Neoadjuvant PD-1/PD-L1 inhibitors combined with chemotherapy had a higher ORR than mono-immunotherapy in untreated HNSCC: Meta-analysis

Neoadjuvant PD-1/PD-L1 inhibitors combined with chemotherapy had a higher ORR than mono-immunotherapy in untreated HNSCC: Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Neoadjuvant PD-1/PD-L1 inhibitors combined with chemotherapy had a higher ORR than mono-immunotherapy in untreated HNSCC: Meta-analysis Shaoshi Chen, Yifan Yang, Ru Wang, Jugao Fang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2766925/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Oct, 2023 Read the published version in Oral Oncology → Version 1 posted You are reading this latest preprint version Abstract Background: HNSCC is one of the most common types of cancer worldwide and immune checkpoint inhibitor has shown favorable therapeutic effect in R/M HNSC. However, the application of immunotherapy in untreated HNSCC still needs to be discovered since most R/M HNSCC patients have been treated before and their drug susceptibility and immune tumor microenvironment have changed. This meta-analysis tries to compare immunotherapy and immunochemotherapy in untreated HNSCC and give a reference for clinic application. Methods: Electronic databases, including PubMed, Embase, and Web of Science, were systematically searched from inception through August 31, 2022. The primary outcomes were efficacy, evaluated by objective response rate, 1-year OS and 1-year PFS, and safety, evaluated by grade 3–4 adverse reaction rate. Results: A total of 1092 patients from twenty-four studies were included, 282 (25.8%) of which had ORR reported. The average ORR was 37% (95%CI = 26%-49%). Immunochemotherapy could have higher ORR than immunotherapy patients (ORR: 61% vs 22%), and favorable 1-year overall survival from PD-L1 inhibitor (OS = 84%, 95%CI 76%-93%). Radiotherapy after neoadjuvant immunotherapy was equal with the other treatments like chemotherapy and surgery (84% vs 88%, subgroup df p = 0.7). There was no apparent difference between immunotherapy and immunochemotherapy (32% vs 42%, subgroup df p = 0.60). Conclusion: HNSCC patients could benefit more from neoadjuvant immunochemotherapy. head and neck squamous cell carcinoma PD-L1 inhibitor immunotherapy chemotherapy objective response rate Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Head and neck cancer is the sixth most common cancer worldwide, where squamous cell carcinoma (HNSCC) accounts for over 90% of patients. However, the 5-year survival of HNSCC remained at 40–50% stably in the past decades[ 1 ]. Immune checkpoint inhibitors as a promising approach might play a role in HNSCC treatment. Since PD-L1 inhibitors pembrolizumab and nivolumab had impressive effects on recurrent/metastatic (R/M) HNSCC, they were both approved by FDA for platinum-refractory advanced HNSCC[ 2 ]. Immunotherapy could induce tumor microenvironment change and enhance the sensibility of subsequent therapy[ 3 ]. The time or sequence of treatment protocol might be one of the keys to overcoming difficulties in tumor precision therapy[ 4 ]. Neoadjuvant treatment aims to reduce potential metastasis, convert unresectable to resectable disease, and restore organ functions. The application of PD-L1 inhibitors in neoadjuvant treatment might enhance those effects. Therefore, we performed a meta-analysis based on the current clinical trials to evaluate side effects and benefits from neoadjuvant immunotherapy in HNSCC, such as ORR and OS. 2. Materials And Methods 2.1 Inclusion criteria of studies Clinical trials studying the intervention of ICI inhibitors as induction chemotherapy in HNSCC patients without distant metastasis were involved in this analysis. All the studies were limited to those officially published in English. Every patient had a potentially curable primary lesion, and the primary tumor sites included the oral cavity, oropharynx, hypopharynx, and larynx, except the nasopharynx. The Institute of Health Economics (IHE) quality appraisal tool evaluated the methodological quality of case series studies[ 5 , 6 ]. Two major sets of regimens were compared: immunotherapy versus immunochemotherapy as neoadjuvant treatment, immunotherapy followed by radiotherapy versus non-radiotherapy. 2.2 Search strategy PubMed (NLM NIH), Embase (Elsevier), and Web of Science (Clarivate) were searched from inception through August 31, 2022. The search strategies used a combination of subject headings (e.g., MeSH in PubMed) and keywords such as head and neck cancer, head and neck squamous cell carcinoma, oral cancer, oropharyngeal cancer, program cell death one receptor, PD-1 protein, antineoplastic combined chemotherapy protocols (Fig. 1 ). References were uploaded to EndNote (Clarivate Analytics, Philadelphia, Pennsylvania) and screened for relevance. Our protocol has been registered in the PROSPERO platform (ID: CRD42022364602). 2.3 Data extraction Several parameters were extracted from each article: trial name, publication year, study design, drug and dose, number of participants, age, gender, tumor stage, primary tumor site, objective response rate (ORR), overall survival (OS), progression-free survival (PFS), the median time of follow-up, median OS, and median PFS. ORR was extracted as the percentage of patients with complete or partial response according to the guideline of response evaluation criteria in solid tumors (RECIST version 1.1)[ 7 ]. 