\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Role of PD-1/PD-L1 inhibitors in the treatment of recurrent/metastatic
head and neck squamous cell carcinoma: a systematic review and
meta-analysis}



\author[1]{gaofei Yin}%
\author[1]{Wei Guo}%
\author[1]{Hanyuan Duan}%
\author[1]{zhigang Huang}%
\affil[1]{Beijing Tongren Hospital Department of Otorhinolaryngology and Head and Neck Surgery}%


\vspace{-1em}



  
  \date{June 10, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background: The use of immunotherapy to treat recurrent/metastatic
squamous cell carcinoma of the head and neck has become a popular
research topic in recent years, and many clinical trials have been
carried out. Objectives: To systematically evaluate the efficacy and
safety of PD-1/PD-L1 inhibitors in the treatment of recurrent/metastatic
head and neck squamous cell carcinoma. Methods: We searched PubMed,
Embase, Cochrane Library and other databases up to 1 November 2019 for
publications reporting the use of PD-1/PD-L1 inhibitors in the treatment
of squamous cell carcinoma of the head and neck. Revman 5.0 was used for
combination analysis, and the overall survival (OS), progression-free
survival (PFS), overall response rate (ORR), and adverse events were
determined. Results: Five articles were included. Compared with other
treatment methods, this meta-analysis showed that treatment with
PD-1/PD-L1 inhibitors can significantly improve OS (P \textless{}
0.0001), but there was no significant improvement in PFS or ORR. The
risk of anaemia and nausea was significantly reduced by treatment with
PD-1/PD-L1 inhibitors. Conclusions and Significance: Treatment with
PD-1/PD-L1 inhibitors alone can improve the overall survival rate for
recurrent/metastatic squamous cell carcinoma of the head and neck but
there is no obvious advantage in other aspects and adverse events.%
\end{abstract}%



\sloppy


\textbf{Main text introduction}

Squamous cell carcinoma of the head and neck (HNSCC) is the most common
malignant tumour in that region. According to the latest GLOBOCAN report
{[}1{]}, HNSCC is the ninth most common malignant tumour in the world.
In 2018, the number of new cases worldwide was 843860, accounting for
4.6\% of all new cancer cases. Because of the nature of this disease,
there are a large number of patients who are at the late stage or local
late stage at the time of treatment. The 5-year survival rate of these
patients with traditional treatment is only 40\% {[}2{]}, and the
treatment of patients with recurrent/distant metastasis is more
difficult. At present, the first-line treatment for advanced HNSCC is
cetuximab combined with cisplatin and 5-FU, but there are low response
rates combined with drug resistance {[}3{]}.

With the anti-tumour effect of immunotherapy in non-small cell lung
cancer and other tumours, the study of immunosuppressive checkpoint
inhibitors in HNSCC has become a popular research topic at the present
time. In addition, Nivolumab {[}4{]} and Pembrolizumab {[}5{]} have been
approved by the FDA to be used in the treatment of recurrent or
metastatic HNSCC in the event of platinum treatment failure. There are a
growing number of corresponding clinical trials, but there has been no
summary analysis showing the efficacy of programmed cell death protein 1
(PD-1) and programmed cell death ligand protein 1 (PD-L1) inhibitors.

This study aimed to evaluate treatment of HNSCC with PD-1/PD-L1
inhibitors through a meta-analysis of all previous randomized controlled
trials to form a preliminary reference for follow-up clinical trials and
clinical treatment.

\textbf{Materials and methods}

Search strategy

Two authors conducted the search and study review independently. We
searched PubMed, Embase, Cochrane Library, CVID, CBM, CNKI and Web of
Science up to 1 November 2019. The search terms used were: PD-1/PD-L1
inhibitors or Pembrolizumab or Keytruda or Nivolumab or Opdivo or
Durvalumab or MEDI4736 or Atezolizumab or checkpoint inhibitors and head
and neck cancer or HNC or head and neck squamous cell carcinoma or head
and neck neoplasms or HNSCC. We also searched `clinicaltrials.gov' with
the search term Head and Neck Squamous Cell Carcinoma, and we also
searched for Squamous cell carcinoma of head and neck, Squamous cell
carcinoma of the head and neck, head and neck cancer, head and neck
neoplasms or HNSCC and PD-1/PD-L1 inhibitors or Pembrolizumab or
Keytruda or Nivolumab or Opdivo or Durvalumab or MEDI4736 or
Atezolizumab or checkpoint inhibitors.

