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\begin{document}

\title{PD-L1-positive recurrent and metastatic cervical cancer responsive to
first-line Sintilimab with chemotherapy plus Bevacizumab treatment: a
case report}



\author[1]{Hu Feng}%
\author[1]{FuJun Yang}%
\author[2]{Jingjing Mao}%
\author[1]{Shasha Bi}%
\author[1]{Shanshan Sun}%
\author[1]{Hongbo Yang}%
\author[1]{Haoxing Zhou}%
\author[2]{Shanshan Song}%
\affil[1]{Weihai Municipal Hospital}%
\affil[2]{YuceBio Technology Co Ltd}%


\vspace{-1em}



  
  \date{June 06, 2024}


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\selectlanguage{english}
\begin{abstract}
Cervical cancer is the most common malignant tumor of the female
reproductive system. Its incidence rate ranks first among that of female
malignant tumors in China and has steadily increased in recent years
{[}Juanjuan Jin et al., 2021{]}.%
\end{abstract}%



\sloppy


\textbf{PD-L1-positiverecurrent andmetastaticcervical cancer responsive
to first-lineSintilimab with chemotherapy plusBevacizumabtreatment: a
case report}

Hu Feng\textsuperscript{\#a}, Jingjing Mao\textsuperscript{\#b}, Shasha
Bi\textsuperscript{c},Shanshan Sun\textsuperscript{a},Hongbo
Yang\textsuperscript{a},Haoxing Zhou\textsuperscript{a}, Shanshan
Song\textsuperscript{b}, Fujun Yang\textsuperscript{a,*}

\textsuperscript{a}Department of Oncology, Weihai Municipal Hospital,
Cheeloo College of Medicine, Shandong University, Weihai, Shandong,
264200, China

\textsuperscript{b}YuceBio Technology Co., Ltd., Shenzhen, China

\textsuperscript{c}Department of Pathology , Weihai Municipal Hospital,
Cheeloo College of Medicine, Shandong University, Weihai, Shandong,
264200, China

\textsuperscript{*}Corresponding author at: Department of Oncology,
Weihai Municipal Hospital Affiliated to Shandong University, No. 70,
Heping Road, Weihai 264200, Shandong, P.R. China

E-mail address: yangfujun228@163.com

Tel/Fax:+86-18660377195

\textbf{Keywords:}recurrent and metastatic cervical cancer, checkpoint
inhibitors, immunotherapy, PD-L1, angiogenesis inhibitors, chemotherapy

\textbf{1. Background}

Cervical cancer is the most common malignant tumor of the female
reproductive system. Its incidence rate ranks first among that of female
malignant tumors in China and has steadily increased in recent years
{[}Juanjuan Jin et al., 2021{]}. Palliative platinum-based chemotherapy
is the standard first-line treatment for metastatic and recurrent
cervical cancers. However, the prognosis after intervention remains poor
and, therefore, effective second-line treatment options are urgently
needed {[}Stergios Boussios et al., 2016{]}. The results of an interim
analysis of data from the phase II clinical trial KEYNOTE-158
(ClinicalTrials.gov identifier: NCT02628067) showed that pembrolizumab
had a promising antitumor activity in patients with previously-treated
advanced cervical cancer. The objective response rate(ORR) in the
total population was 12.2\%, with three patients achieving a complete
response (CR) and nine achieving a partial response(PR).

The beneficial role of immunotherapy for cervical cancer is
well-established nowadays. In the KEYNOTE-158 study, all responses to
pembrolizumab occurred in patients with programmed death-ligand 1
(PD-L1)-positive tumors {[}Hyun Cheol Chung et al., 2019{]}, suggesting
that immunotherapy is a suitable therapeutic option for patients with
advanced cervical cancer. Here, we describe the case of a patient with
PD-L1-positive recurrent cervical cancer with distant metastasis to the
lymph nodes who responded to first-line sintilimab with chemotherapy
plus bevacizumab therapy and achieved CR as assessed using the RECIST
v1.1 criterion.

\textbf{2. Patient presentation}

A 53-year-old woman was diagnosed with stage IB2 poorly-differentiated
squamous cell carcinoma (SCC) of the cervix and a history of human
papillomavirus (HPV) 16 infection on July 31, 2019.

The patient underwent type III radical hysterectomy, pelvic
lymphadenectomy, and bilateral adnexectomy on September 4, 2019 and
received two cycles of paclitaxel plus cisplatin chemotherapy, one on
September 18, 2019 and another on October 9, 2019.