2.4 Statistical Analysis Continuous variables were reported as mean ± standard deviation (or median and range). Subgroup analysis of ORR was performed according to the treatment used. Statistical heterogeneity was detected using the Cochran Q chi-square test and inconsistency index. A fixed-effects model was used if the studies had low heterogeneity (P > 0.1, I2 < 50%). Otherwise, a random-effect model was applied. All statistical analyses were conducted with Review Manager version 5.4 and STATA version 16. 3. Results 3.1 Study Characteristics A literature search identified 754 records after removing duplicates (Table 1 ). Twenty-four studies with neoadjuvant immune therapy met the inclusion criteria after screening by title, abstract, and full text. And 12 studies reported ORR data (Fig. 2 )[ 8 – 19 ]. Most of the studies were published in full-text articles, while five were in abstracts. Institute of Health Economics (IHE) qualified all the case series studies. According to funnel plots and Egger’s test, there was no publication bias among this set of studies included in the meta-analysis. Table 1 Characteristics of Studies of Neoadjuvant Immunotherapy in Head and Neck Cancer 3.2 Patients Characteristics A total of 1092 patients were included, 282 (25.8%) of which had ORR reported. Most patients were male (74.7%); the median age was 57.1 years. The most common primary tumor site was the oral cavity (n = 433, 43%), while the larynx and hypopharynx accounted for 12.4% and 12.1%, respectively. 3.3 Higher Objective Response Rate in Immunochemotherapy Group Based on ORR, the subgroup analysis aimed to assess the clinical efficacy difference between the PD-1 inhibitor alone and the PD-1 inhibitor combined with chemotherapy. A total of 281 patients from 12 studies with reported ORR were interested in this meta-analysis (Fig. 2 ). Regardless of immunochemotherapy and immunotherapy, the average ORR was 37% (95%CI = 26%-49%). The subgroup result indicated that immunochemotherapy could have higher ORR than immunotherapy patients (ORR: 61% vs 22%). 3.4 Favorable 1-Year Overall Survival and 1-year PFS in PD-1 Inhibitor Ten studies of 585 patients reported that targeted patients had favorable 1-year overall survival from PD-1 inhibitor (OS = 84%, 95%CI 76%-93%). Subgroup analysis indicated that radiotherapy after neoadjuvant immunotherapy did not have better outcomes than the other treatment like chemotherapy and surgery (84% vs 88%, subgroup df p = 0.73; Fig. 3 ). Seven studies of 230 patients showed that 1-year PFS was 82%, ranging from 69%-95%. Subgroup analysis based on radiotherapy and non-radiotherapy showed their 1-year PFS were 81% and 86% (subgroup df p = 0.80; Fig. 4 ) 3.5 Treatment-related Adverse Events A total of 1056 patients from twenty-two studies indicated that the grade 3–4 adverse reaction rate was 35% (95%CI = 16%-55%). And the subgroup analysis showed there was no apparent difference between immunotherapy and immunochemotherapy (32% vs 42%, subgroup df p = 0.60; Fig. 5 ). 4. Discussion 4.1 Addition of chemotherapy in PD-1 inhibitors could improve ORR Immunotherapy has shown heart-stirring effects on R/M HNSCC and potential clinical benefits for HNSCC patients, but its effects as neoadjuvant treatments in HNSCC need to be discovered. This meta-analysis summarizes the current clinical immunotherapy trials of untreated HNSCC patients since most R/M HNSCC patients had been treated before, and their gene expression had changed. Through analysis of 12 studies, including 281 patients, we figured out combining chemotherapy and PD-1 inhibitors in neoadjuvant treatment could improve ORR compared with immunotherapy only (61% vs 22%). Neoadjuvant therapies have multiple choices. For example, the application of induction chemotherapy in HNSCC is wildly used, and the standard treatment plans included docetaxel plus cisplatin and fluorouracil (TPF) and cisplatin and fluorouracil (PF). The clinical trial showed that both could inhibit tumor growth, where ORR in TPF and PF are 68% and 54%, respectively[ 20 ]. Although PD-1 inhibitors have a similar ORR to PF, it does not mean the TPF patients’ prognoses surpass PD-1 inhibitors. ORR is an excellent clinical parameter to evaluate the tumor treatment response based on imageology, but it has limitations, especially in immunotherapy. Inflammatory pseudotumor is a benign process involving acute and chronic inflammatory cells histologically, which has similar imaging findings[ 21 ]. Due to the immune effects of PD-1 inhibitors, this phenomenon often occurs in immunotherapy patients, and the solid mass includes tumor and immune cells, leading to a bias in ORR evaluation. Hence, the immune-related ORR might be underestimated compared with TPF chemotherapy in HNCSS, and the patients might get more potential clinical benefits from immunotherapy. 4.2 Immunotherapy has a high 1-year OS and 1-year PFS The primary clinical outcomes for tumor patients are OS and PFS, both of which could evaluate the clinical benefits patients get. The immunotherapy patients have considerable 1-year OS and 1-year PFS, with 84% and 82% respectively, while 1-year OS in TPF and PF were 72% and 52%; 1-year PFS in TPF and PF were 47% and 30.6%, respectively [ 20 ]. This difference could be due to two reasons: PD-1 inhibitors could increase the incidence of 1-year OS and 1-year PFS; or a bias occurred. The most likely bias was probably because most patients in this meta-analysis were oral cavity (43%), rather than the oropharynx in the chemotherapy study (46.1%). Moreover, there was a clear relationship between human papillomavirus (HPV) infection and prognosis in oropharyngeal squamous cell carcinoma (OPSCC), while this correlation might not work in oral cavity cancer[ 22 ]. further study needs to distinguish which is the major. 