Study selection

Randomized controlled trials (RCT) were used, and the inclusion criteria
for our meta-analysis were as follows: 1) single drug treatment with
PD-1/PD-L1 inhibitors; 2) the papers should have exact data whether in
the time domain or frequency domain; 3) the groups being compared were
treated with chemotherapy, targeted therapy, a combination of two
immunosuppressive inhibitors or other drug combinations. Exclusion
criteria for the meta-analysis were as follows: 1) non-randomized
trials; 2) studies that were not published in English or Chinese; 3)
studies that did not report the end points of overall response rate
(ORR), overall survival (OS), and progression-free survival (PFS).

Data extraction and quality assessment

Two authors independently examined all potentially relevant studies
identified through the search. We read all of the papers to determine
whether they met our inclusion criteria and decided whether they should
be included. Any disagreements were resolved by consensus. Data were
extracted by one researcher and supervised by another researcher and
included: 1) author information; 2) publication year; 3) number of
patients in the study; 4) treatment plan; 5) study design; 6) the main
results.

Data synthesis and statistical analysis

We used Review Manager software (version 5.0; Cochrane Collaboration,
London, UK) as the tool for calculating the outcomes. The relative risk
(RR) and 95\% confidence interval (CI) were used to compare the outcomes
between the different groups. The chi-squared test was used to test
heterogeneity. Cochran's Q test was applied to assess the heterogeneity
of the different studies. The inconsistency of each study was measured
with the I2 statistic. When I2 [?] 50\%, a random effects model was used
to take account of clinical heterogeneity in the data, otherwise a fixed
effects model was used. Sensitivity analysis was used to analyze the
effect of poor quality studies, and publication bias was analysed using
an inverted funnel chart test.

\textbf{Results}

Description of the studies

In total, 1540 articles were initially identified and five were finally
selected according to the exclusion criteria, with a total of 2005
patients The specific screening process is shown in Figure 1. The five
articles included four phase III RCT clinical trials and one phase II
RCT clinical trial. Treatment with PD-1/PD-L1 inhibitors was one of the
intervention programmes, and this was compared with other treatment
methods. Overall response rate (ORR), overall survival (OS), and
progression-free survival (PFS) were the end points in each study. The
median follow-up time ranged from 5.2 to 17 months. Specific information
on each study is shown in Table 1 and the results of methodological
quality evaluation for each study are shown in Table 2.

{[}Figure 1 near here{]}

Outcome results of meta-analysis

Overall response rate (ORR): All five of the articles reported the ORR
of the patients in each group. Through software analysis (Figure 2),
there was heterogeneity between the studies (I2 = 87\%), so using the
random effects model, the results showed that there was no statistically
significant difference between the group treated with PD-1/PD-L1 and the
group with other treatments (P = 0.35).

{[}Figure 2 near here{]}

Overall survival (OS): Four of the five articles reported the OS in each
experimental group. Through software analysis (Fig. 3), there was no
heterogeneity (I2 = 0\%), so the fixed effects model was used. The
results showed that treatment with PD-1/PD-L1 inhibitors alone could
reduce the risk of death in patients with recurrent/metastatic HNSCC,
and the difference between patients treated with PD-1/PD-L1 and the
group with other treatments was statistically significant (P = 0.004).

{[}Figure 3 near here{]}

Progression-free survival (PFS): Four of the five articles reported the
PFS of patients in each group. Through software analysis (Figure 4),
there was no heterogeneity (I2 = 0\%), so the fixed effects model was
used. The results showed that there was no statistically significant
difference in PFS between the group treated with PD-1/PD-L1 and the
group with other treatments (P = 0.47).

