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\begin{document}

\title{Efficacy of Helical Tomography (HT) with Concurrent Chemoradiotherapy
(CCRT) +Epidermal growth factor receptor (EGFR) inhibitor in Locally
advanced nasopharyngeal carcinoma (LANC) patients invading carotid
artery and risk of fatal bleeding}



\author[1]{kun liu}%
\author[1]{Yang wang}%
\author[1]{Lin Ma}%
\author[2]{SM Yang}%
\author[1]{Xinxin Zhang}%
\affil[1]{Chinese PLA General Hospital}%
\affil[2]{Department of Otolaryngology Head and Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital,}%


\vspace{-1em}



  
  \date{May 15, 2024}


\begingroup
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\let\endcenter\endflushleft
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\selectlanguage{english}
\begin{abstract}
Abstract: Objectives: Are LANC patients with carotid artery invasion are
at risk of massive neck hemorrhage after radiotherapy? Design: This
retrospective study aims to assess the efficacy of HT with CCRT +/-EGFR
inhibitor in LANC patients invading carotid artery and risk of fatal
bleeding. Settings: Otolaryngology Head and Neck Surgery department in
our hospital in China . Participants: Of 130 LANC patients with carotid
artery invasion admitted to our hospital between January 2012 and
September 2019. Main outcome measures: The 5-year survival rate of three
degrees of the carotid artery invasion (\textless{}180\selectlanguage{ngerman}°,
180°\selectlanguage{english}[?]IG\textless{}270deg, \selectlanguage{english}[?]270deg) . Univariate and Multivariate Cox
regression analysis were used for survival correlation factors. Results:
The incidence of fatal bleeding after radiotherapy was 2.3\% (3/130).
The primary site of the three cases were all the pharyngeal recess, with
more than 270o carotid artery invasion. Patients with hemoglobin levels
\textgreater{}110 g/L had a higher PFS, DMFS and OS than with that \selectlanguage{english}[?]110
g/L (P\textless{}0.05). Multivariate analysis showed that the EGFR
inhibitor was an independent risk factor for PFS and DMFS, while the
lowest hemoglobin level was an independent risk factor for OS.
Conclusion: In LANC patients whose carotid artery invasion was
\textless{}270o, HT combined with CCRT and EGFR inhibitor after
induction chemotherapy had mild and tolerable side effects, better PFS
and DMFS, with no massive hemorrhage. In patients \selectlanguage{english}[?]270o, diabetes with
poor control or re-radiotherapy led to a higher risk of massive
hemorrhage after radiotherapy.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Abstract:}

\textbf{Objectives:}

Are LANC patients with carotid artery invasion are at risk of massive
neck hemorrhage after radiotherapy?

\textbf{Design:}

This retrospective study aims to assess the efficacy of HT with CCRT
+/-EGFR inhibitor in LANC patients invading carotid artery and risk of
fatal bleeding.

\textbf{Settings:}

Otolaryngology Head and Neck Surgery department in China .

\textbf{Participants:}

Of 130 LANC patients with carotid artery invasion admitted to our
hospital between January 2012 and September 2019.

\textbf{Main outcome measures:}

The 5-year survival rate of three degrees of the carotid artery invasion
(\textless{}180\selectlanguage{ngerman}°, 180°\selectlanguage{english}[?]IG\textless{}270deg, \selectlanguage{english}[?]270deg) . Univariate and
Multivariate Cox regression analysis were used for survival correlation
factors.

\textbf{Results:}

The incidence of fatal bleeding after radiotherapy was 2.3\% (3/130).
The primary site of the three cases were all the pharyngeal recess, with
more than 270o carotid artery invasion. Patients with hemoglobin levels
\textgreater{}110 g/L had a higher PFS, DMFS and OS than with that \selectlanguage{english}[?]110
g/L (P\textless{}0.05). Multivariate analysis showed that the EGFR
inhibitor was an independent risk factor for PFS and DMFS, while the
lowest hemoglobin level was an independent risk factor for OS.