4.3 Radiotherapy is equal to the other treatment in PD-L1 inhibitors Radiotherapy is the main treatment in HNSCC, whose combination with immunotherapy could induce antitumor effects in multiple cancers. It not only generated the cytotoxic effect on the cancer cells, but also rebuild the tumor microenvironment, where the radiotherapy failure with PD-L1 expression might be reversed by PD-1 inhibitors, leading to an increase in efficacy[ 23 ]. But this process persisted only a short time. Hence, the key to this increased efficacy is time and sequence rather than a simple combination[ 4 ]. Dovedi et al. pointed out that this therapeutic benefit only occurred when concurrent immunoradiotherapy or immunotherapy following radiotherapy immediately, instead of delaying administration of PD-1 inhibitors by seven days after completion of radiotherapy[ 24 ]. Therefore, neoadjuvant immune treatment might be optional by creating an immune-active tumor microenvironment for further radiotherapy[ 25 ]. However, the subgroup analysis of both 1-year OS and 1-year PFS indicated no difference between radiotherapy and non-radiotherapy. There were no comparable three or five clinical outcomes because the follow-up time of involved studies in our meta-analysis was less than three years. Therefore, it is easier to figure out which treatment is better than the others once the clinical outcomes are reported on a three-year or five-year scale. 4.4 Treatment-related adverse events In this meta-analysis, the overall grade 3 to 4 adverse reaction rate was 35% (95%CI = 16%-55%), which is different from a previous meta-analysis (8.4%, 95%CI = 0.2%-23.2%)[ 26 ]. But this previous meta-analysis involved ten studies, including eight immunotherapy studies especially and two immunochemotherapy studies. The absence of enough chemotherapy combination studies might account for why this difference occurred. Besides, another meta-analysis involving 17197 immunotherapy patients in multiple cancers from 161 studies indicated that the grade 3 to 4 adverse reaction rate in immunochemotherapy was 68.3% (95%CI = 60.7%-75%)[ 27 ]. HNSCC was similar to other involved cancer like immunosuppressed tumor microenvironment but different, such as HPV. Our meta-analysis could provide a reference for untreated HNSCC. Although the subgroup analysis in this meta-analysis showed no significant statistical difference between immunochemotherapy and immunotherapy, there was a tendency which immunochemotherapy had a higher adverse reaction rate. It was hard to tell whether immunotherapy would not enhance the side effects of chemotherapy or whether the addition of chemotherapy could increase the adverse reaction rate in immunotherapy. More convincing results need more immunotherapy-applied studies involved. 5. Limitation There are several limitations to this meta-analysis. Firstly, the number of clinical trials and included patients needed to be increased. Besides, the variation in the primary tumor site, treatment protocols, immunotherapeutic subagents, and study design all account for this meta-analysis's heterogeneity and power. In the end, long-term clinical outcomes like 5-year OS have not been reported. 6. Conclusion This meta-analysis indicated that HNSCC patients could get clinical benefits from neoadjuvant immunotherapy, especially a combination of chemotherapy. But the conclusive evidence of this treatment protocol needs more long-term clinical data. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials All data generated or analysed during this study are included in this published article [and its supplementary information files]. Competing interests The authors declare no conflict of interest. Funding This study was funded by grants from Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (Grant No. KZ201910025034), The Capital Health Research and Development of Special (No.2022-1-2051), National Key R&D Program of China (No. 2020YFB1312805), and Beijing Municipal Administration of Hospitals’ Ascent Plan (Grant No. DFL20180202). Authors' contributions resources, Shaoshi Chen.; data curation, Shaoshi Chen; writing—original draft preparation, Shaoshi Chen; writing—review and editing, Shaoshi Chen; visualization, Shaoshi Chen; supervision, Yifan Yang. Ru Wang. Jugao Fang; project administration, Jugao Fang; funding acquisition, Jugao Fang. All authors have read and agreed to the published version of the manuscript. Acknowledgments During the formation of this meta-analysis, I have receiver a great deal of support and assistance. Firstly, I would like to thank my supervisor, Jugao Fang, whose expertise was invaluable in formulating the research questions and methodology. His insightful feedback sharpened my thinking and brought my work to a higher level. Secondly, I would particularly like to acknowledge Yifan Yang and Ru Wang, for their guideline and patient support. Finally, I would like to thank my parents for sympathetic ear and their understanding of my decision to be a doctor. You are always there for me. References Canning M, Guo G, Yu M, Myint C, Groves MW, Byrd JK, et al. Heterogeneity of the Head and Neck Squamous Cell Carcinoma Immune Landscape and Its Impact on Immunotherapy. Front Cell Dev Biol. 2019;7:52. Cohen EEW, Soulieres D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019;393(10167):156-67. Saleh K, Khalifeh-Saleh N, Kourie HR, Nasr F, Chahine G. Do immune checkpoint inhibitors increase sensitivity to salvage chemotherapy? Immunotherapy. 