{[}Figure 4 near here{]}

Adverse events

The five articles included in the study reported the adverse events of
diarrhoea, asthenia, rash, fatigue, anaemia and nausea after treatment.
Meta-analysis showed that there was no significant difference in
diarrhoea, asthenia, rash or fatigue between the PD-1/PD-L1 inhibitor
treatment group and the other treatment group, but PD-1/PD-L1 inhibitor
treatment significantly reduced the risk of anaemia (P \textless{}
0.0001) and nausea (P \textless{} 0.0001), as shown in Table 3.

Publication bias analysis

A funnel chart test was carried out for OS, PFS, ORR and adverse
reaction results to judge the effect of possible publication bias.
However, due to the inclusion of less than 10 documents, it was
impossible to use a forest map to judge publication bias. In order to
reduce the effects of publication bias, we searched the unpublished
clinical trial registry data. We use search terms Head and Neck Squamous
Cell Carcinoma, and also searched for Squamous cell carcinoma of head
and neck, Squamous cell carcinoma of the head and neck, head and neck
cancer, head and neck neoplasms or HNSCC and PD-1/PD-L1 inhibitors or
Pembrolizumab or Keytruda or Nivolumab or Opdivo or Durvalumab or
MEDI4736 or Atezolizumab or checkpoint inhibitors. We found 217 studies
but after removal of duplicates and consideration of inclusion criteria,
we had to remove them all.

\textbf{Discussion}

In recent years, with the development of immunotherapy, there has been
an increasing number of immunotherapy studies on HNSCC, and there are
also drugs approved for treatment of recurrent/metastatic HNSCC after
platinum treatment failure. The two trials involved in this paper,
checkmate-141 {[}8{]} and keynote-012 {[}7{]}, are the basis for the
approval of nivolumab and pembrolizumab, both of which are PD-1
inhibitors. PD-1 is a programmed death protein, which is an important
immune checkpoint for tumours with which they can evade immune
surveillance. It is expressed on the surface of activated T cells, B
cells and NK cells {[}11{]}. Like many solid tumours, HNSCC can evade
the immune response of host cells by expressing immunosuppressive
ligands. For example, PD-L1 has two major ligands, PD-L1/PD-L2, which
exist in tumour cells, antigen-presenting cells and stromal cells. The
tumour microenvironment induces infiltration of T cells with a high
expression of PD-1 and tumour cells with a high expression of
PD-L1/PD-L2. The combination of the two leads to the continuous
activation of the PD-1 pathway, the down-regulation of T cell function
and inhibition of the anti-tumour effect of the immune system. At
present, the main antibodies against PD-1 are nivolumab and
pembrolizumab, and the main antibodies against PD-L1 are atezolizumab,
avelumab and durvalumab.

Of the five articles, three were PD-1/PD-L1 inhibitor single drug
treatments compared with chemotherapy. The first article was a PD-L1
inhibitor single drug treatment compared with CTLA-4 inhibitor; the
second was a PD-L1 inhibitor single drug treatment compared with PD-L1
inhibitor combined with CTLA-4 inhibitor; the third article was a PD-L1
inhibitor single drug treatment compared with chemotherapy and a PD-1
inhibitor treatment combined with chemotherapy. Meta-analysis results
showed that there were differences in OS among the groups, but no
differences in PFS and ORR. In the article by Burtness et al. {[}10{]},
the ORR was 17\% in the study group compared with 36\% in the control
EXTREME group. Although immunotherapy is a promising treatment, its
efficacy in patients is limited. The effective rate of single drug
treatment in patients with HNSCC was only about 20\%. The effective
rates in the five articles included in this paper were 14.6\%, 13.3\%,
26.1\%, 9.2\% and 17\%. The median survival times in the five articles
were 8.4 months (6.4--9.4), 7.5 months (5.5--9.1), 9.5 months (9.1--NR),
6.0 months (4.0--11.3), and 14.9 months (no range reported) in the
groups with PD-L1 inhibitor single drug treatment. Apart from one
article, the median survival time was higher than that of the control
group, including the standard chemotherapy, single treatment with CTLA-4
inhibitor, but lower than that of PD-1 inhibitor combined with CTLA-4
inhibitor (6.0 vs 7.6 months).