\textbf{Conclusion:}

In LANC patients whose carotid artery invasion was \textless{}270o, HT
combined with CCRT and EGFR inhibitor after induction chemotherapy had
mild and tolerable side effects, better PFS and DMFS, with no massive
hemorrhage. In patients \selectlanguage{english}[?]270o, diabetes with poor control or
re-radiotherapy led to a higher risk of massive hemorrhage after
radiotherapy.

\textbf{Keywords} : Locally advanced nasopharyngeal carcinoma, Carotid
invasion, Helical tomography, Induction chemotherapy, Concurrent
chemoradiotherapy, EGFR inhibitor, Massive neck hemorrhage, Risk factor

\textbf{Key points:}

\begin{enumerate}
\tightlist
\item
  This article is the first one to study the survival rate of different
  degrees of carotid artery invaded by nasopharyngeal carcinoma.
\item
  The incidence of fatal bleeding after radiotherapy was only 2.3\%
  (3/130).
\item
  The circumference of tumor attachment to the artery and the
  disappearance of fat gaps were utilized to estimate the extent of
  carotid artery invasion , which was classified into three subtypes
  according to the involvement grade before therapy.
\item
  In LANC patients whose carotid artery invasion was \textless{}270o,
  helical tomotherapy combined with concurrent chemotherapy and EGFR
  inhibitor after induction chemotherapy had mild and tolerable side
  effects, better PFS and DMFS, with no massive hemorrhage.
\item
  In patients whose primary tumor was pharyngeal recess with carotid
  artery invasion \selectlanguage{english}[?]270o, diabetes with poor control or re-radiotherapy
  led to a higher risk of massive hemorrhage after radiotherapy.
\end{enumerate}

\textbf{1 Introduction}

Nasopharyngeal carcinoma (NPC) is a malignant neoplasm with high
radiosensitivity that has a unique etiology and geographic distribution.
Due to the special anatomical location of the tumor, approximately 70\%
of newly diagnosed NPC cases are classified as locoregionally advanced
disease, namely locally advanced nasopharyngeal carcinoma (LANC). NPC
lesions often infiltrate the surrounding area, such as parapharyngeal
space and internal carotid artery{[}1-2{]}. Concurrent chemoradiotherapy
(CCRT), with epidermal growth factor receptor (EGFR) inhibitors, is an
effective treatment option for LANC{[}3{]}.

\textbf{1.1 Objectives/Aims}

Though radiotherapy killing tumor tissues, it may cause necrosis of
surrounding tissues and exposure of the carotid artery, leading to fatal
hemorrhage in certain patients with carotid artery invasion. No relevant
studies have reported the therapeutic effects and associated risk
factors for fatal massive hemorrhage in patients with LANC accompanied
by carotid artery invasion. This retrospective study analyzed the
therapeutic effects and associated risk factors in such patients.

\textbf{1.2 Design}

In clinical treatment, patients with nasopharyngeal carcinoma surrounded
by carotid artery have occasionally died of neck bleeding after
treatment. Is it related to the degree of carotid artery wrapping, or is
it related to the treatments ?

\textbf{1.3 Participants}

A total of 130 LANC patients (male 98, female 32; age range 10 to 74
years, mean age 48 years) with carotid artery invasion were recruited
between January 2012 and September 2019 (Table 1). All patients had
histologically proven stage III-IVA squamous cell carcinoma, largely
non-keratinizing type, according to the most recent edition of the
American Joint Committee on Cancer (AJCC) tumor/node/metastasis (TNM)
classifications and prognostic stage groups . To rule out synchronous
primary cancers and metastatic diseases, all patients were fully
evaluated by positron emission tomography--computed tomography (PET-CT),
magnetic resonance imaging (MRI) of the head and neck and fiberoscopic
nasopharyngoscopy. Patients with synchronous primary cancers and/or
metastatic disease were excluded. All patients had an Eastern
Cooperative Oncology Group (ECOG) performance status of 0 or 1, and
adequate renal, hepatic and bone marrow functions before
chemoradiotherapy.

\textbf{1.4 Main outcome measures}

\textbf{1.4.1 Treatments}

\textbf{Chemotherapy and EGFR inhibitor therapy}

Two to four cycles of induction chemotherapy followed by concurrent
chemoradiotherapy were given to all patients. EGFR-positive patients
received Nimotuzumab, while EGFR-negative patients received Cetuximab
(Table 2). All patients received oral mucositis prophylaxis followed by
conventional mucositis treatment combined with quinolone antibiotics
{[}4{]}.