2018(1750-7448 (Electronic)):10(3):163-5. Wahida A, Buschhorn L, Frohling S, Jost PJ, Schneeweiss A, Lichter P, et al. The coming decade in precision oncology: six riddles. Nat Rev Cancer. 2022. C M, B G, D S, C H. Development of a Quality Appraisal Tool for Case Series Studies Using a Modified Delphi Technique. Edmonton AB: Institute of Health Economics. 2012. Guo B, Moga C, Harstall C, Schopflocher D. A principal component analysis is conducted for a case series quality appraisal checklist. J Clin Epidemiol. 2016;69:199-207 e2. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. Curti BD, Koguchi Y, Leidner RS, Rolig AS, Sturgill ER, Sun Z, et al. 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JAMA Oncol. 2020;6(10):1563-70. Vos JL, Elbers JBW, Krijgsman O, Traets JJH, Qiao X, van der Leun AM, et al. Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma. Nat Commun. 2021;12(1):7348. Zhang Z, Wu B, Peng G, Xiao G, Huang J, Ding Q, et al. Neoadjuvant Chemoimmunotherapy for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm Phase 2 Clinical Trial. Clin Cancer Res. 2022:Of1-of9. Zhong LP, Huang YY, Sun JJ, Li J, Dong MJ, Zhu GP, et al. Inductive anti-PD-1 and albumin paclitaxel/cisplatin on pathological response in patients with locally advanced oral squamous cell carcinoma: A single arm trial. Annals of Oncology. 2021;32:S1443. Zhong LP, Ju WT, Xia RH, Zhu Q, Zhu G, Dou S, et al. Inductive camrelizumab and apatinib for patients with locally advanced and resectable oral squamous cell carcinoma: A single-arm trial (Icemelting trial). Journal of Clinical Oncology. 2021;39(15 SUPPL). Vermorken JB, Remenar E Fau - van Herpen C, van Herpen C Fau - Gorlia T, Gorlia T Fau - Mesia R, Mesia R Fau - Degardin M, Degardin M Fau - Stewart JS, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007(1533-4406 (Electronic)):357(17):1695-704. Patnana M, Sevrukov AB, Elsayes KM, Viswanathan C, Lubner M, Menias CO. Inflammatory pseudotumor: the great mimicker. AJR Am J Roentgenol. 2012;198(3):W217-27. Hubbers CU, Akgul B. HPV and cancer of the oral cavity. Virulence. 2015;6(3):244-8. Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol. 2017;14(6):365-79. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74(19):5458-68. Karam SD, Raben D. Radioimmunotherapy for the treatment of head and neck cancer. Lancet Oncol. 2019;20(8):e404-e16. Masarwy R, Kampel L, Horowitz G, Gutfeld O, Muhanna N. Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer: A Systematic Review and Meta-analysis. JAMA Otolaryngol Head Neck Surg. 2021;147(10):871-8. Zhou X, Yao Z, Bai H, Duan J, Wang Z, Wang X, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis. Lancet Oncol. 2021;22(9):1265-74. Additional Declarations No competing interests reported. Supplementary Files supplementaryfigures.docx Cite Share Download PDF Status: Published Journal Publication published 01 Oct, 2023 Read the published version in Oral Oncology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2766925","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":191810732,"identity":"936f0547-204e-4d2a-80d3-a22564c261a6","order_by":0,"name":"Shaoshi Chen","email":"","orcid":"","institution":"Beijing Tongren Hospital, Capital Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shaoshi","middleName":"","lastName":"Chen","suffix":""},{"id":191810733,"identity":"f8eb003e-f6fe-42ef-b7aa-86eb003f7348","order_by":1,"name":"Yifan Yang","email":"","orcid":"","institution":"Beijing Tongren Hospital, Capital Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yifan","middleName":"","lastName":"Yang","suffix":""},{"id":191810734,"identity":"1d3b7c38-f55c-460d-aca0-6ed45d1b62d0","order_by":2,"name":"Ru Wang","email":"","orcid":"","institution":"Beijing Tongren Hospital, Capital Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ru","middleName":"","lastName":"Wang","suffix":""},{"id":191810735,"identity":"96837146-dcfa-4a05-976f-349bf4e42c7f","order_by":3,"name":"Jugao Fang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYBAC9gYgIQFmNTY+/ECMFp4DMC08h5uNJYjWAgYS6W0CPERpYT97+IVlW608v+TDNqB1dnK6DYS08OSlWUi2HTecOTux7UEBQ7Kx2QECWuwZcswMJNuOMW64ndhuIMFwIHEbIS08/G/AWuw33DzYJsFDlBaJHOMHkm01iRtuMBKt5Y0Zg8S5A8kzexKBgWxAhF94+HOMP0uU1dn2sx9/+PBDhZ0cQS1AwCYtwXAYyjYgrBwEmD9+YKgjTukoGAWjYBSMTAAAsW5COj+6bS0AAAAASUVORK5CYII=","orcid":"","institution":"Beijing Tongren Hospital, Capital Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jugao","middleName":"","lastName":"Fang","suffix":""}],"badges":[],"createdAt":"2023-04-02 07:14:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2766925/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2766925/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1016/j.oraloncology.2023.106479","type":"published","date":"2023-10-01T06:11:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":35893418,"identity":"1db857bb-09a0-471a-86f5-6b141e6f99f5","added_by":"auto","created_at":"2023-04-17 20:28:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":36395,"visible":true,"origin":"","legend":"\u003cp\u003eFlow Diagram\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2766925/v1/8b92d24e15cde97a37929a3d.png"},{"id":35893417,"identity":"dffa45e9-b875-4a81-953f-0d69317b6aef","added_by":"auto","created_at":"2023-04-17 20:28:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":138497,"visible":true,"origin":"","legend":"\u003cp\u003eORR analysis of immunotherapy in HNSCC. 