have made the necessary adjustments to our introduction and discussion sections to reflect this.

Clarification of Novelty and Contribution

Although our meta-analysis and that of Pasqualotto et al. may seem similar in title, the content of our studies is entirely different. The study by Pasqualotto et al. primarily compares neoadjuvant therapy with PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone and adjuvant therapy with PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone for resectable non-small cell lung cancer (NSCLC). This paper included seven RCTs (IMpower010, KEYNOTE-091, CheckMate 816, KEYNOTE-671, NADIM II, NEOTORCH, and TD-FOREKNOW).

• Two of these RCTs (CheckMate 816 and TD-FOREKNOW) focused solely on neoadjuvant therapy.

• Two RCTs (IMpower010 and KEYNOTE-091) were limited to adjuvant therapy.

• The remaining three RCTs (NADIM II, KEYNOTE-671, and NEOTORCH) involved perioperative use (neoadjuvant plus adjuvant) of PD-1/PD-L1 inhibitors.

Moreover, the paper's analysis only conducted separate subgroup survival analyses for neoadjuvant and adjuvant therapies, without an isolated analysis (survival and adverse effects) for perioperative use of PD-1/PD-L1 inhibitors. While PD-1/PD-L1 inhibitors (PI) have shown promising results in both neoadjuvant and adjuvant settings for resectable NSCLC, robust evidence from large-scale studies on their use in the perioperative setting (neoadjuvant plus adjuvant) is still lacking. Given that there have been several meta-analyses on neoadjuvant and adjuvant therapy alone, including the aforementioned study by Pasqualotto et al., these were not the focus of our research.

While PD-1/PD-L1 inhibitors have demonstrated their benefits in both standalone neoadjuvant and adjuvant therapies, this does not necessarily imply that their use in a perioperative setting will offer the same advantages. Therefore, our meta-analysis primarily compares the PPI group (neoadjuvant PD-1/PD-L1 inhibitors plus chemotherapy followed by adjuvant PD-1/PD-L1 inhibitors post-surgery) versus the Chemotherapy group (neoadjuvant chemotherapy alone). Our study includes six RCTs (AEGEAN, CheckMate 77T, KEYNOTE-671, NADIM II, Neotorch, and RATIONALE-315).

• Three of these RCTs (NADIM II, KEYNOTE-671, and NEOTORCH) overlap with those analyzed by Pasqualotto et al.

• The remaining three RCTs (AEGEAN, CheckMate 77T, and RATIONALE-315) are more recent studies published within the past year.

Thus, while our study shares a similar title with Pasqualotto et al.’s, it is fundamentally a different meta-analysis. Furthermore, our subgroup analysis and complication analysis are more detailed than those in Pasqualotto et al.’s study. We have conducted detailed subgroup analyses based on factors such as PD-L1 expression levels, tumor stage, and other relevant biomarkers, which were not extensively covered in the previous meta-analysis. These analyses offer insights into how different patient populations may respond to these therapies, potentially guiding more personalized treatment strategies.

Justification for Publication:

We understand the importance of ensuring that new research adds significant value to the existing body of knowledge. By incorporating the latest data and focusing on the perioperative approach, we believe our meta-analysis provides new insights that can help guide clinical practice and future research in the treatment of resectable NSCLC. We hope that the revisions we have made to the manuscript demonstrate the relevance and importance of our findings.

Once again, we sincerely appreciate your feedback and the opportunity to improve our manuscript. We have made the necessary revisions to address your concerns and believe that these changes strengthen the overall quality and contribution of our work. We look forward to your further comments and hope that our revised manuscript meets your expectations.

Comment 2: Please make an Excel spreadsheet with the complete data extraction available. Additionally, describe in your methods how you created Figure 3 and provide the script for its execution in your supplementary material.

Response: Thank you for your constructive feedback and for highlighting the need for transparency in data extraction and the methodology used to create our figures. We appreciate the opportunity to address these points and improve the clarity and reproducibility of our work.

Excel Spreadsheet for Data Extraction:

We understand the importance of providing a complete and transparent data extraction process. To address this, we have prepared an Excel spreadsheet containing all the data extracted from the included studies. This spreadsheet includes details such as study characteristics, patient demographics, survival outcomes (OS, EFS), pathological responses, and adverse events (AEs). Each data point is clearly labeled and referenced to the corresponding study to ensure transparency.

We will include this Excel file as supplementary material to the manuscript, making it accessible to readers and reviewers. This will allow for full transparency in how data were collected and analyzed in our meta-analysis.

Description of Methods for Figure 3

Figure 3 presents the comparisons of overall survival rate (OSR) and event-free survival rate (EFSR) between the PPI and chemotherapy groups at various time points. The process of creating Figure 3 was relatively straightforward and did not require specialized coding.

Figures 3A and 3B were generated using Excel, as illustrated in the figures below. The survival rates and standard deviations at various time points were calculated by pooling the data from the included studies using SPSS software.

To better illustrate the trend of survival differences between the two groups over time, we further created Figures 3C and 3D. The data for these figures were derived from the comparison of survival rate differences between the two groups in RevMan 5.3 (Figures S2 and S3). We extracted the RR values and their 95% confidence intervals for OSR and EFSR at each time point and then imported them into SPSS for plotting. The detailed process of creating these figures is outlined below.

The creation of these two figures allows readers to better understand the survival rates at different time points for each group and the trend of survival differences between the two groups over time. Your inquiry into the above issues suggests that you are also an expert in evidence-based statistics, and we hope to have more opportunities for collaboration in evidence-based research in the future.

Finally, we sincerely appreciate your careful review of our paper and the valuable insights you provided. Your comments have greatly contributed to the improvement of the quality of our manuscript.

We tried our best to improve the manuscript and made some changes in the manuscript. These changes do not influence the framework of the paper.

We sincerely appreciate the reviewers’ work and hope that the corrections make the paper satisfactory. At the same time, we look forward to hearing positive decisions/comments from the editors/external reviewers as soon as possible.

Once again, thank you very much for your comments and suggestions.

Thank you and best regards.

Sincerely,

Corresponding Author:

Name: Qimin Zhang

E-mail: thx

Attachment Submitted filename: Response to reviewers.docx

10.1371/journal.pone.0310808.r003
Decision Letter 1
Raza Afsheen Academic Editor
© 2024 Afsheen Raza
2024
Afsheen Raza
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version1
4 Sep 2024

Perioperative PD-1/PD-L1 inhibitors for resectable non-small cell lung cancer: a meta-analysis based on randomized controlled trials

PONE-D-24-26934R1

Dear Dr. Zhang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Afsheen Raza, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

10.1371/journal.pone.0310808.r004
Acceptance letter
Raza Afsheen Academic Editor
© 2024 Afsheen Raza
2024
Afsheen Raza
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
15 Sep 2024

PONE-D-24-26934R1

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