She received concurrent chemoradiation treatment, administered through
intensity-modulated radiation therapy following a schedule of 180 cGy \selectlanguage{ngerman}×
28 fractions; the total exposure dose was 5040 cGy. The range of
external irradiation target comprised the vaginal stump and 2 cm below
the vaginal stump, as well as the obturator lymph drainage area and the
iliac total, internal, and external lymph drainage areas. Additionally,
high dose rate Iridium-192 brachytherapy targeting the vaginal stump was
administered following a schedule of 600 cGy × 2 fractions; the total
exposure dose was 1200 cGy. No obvious adverse reactions were observed
after treatment. Based on follow-up analyses consisting of pelvic
computed tomography (CT) scans and assessments of SCC tumor markers
every 6 months after treatment completion, the disease was assessed as
stable.

Unfortunately, the patient showed multiple lymph node enlargements in
the left neck one year after treatment completion. Positron emission CT
(PET-CT) revealed multiple lymph node enlargements in the left axilla
and retroperitoneum in the mediastinal region eight of the left neck,
increased \textsuperscript{8}F-fluorodeoxyglucose metabolism, and
maximum standardized uptake value of 22.5, indicating lymph node
metastasis of cervical cancer (Fig. 1). Biopsy and immunocytochemistry
results of the enlarged left supraclavicular lymph node confirmed SCC
with metastasis of cervical cancer. The tumor marker SCC antigen
(SCC-Ag) level was 36.4 ng/mL, which was significantly higher than the
normal reference range of 0--1.5 ng/mL. The changes in SCC-Ag level were
used to monitor the tumor load and the tumor response to the
administered treatment.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Fig. 1. A--G. Positron emission tomography--computed tomography (PET-CT)
scan of the chest of the patient showed multiple enlarged lymph nodes.
(A--B). PET-CT showed lymph node metastasis in her left neck. (C). Left
axillary lymph node metastasis. (D--E). Lymph node metastasis in zone
eight of the mediastinum. (F--G). Retroperitoneal lymph node metastases
and increased fluorodeoxyglucose metabolism.

Metastases were detected using next-generation sequencing (YuceOne\selectlanguage{ngerman}® Pro
1012 genes). The results revealed a high tumor mutational burden (11
mutations per megabase)\selectlanguage{english},and PD-L1 positivity, and a combined positive
score(CPS) PD-L1 CPS 90. Cervical cancer is considered a relatively
chemotherapy-resistant disease, and clinical trials have shown good
safety of sintilimab with chemotherapy plus bevacizumab. Because the
patient was in good physical condition with a Karnofsky Performance
Status(KPS)score of 90, with the consent of the patient, she underwent
four cycles of Sintilimab {[}200 mg every 3 weeks (Q3W){]} plus
Paclitaxel Injection {[}AlbuminBound (300 mg Q3W) and cisplatin (120 mg
Q3W) and Bevacizumab (500 mg Q3W){]} treatment from December, 2020 to
March, 2021. Maintenance therapy consisted of Sindilumab 200 mg Q3W.

PET-CT showed multiple swollen lymph nodes in the left neck on February
28, 2020. The lymph nodes were significantly reduced compared with that
observed in the pre-treatment scan (about 80\%) and no abnormal increase
in metabolism was observed on June 29, 2021 (Fig. 2). The patient
underwent a follow-up visit on October 18, 2021, and was found to be in
a stable condition. SCC-Ag levels decreased to normal levels (Fig. 3).
The patient achieved CR according to the RECIST v1.1 criterion.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Fig. 2. A1, B1, C1, D1, E1, F1. Positron emission tomography--computed
tomography (PET-CT) scan of the patient before the start of the
treatment consisting of sindilizumab plus chemotherapy and bevacizumab
revealed that the patient had multiple enlargements and increased
metabolism in the left neck, left axilla, mediastinum, and
retroperitoneum (SUV max 22.5) on December 23, 2020.

A2, B2, C2, D2, E2, F2. PET-CT scan of the patient revealed that the
lymph nodes were significantly reduced, and no abnormal increase in
metabolism was observed that was responsive to sintilimab plus
chemotherapy and bevacizumab on June 29, 2021.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Fig. 3. Comparison of serum squamous cell carcinoma antigen (SCC-Ag)
levels at different times. The concentrations of SCC antigen was 36.4
ng/mL on December 28, 2020, and dropped to 0.3 ng/mL on June 9, 2021.