The use of immunotherapy combined with other adjuvant therapies has been
increasing in recent years. For example, the sensitization effect and
mechanism of action of chemotherapy and radiotherapy are all supported
by the literature. Therefore, it is also hoped that the response rate
can be improved by combining immunotherapy with other therapies to
further extend survival time. In recent and ongoing clinical trials, in
addition to the use of PD-1/PD-L1 inhibitors as a single drug for
treatment, the trials include their combination with other
immunosuppressants, chemotherapy and radiotherapy, etc. Table 4 shows
the current stages of the ongoing phase III clinical trials (registered
at clinicaltrials.gov) for immunotherapy of HNSCC. In addition, a
clinical trial of neoadjuvant immunotherapy for patients with locally
advanced or operable HNSCC is also being carried out, combined with
radiotherapy and chemotherapy to regulate the immune environment and to
work alongside immunotherapy to improve the therapeutic effect {[}12{]}.
These trials are expected to provide high-level clinical evidence to
support the management of future therapy.

Unlike other treatments, there are many immune-related adverse events
associated with immunotherapy such as anaemia, renal failure, pneumonia,
etc. {[}13{]}. In the five articles included in this paper, four of them
recorded adverse events including diarrhoea, asthenia, rash, fatigue,
anaemia, nausea, etc. Our meta-analysis showed that PD-1/PD-L1
inhibitors did not increase the risk of adverse events, but in fact,
reduced the risk of anaemia and gastrointestinal reactions. The main
reason may be because the control group was mainly composed of
chemotherapy or chemotherapy-based comprehensive treatments. No matter
what kind of treatment, the incidence of adverse events in patients was
more than 10\%. In the articles included in this study, the adverse
events caused by immunotherapy included skin reaction, endocrine,
gastroenteric, therapeutic, pulmonary, infection reaction, renal injury,
hypothyroidism, and pneumatic events. In the four articles included in
this study and mentioning adverse reactions, the incidences of adverse
reactions in the PD-1/PD-L1 treatment groups were higher than those in
the immunotherapy combined with other auxiliary treatment groups (26\%
vs 12\%; 63.1\% vs 55.4\%/57.9\%; 58.9\% vs 37.5\%; 26\% vs 12\%).
Therefore, from the point of view of adverse reactions, combination
therapy may improve the response rate and improve the therapeutic
effect. There are also no increased risks from the point of view of side
effects. It also provides help for the formulation of future treatment
plans and the improvement of intolerable treatments.

\textbf{Conclusion}

This study shows that, based on the current evidence, PD-1/PD-L1
inhibitors alone can improve the OS of patients with
recurrent/metastatic head and neck squamous cell carcinoma, without
serious adverse reactions, but the ORR still needs to be improved. In
future research, the combination of drugs and new adjuvant treatments
will help immunotherapy play a better role in the treatment of HNSCC.

\textbf{Methodological considerations / limitations:}

The number of studies included in this paper is limited, and the
conclusions need to be verified by a larger number of articles.

\textbf{References}

{[}1{]} Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and
mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin.
2018;68(6):394--424.

{[}2{]} Winquist E, Agbassi C, Meyers BM, et al. Systemic therapy in the
curative treatment of head and neck squamous cell cancer: a systematic
review. J Otolaryngol Head Neck Surg. 2017;46(1):29.

{[}3{]} Lydiatt W, O'Sullivan B, Patel S. Major changes in head and neck
staging for 2018. Am Soc Clin Oncol Educ Book. 2018;38:500--514.