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Subgroup analysis based on combination of radiotherapy\u003c/p\u003e","description":"","filename":"figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-2766925/v1/44d5ddf16446d6852752dd9e.png"},{"id":35893744,"identity":"0aea0ec7-9bbf-437c-b20c-15249c2f9954","added_by":"auto","created_at":"2023-04-17 20:36:48","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":156410,"visible":true,"origin":"","legend":"\u003cp\u003eGrade 3-4 adverse reaction rate of immunotherapy in HNSCC. Subgroup analysis based on combination of chemotherapy\u003c/p\u003e","description":"","filename":"figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-2766925/v1/b10da579cf199144edbcaa13.png"},{"id":58786426,"identity":"0cfafa2e-98e0-487a-a433-ef9068f3e18e","added_by":"auto","created_at":"2024-06-21 06:11:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":991910,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2766925/v1/04322e1f-c8be-4a59-a00e-606569b62b7c.pdf"},{"id":35893422,"identity":"84518982-484c-4279-bd9f-113d852f3028","added_by":"auto","created_at":"2023-04-17 20:28:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":610218,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryfigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-2766925/v1/f669a030eb2d5fc425313e1c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neoadjuvant PD-1/PD-L1 inhibitors combined with chemotherapy had a higher ORR than mono-immunotherapy in untreated HNSCC: Meta-analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eHead and neck cancer is the sixth most common cancer worldwide, where squamous cell carcinoma (HNSCC) accounts for over 90% of patients. However, the 5-year survival of HNSCC remained at 40\u0026ndash;50% stably in the past decades[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Immune checkpoint inhibitors as a promising approach might play a role in HNSCC treatment. Since PD-L1 inhibitors pembrolizumab and nivolumab had impressive effects on recurrent/metastatic (R/M) HNSCC, they were both approved by FDA for platinum-refractory advanced HNSCC[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Immunotherapy could induce tumor microenvironment change and enhance the sensibility of subsequent therapy[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The time or sequence of treatment protocol might be one of the keys to overcoming difficulties in tumor precision therapy[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Neoadjuvant treatment aims to reduce potential metastasis, convert unresectable to resectable disease, and restore organ functions. The application of PD-L1 inhibitors in neoadjuvant treatment might enhance those effects. Therefore, we performed a meta-analysis based on the current clinical trials to evaluate side effects and benefits from neoadjuvant immunotherapy in HNSCC, such as ORR and OS.\u003c/p\u003e"},{"header":"2. Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Inclusion criteria of studies\u003c/h2\u003e \u003cp\u003eClinical trials studying the intervention of ICI inhibitors as induction chemotherapy in HNSCC patients without distant metastasis were involved in this analysis. All the studies were limited to those officially published in English. Every patient had a potentially curable primary lesion, and the primary tumor sites included the oral cavity, oropharynx, hypopharynx, and larynx, except the nasopharynx. The Institute of Health Economics (IHE) quality appraisal tool evaluated the methodological quality of case series studies[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Two major sets of regimens were compared: immunotherapy versus immunochemotherapy as neoadjuvant treatment, immunotherapy followed by radiotherapy versus non-radiotherapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Search strategy\u003c/h2\u003e \u003cp\u003ePubMed (NLM NIH), Embase (Elsevier), and Web of Science (Clarivate) were searched from inception through August 31, 2022. The search strategies used a combination of subject headings (e.g., MeSH in PubMed) and keywords such as head and neck cancer, head and neck squamous cell carcinoma, oral cancer, oropharyngeal cancer, program cell death one receptor, PD-1 protein, antineoplastic combined chemotherapy protocols (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). References were uploaded to EndNote (Clarivate Analytics, Philadelphia, Pennsylvania) and screened for relevance. Our protocol has been registered in the PROSPERO platform (ID: CRD42022364602).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data extraction\u003c/h2\u003e \u003cp\u003eSeveral parameters were extracted from each article: trial name, publication year, study design, drug and dose, number of participants, age, gender, tumor stage, primary tumor site, objective response rate (ORR), overall survival (OS), progression-free survival (PFS), the median time of follow-up, median OS, and median PFS. ORR was extracted as the percentage of patients with complete or partial response according to the guideline of response evaluation criteria in solid tumors (RECIST version 1.1)[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical Analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (or median and range). Subgroup analysis of ORR was performed according to the treatment used. Statistical heterogeneity was detected using the Cochran Q chi-square test and inconsistency index. A fixed-effects model was used if the studies had low heterogeneity (P\u0026thinsp;\u0026gt;\u0026thinsp;0.1, I2\u0026thinsp;\u0026lt;\u0026thinsp;50%). Otherwise, a random-effect model was applied. All statistical analyses were conducted with Review Manager version 5.4 and STATA version 16.