\textbf{3. Discussion}

The prognosis of patients with recurrent and metastatic cervical cancers
remains poor. Treatment with chemotherapeutic drugs is rarely curative,
and should be considered palliative. In the last few years, a better
understanding of HPV tumor-host immune system interactions and the
development of new therapeutic strategies targeting immune checkpoints
have drawn increasing attention to the use of immunotherapy in patients
with cervical cancer. Moreover, next-generation sequencing has emerged
as an attractive option for identifying actionable driver mutations and
suitable prognostic markers. In this case, high PD-L1 expression was
detected using mIHC(Multiple ImmunoHistoChemistry). Immune checkpoint
inhibitors have shown antitumor activity against multiple types of
tumors. Given that the presence of a virus leads to antigen production
and plays a major role in the oncogenesis of cervical cancer, evaluating
immune checkpoint inhibition as a treatment strategy in this setting is
of great interest. Notably, PD-L1 expression has been identified as a
characteristic feature of virus-induced cancers, and upregulation of
PD-1 and PD-L1 has been reported in high-risk HPV-associated cervical
intraepithelial neoplasia {[}Heeran et al., 2016; Mezache et al.,
2015{]}.

Sintilimab (Tyvyt\selectlanguage{ngerman}®) is a monoclonal antibody against PD-1 that blocks
the interaction between PD-1 and its ligands and effectively activates T
cells, enhancing their anti-tumor activity. However, previous studies
have reported several side effects of sintilimab. Nonetheless,
sintilimab has been reported to have similar antitumor effects and a
better safety profile than those of nivolumab and pembrolizumab for
Hodgkin lymphoma, natural killer/T cell lymphoma, and advanced non-small
cell lung cancer {[}Lin Zhang et al., 2020{]}. Recently, in an abstract
presented at the 57th Annual Meeting of the American Society of Clinical
Oncology (ASCO 2021), the efficacy and safety of the use of
sindillizumab combined with anlotinib in patients with recurrent
advanced cervical cancer was described. Anlotinib is an oral
small-molecule inhibitor of multiple receptor tyrosine kinases with a
broad spectrum of inhibitory effects on tumor angiogenesis and growth
{[}Yahiya Y Syed., 2018{]}.

Bevacizumab is an anti-angiogenic agent efficacious for cervical cancer
that represents a shift in the treatment paradigm for this disease. In
the phase III GOG 240 trial of first-line systemic treatment in women
with metastatic or persistent or recurrent cervical cancer (N = 452),
the addition of bevacizumab to standard chemotherapeutic combinations
(cisplatin plus paclitaxel, topotecan plus paclitaxel) significantly
improved the median overall survival to 16.8 months, compared with the
overall survival of 13.3 months achieved with chemotherapy alone (P =
0.007) {[}Tewari et al., 2014{]}. This demonstrates the utility of
adding a nonchemotherapeutic agent to the treatment armamentarium for
advanced cervical cancer and highlights the pressing need for developing
novel therapies that improve clinical outcomes while being well
tolerated.

In summary, this case report demonstrates that the combination of
sintilimab plus chemotherapy and bevacizumab is effective for the
treatment of recurrent and metastatic cervical cancer with high PD-L1
expression. The total duration of the treatment with these four agents
for our patient was three months, and follow-up maintenance therapy with
sintilimab Q3W achieved CR efficacy. Although this provides a new
treatment option for patients with recurrent and metastatic cervical
cancer, the long-term survival benefit for patients needs to be further
investigated. Finally, this case report also highlights the importance
of continuous research to determine the optimal combination and settings
of immunotherapy.

\textbf{CRediT authorship contribution statement}

\textbf{Fujun Yang:} conceptualization, data curation, investigation,
resources, and writing--review and editing. \textbf{Hu
Feng:}conceptualization, project administration, data curation,
investigation, resources, writing--original draft, and writing--review
and editing. \textbf{Jingjing Mao:}investigation, resources,
writing--original draft, and writing--review and editing.\textbf{Shansha
Bi} : writing--review and editing. \textbf{Shanshan
Sun\textsuperscript{:}} writing--review, and editing. \textbf{Hongbo
Yang:} writing--review and editing. \textbf{Haoxing
Zhou:}writing--review and editing. \textbf{Shanshan Song:}
writing--review and editing.

\textbf{Consent}

Written informed consent was obtained from the patient for publication
of this case report and accompanying images. A copy of the written
consent is available for review by the Editor-in-Chief of this journal
upon request.

\textbf{Declaration of Conflicts of Interest} : The authors declare that
there are no conflicts of interest.

\textbf{References}

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