{[}4{]} Gillison ML, Blumenschein G Jr, Fayette J, et al. CheckMate 141:
1-year update and subgroup analysis of nivolumab as first-line therapy
in patients with recurrent/metastatic head and neck cancer. Oncologist.
2018;23(9):1079--1082.

{[}5{]} Larkins E, Blumenthal GM, Yuan W, et al. FDA Approval Summary:
Pembrolizumab for the treatment of recurrent or metastatic head and neck
squamous cell carcinoma with disease progression on or after
platinum-containing chemotherapy. Oncologist. 2017;22(7):873--878.

{[}6{]} Cohen EEW, Souli\selectlanguage{ngerman}ères D, Le Tourneau C, 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--167.

{[}7{]} Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for
recurrent squamous-cell carcinoma of the head and neck. N Engl J Med.
2016;375(19):1856--1867.

{[}8{]} Kiyota N, Hasegawa Y, Takahashi S, et al. A randomized,
open-label, Phase III clinical trial of nivolumab vs. therapy of
investigator's choice in recurrent squamous cell carcinoma of the head
and neck: A subanalysis of Asian patients versus the global population
in Checkmate 141. Oral Oncol. 2017;73:138--146.

{[}9{]} Siu LL, Even C, Mesía R, et al. Safety and efficacy of
durvalumab with or without tremelimumab in patients with
PD-L1-low/negative recurrent or metastatic HNSCC: The Phase 2 CONDOR
randomized clinical trial. JAMA Oncol. 2019;5(2):195--203.

{[}10{]} Burtness BA, Harrington KJ, Greil R, Soulieres D. KEYNOTE-048:
Phase III study of first-line pembrolizumab (P) for recurrent/metastatic
head and neck squamous cell carcinoma (R/M HNSCC). Ann Oncol.
2018;29(suppl\_8).

{[}11{]} Pardoll DM. The blockade of immune checkpoints in cancer
immunotherapy. Nat Rev Cancer. 2012;12(4):252--264.

{[}12{]} Bauman JE, Cohen E, Ferris RL, Adelstein DJ, Brizel DM, Ridge
JA, et al. Immunotherapy of head and neck cancer: emerging clinical
trials from a National Cancer Institute Head and Neck Cancer Steering
Committee Planning Meeting. Cancer. 2017;123:1259--1271.

{[}13{]} McKay RR, Martini D, Moreira RB, Hamieh L, Norton C, Mullane
SA, et al. Outcomes of PD-1/PD-L1 responders who discontinue therapy for
immune-related adverse events (irAEs): results of a cohort of patients
(pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol.
2017;35(suppl 6S):abstr 467.

\textbf{Figure captions}

Figure 1. Flow chart of the search strategy.

Figure 2. PD-1/PD-L1 inhibitors vs control treatment in overall response
rate (ORR).

Figure 3. PD-1/PD-L1 inhibitors vs control treatment in overall survival
(OS).

Figure 4. PD-1/PD-L1 inhibitors vs control treatment in progression-free
survival (PFS).

\textbf{Hosted file}

\verb`Table 1-meta.docx`  available at \url{https://authorea.com/users/316464/articles/446605-role-of-pd-1-pd-l1-inhibitors-in-the-treatment-of-recurrent-metastatic-head-and-neck-squamous-cell-carcinoma-a-systematic-review-and-meta-analysis}

\textbf{Hosted file}

\verb`Table 2-meta.docx`  available at \url{https://authorea.com/users/316464/articles/446605-role-of-pd-1-pd-l1-inhibitors-in-the-treatment-of-recurrent-metastatic-head-and-neck-squamous-cell-carcinoma-a-systematic-review-and-meta-analysis}

\textbf{Hosted file}

\verb`Table 3-meta.docx`  available at \url{https://authorea.com/users/316464/articles/446605-role-of-pd-1-pd-l1-inhibitors-in-the-treatment-of-recurrent-metastatic-head-and-neck-squamous-cell-carcinoma-a-systematic-review-and-meta-analysis}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/fig/fig}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/fih/fih}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/fii/fii}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/fig4/fig4}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