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study Characteristics\u003c/h2\u003e \u003cp\u003eA literature search identified 754 records after removing duplicates (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Twenty-four studies with neoadjuvant immune therapy met the inclusion criteria after screening by title, abstract, and full text. And 12 studies reported ORR data (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)[\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Most of the studies were published in full-text articles, while five were in abstracts. Institute of Health Economics (IHE) qualified all the case series studies. According to funnel plots and Egger\u0026rsquo;s test, there was no publication bias among this set of studies included in the meta-analysis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of Studies of Neoadjuvant Immunotherapy in Head and Neck Cancer\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/122228_c8a1650c59388082/122228_custom_files/img1681760350.png\"\u003e\u003cbr\u003e\u003c/p\u003e\u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Patients Characteristics\u003c/h2\u003e \u003cp\u003eA total of 1092 patients were included, 282 (25.8%) of which had ORR reported. Most patients were male (74.7%); the median age was 57.1 years. The most common primary tumor site was the oral cavity (n\u0026thinsp;=\u0026thinsp;433, 43%), while the larynx and hypopharynx accounted for 12.4% and 12.1%, respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Higher Objective Response Rate in Immunochemotherapy Group\u003c/h2\u003e \u003cp\u003eBased on ORR, the subgroup analysis aimed to assess the clinical efficacy difference between the PD-1 inhibitor alone and the PD-1 inhibitor combined with chemotherapy. A total of 281 patients from 12 studies with reported ORR were interested in this meta-analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Regardless of immunochemotherapy and immunotherapy, the average ORR was 37% (95%CI\u0026thinsp;=\u0026thinsp;26%-49%). The subgroup result indicated that immunochemotherapy could have higher ORR than immunotherapy patients (ORR: 61% vs 22%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Favorable 1-Year Overall Survival and 1-year PFS in PD-1 Inhibitor\u003c/h2\u003e \u003cp\u003eTen studies of 585 patients reported that targeted patients had favorable 1-year overall survival from PD-1 inhibitor (OS\u0026thinsp;=\u0026thinsp;84%, 95%CI 76%-93%). Subgroup analysis indicated that radiotherapy after neoadjuvant immunotherapy did not have better outcomes than the other treatment like chemotherapy and surgery (84% vs 88%, subgroup df p\u0026thinsp;=\u0026thinsp;0.73; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSeven studies of 230 patients showed that 1-year PFS was 82%, ranging from 69%-95%. Subgroup analysis based on radiotherapy and non-radiotherapy showed their 1-year PFS were 81% and 86% (subgroup df p\u0026thinsp;=\u0026thinsp;0.80; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Treatment-related Adverse Events\u003c/h2\u003e \u003cp\u003eA total of 1056 patients from twenty-two studies indicated that the grade 3\u0026ndash;4 adverse reaction rate was 35% (95%CI\u0026thinsp;=\u0026thinsp;16%-55%). And the subgroup analysis showed there was no apparent difference between immunotherapy and immunochemotherapy (32% vs 42%, subgroup df p\u0026thinsp;=\u0026thinsp;0.60; Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Addition of chemotherapy in PD-1 inhibitors could improve ORR\u003c/h2\u003e \u003cp\u003eImmunotherapy has shown heart-stirring effects on R/M HNSCC and potential clinical benefits for HNSCC patients, but its effects as neoadjuvant treatments in HNSCC need to be discovered. This meta-analysis summarizes the current clinical immunotherapy trials of untreated HNSCC patients since most R/M HNSCC patients had been treated before, and their gene expression had changed.\u003c/p\u003e \u003cp\u003eThrough analysis of 12 studies, including 281 patients, we figured out combining chemotherapy and PD-1 inhibitors in neoadjuvant treatment could improve ORR compared with immunotherapy only (61% vs 22%). Neoadjuvant therapies have multiple choices. For example, the application of induction chemotherapy in HNSCC is wildly used, and the standard treatment plans included docetaxel plus cisplatin and fluorouracil (TPF) and cisplatin and fluorouracil (PF). The clinical trial showed that both could inhibit tumor growth, where ORR in TPF and PF are 68% and 54%, respectively[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough PD-1 inhibitors have a similar ORR to PF, it does not mean the TPF patients\u0026rsquo; prognoses surpass PD-1 inhibitors. ORR is an excellent clinical parameter to evaluate the tumor treatment response based on imageology, but it has limitations, especially in immunotherapy. Inflammatory pseudotumor is a benign process involving acute and chronic inflammatory cells histologically, which has similar imaging findings[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Due to the immune effects of PD-1 inhibitors, this phenomenon often occurs in immunotherapy patients, and the solid mass includes tumor and immune cells, leading to a bias in ORR evaluation. Hence, the immune-related ORR might be underestimated compared with TPF chemotherapy in HNCSS, and the patients might get more potential clinical benefits from immunotherapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Immunotherapy has a high 1-year OS and 1-year PFS\u003c/h2\u003e \u003cp\u003eThe primary clinical outcomes for tumor patients are OS and PFS, both of which could evaluate the clinical benefits patients get. The immunotherapy patients have considerable 1-year OS and 1-year PFS, with 84% and 82% respectively, while 1-year OS in TPF and PF were 72% and 52%; 1-year PFS in TPF and PF were 47% and 30.6%, respectively [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This difference could be due to two reasons: PD-1 inhibitors could increase the incidence of 1-year OS and 1-year PFS; or a bias occurred. The most likely bias was probably because most patients in this meta-analysis were oral cavity (43%), rather than the oropharynx in the chemotherapy study (46.1%). Moreover, there was a clear relationship between human papillomavirus (HPV) infection and prognosis in oropharyngeal squamous cell carcinoma (OPSCC), while this correlation might not work in oral cavity cancer[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. further study needs to distinguish which is the major.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Radiotherapy is equal to the other treatment in PD-L1 inhibitors\u003c/h2\u003e \u003cp\u003eRadiotherapy is the main treatment in HNSCC, whose combination with immunotherapy could induce antitumor effects in multiple cancers. It not only generated the cytotoxic effect on the cancer cells, but also rebuild the tumor microenvironment, where the radiotherapy failure with PD-L1 expression might be reversed by PD-1 inhibitors, leading to an increase in efficacy[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. But this process persisted only a short time. Hence, the key to this increased efficacy is time and sequence rather than a simple combination[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Dovedi et al. pointed out that this therapeutic benefit only occurred when concurrent immunoradiotherapy or immunotherapy following radiotherapy immediately, instead of delaying administration of PD-1 inhibitors by seven days after completion of radiotherapy[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Therefore, neoadjuvant immune treatment might be optional by creating an immune-active tumor microenvironment for further radiotherapy[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. However, the subgroup analysis of both 1-year OS and 1-year PFS indicated no difference between radiotherapy and non-radiotherapy. There were no comparable three or five clinical outcomes because the follow-up time of involved studies in our meta-analysis was less than three years. Therefore, it is easier to figure out which treatment is better than the others once the clinical outcomes are reported on a three-year or five-year scale.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Treatment-related adverse events\u003c/h2\u003e \u003cp\u003eIn this meta-analysis, the overall grade 3 to 4 adverse reaction rate was 35% (95%CI\u0026thinsp;=\u0026thinsp;16%-55%), which is different from a previous meta-analysis (8.4%, 95%CI\u0026thinsp;=\u0026thinsp;0.2%-23.2%)[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. But this previous meta-analysis involved ten studies, including eight immunotherapy studies especially and two immunochemotherapy studies. The absence of enough chemotherapy combination studies might account for why this difference occurred. Besides, another meta-analysis involving 17197 immunotherapy patients in multiple cancers from 161 studies indicated that the grade 3 to 4 adverse reaction rate in immunochemotherapy was 68.3% (95%CI\u0026thinsp;=\u0026thinsp;60.7%-75%)[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. HNSCC was similar to other involved cancer like immunosuppressed tumor microenvironment but different, such as HPV. Our meta-analysis could provide a reference for untreated HNSCC. Although the subgroup analysis in this meta-analysis showed no significant statistical difference between immunochemotherapy and immunotherapy, there was a tendency which immunochemotherapy had a higher adverse reaction rate. It was hard to tell whether immunotherapy would not enhance the side effects of chemotherapy or whether the addition of chemotherapy could increase the adverse reaction rate in immunotherapy. More convincing results need more immunotherapy-applied studies involved.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Limitation","content":"\u003cp\u003eThere are several limitations to this meta-analysis. Firstly, the number of clinical trials and included patients needed to be increased. Besides, the variation in the primary tumor site, treatment protocols, immunotherapeutic subagents, and study design all account for this meta-analysis's heterogeneity and power. In the end, long-term clinical outcomes like 5-year OS have not been reported.\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eThis meta-analysis indicated that HNSCC patients could get clinical benefits from neoadjuvant immunotherapy, especially a combination of chemotherapy. But the conclusive evidence of this treatment protocol needs more long-term clinical data.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by grants from Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (Grant No. KZ201910025034), The Capital Health Research and Development of Special (No.2022-1-2051), National Key R\u0026amp;D Program of China (No. 2020YFB1312805), and Beijing Municipal Administration of Hospitals\u0026rsquo; Ascent Plan (Grant No. DFL20180202).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eresources, Shaoshi Chen.; data curation, Shaoshi Chen; writing\u0026mdash;original draft preparation, Shaoshi Chen; writing\u0026mdash;review and editing, Shaoshi Chen; visualization, Shaoshi Chen; supervision, Yifan Yang. Ru Wang. Jugao Fang; project administration, Jugao Fang; funding acquisition, Jugao Fang. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the formation of this meta-analysis, I have receiver a great deal of support and assistance.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Firstly, I would like to thank my supervisor, Jugao Fang, whose expertise was invaluable in formulating the research questions and methodology. His insightful feedback sharpened my thinking and brought my work to a higher level.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Secondly, I would particularly like to acknowledge Yifan Yang and Ru Wang, for their guideline and patient support.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Finally, I would like to thank my parents for sympathetic ear and their understanding of my decision to be a doctor. You are always there for me.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCanning M, Guo G, Yu M, Myint C, Groves MW, Byrd JK, et al. Heterogeneity of the Head and Neck Squamous Cell Carcinoma Immune Landscape and Its Impact on Immunotherapy. Front Cell Dev Biol. 2019;7:52.\u003c/li\u003e\n\u003cli\u003eCohen EEW, Soulieres D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019;393(10167):156-67.\u003c/li\u003e\n\u003cli\u003eSaleh K, Khalifeh-Saleh N, Kourie HR, Nasr F, Chahine G. Do immune checkpoint inhibitors increase sensitivity to salvage chemotherapy? Immunotherapy. 2018(1750-7448 (Electronic)):10(3):163-5.\u003c/li\u003e\n\u003cli\u003eWahida A, Buschhorn L, Frohling S, Jost PJ, Schneeweiss A, Lichter P, et al. 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Lancet Oncol. 2021;22(9):1265-74.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"head and neck squamous cell carcinoma, PD-L1 inhibitor, immunotherapy, chemotherapy, objective response rate","lastPublishedDoi":"10.21203/rs.3.rs-2766925/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2766925/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground:\u003cstrong\u003e \u003c/strong\u003eHNSCC is one of the most common types of cancer worldwide and immune checkpoint inhibitor has shown favorable therapeutic effect in R/M HNSC. However, the application of immunotherapy in untreated HNSCC still needs to be discovered since most R/M HNSCC patients have been treated before and their drug susceptibility and immune tumor microenvironment have changed. This meta-analysis tries to compare immunotherapy and immunochemotherapy in untreated HNSCC and give a reference for clinic application.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: Electronic databases, including PubMed, Embase, and Web of Science, were systematically searched from inception through August 31, 2022. The primary outcomes were efficacy, evaluated by objective response rate, 1-year OS and 1-year PFS, and safety, evaluated by grade 3–4 adverse reaction rate.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: A total of 1092 patients from twenty-four studies were included, 282 (25.8%) of which had ORR reported. The average ORR was 37% (95%CI = 26%-49%). Immunochemotherapy could have higher ORR than immunotherapy patients (ORR: 61% vs 22%), and favorable 1-year overall survival from PD-L1 inhibitor (OS = 84%, 95%CI 76%-93%). Radiotherapy after neoadjuvant immunotherapy was equal with the other treatments like chemotherapy and surgery (84% vs 88%, subgroup df p = 0.7). There was no apparent difference between immunotherapy and immunochemotherapy (32% vs 42%, subgroup df p = 0.60).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusion: HNSCC patients could benefit more from neoadjuvant immunochemotherapy.\u003c/p\u003e","manuscriptTitle":"Neoadjuvant PD-1/PD-L1 inhibitors combined with chemotherapy had a higher ORR than mono-immunotherapy in untreated HNSCC: Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-04-17 20:28:43","doi":"10.21203/rs.3.rs-2766925/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5d24db33-94aa-4546-815a-b022353f5e8d","owner":[],"postedDate":"April 17th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-06-21T06:11:50+00:00","versionOfRecord":{"articleIdentity":"rs-2766925","link":"https://doi.org/10.1016/j.oraloncology.2023.106479","journal":{"identity":"oral-oncology","isVorOnly":true,"title":"Oral Oncology"},"publishedOn":"2023-10-01 06:11:50","publishedOnDateReadable":"October 1st, 2023"},"versionCreatedAt":"2023-04-17 20:28:43","video":"","vorDoi":"10.1016/j.oraloncology.2023.106479","vorDoiUrl":"https://doi.org/10.1016/j.oraloncology.2023.106479","workflowStages":[]},"version":"v1","identity":"rs-2766925","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2766925","identity":"rs-2766925","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}