\textbf{Radiotherapy}

Helical tomotherapy (HT) was delivered once daily, 5 days per week, as
previously described {[}5{]}. In brief, the planning dose at D95 (dose
received by 95\% of the target volume) was set at 67.5 grays (Gy) for
the planning gross target volume of the primary tumor (pGTVnx) and the
planning gross target volume of the metastatic lymph node (pGTVnd). The
planning target volume (PTV) was set at 60 Gy and the PTV2 was set at 54
Gy in 30-33 fractions. No more than 5\% of PTV volume received more than
110\% of the prescribed dose. Dose-volume constraints for organs at risk
(OARs) were set as follows: (1) parotid gland V30 \textless{}50\% or
Dmean \selectlanguage{english}[?]28 Gy; (2) brainstem Dmax \selectlanguage{english}[?]54 Gy; (3) spinal cord Dmax \selectlanguage{english}[?]45 Gy;
(4) optic nerve Dmax \selectlanguage{english}[?]54 Gy; (5) temporo-mandibular joint Dmax \selectlanguage{english}[?]60 Gy;
and (6) lens Dmax \selectlanguage{english}[?]5 Gy. HT plans were developed for a field width of
2.5 cm, a pitch of 0.30--0.38, and a modulation factor equal to
2.0--3.0. During radiation therapy, patients underwent megavoltage
computed tomography (MVCT) imaging at least once each week to verify
patient setup. The imaging frequency was determined by the magnitude of
setup errors from initial daily scans. Carotid radiotherapy dose was the
same among different groups.

\textbf{1.4.2 Dose modifications}

The cetuximab dose was reduced if a patient experienced an
uncontrollable and persistent grade 2 acne-like rash. Chemotherapy doses
and regimens were adjusted based on the severity of myelosuppression,
hepatic~and~renal~function and drug sensitivity. For example,
carboplatin was administered instead of cisplatin if grade 1 renal
toxicity was caused by cisplatin.

\textbf{1.4.3 Radiographic evaluation}

Axial scans of the neck obtained using contrast-enhanced MRI were
reviewed by a radiologist. The circumference of tumor attachment to the
artery and the disappearance of fat gaps were utilized to estimate the
extent of carotid artery invasion {[}6{]}, which was classified into
three subtypes according to the involvement grade (IG) (Fig. 1-A-C) as
follows before therapy:

(1) Low-involvement: the tumor invaded and/or contacted less than 180o
of the carotid artery.

(2) Mid-involvement: the tumor invaded and/or contacted more than 180o
but less than 270o of the carotid artery.

(3) High-involvement: the tumor invaded and/or contacted more than 270o
of the carotid artery.

(Fig. 1-A-C)

The MRI maps before (Fig.1-D) and after (Fig.1-d) induction chemotherapy

\textbf{1.4.4 Follow up}

Follow-up examinations were scheduled for patients according the
following arrangements: every 3 months in first year, every 4 months in
second and third year, every 6 months in fourth and fifth years and then
yearly until recurrence or death. Endpoints for this clinical trial were
similar to those in our previous study {[}7{]}. Acute and late
toxicities were graded according to the National Cancer
Institute---Common Terminology Criteria for Adverse Events (CTCAE),
version 5.0, and the Radiation Therapy Oncology Group (RTOG) Late
Radiation Morbidity Scoring Criteria {[}8{]}, respectively.

\textbf{1.5} \textbf{Ethical considerations}

This research abides by international and national regulations in
accordance with the Declaration of Helsinki. The studies involving human
participants were reviewed and approved by the Ethics Committee of our
Hospital. All patients provided written informed consent before being
included in this study (patients under 16 years old were obtained from a
parent or guardian for participants) .

\textbf{1.6 Data Analysis}

Data were analyzed by SPSS 24.0 statistical software (IBM Corporation,
Armonk, NY, USA). 95\% confidence intervals (CIs) were calculated for
means and percentages. Curves of PFS, DMFS, LNRFS, LRFS, NRF and OS were
estimated with the Kaplan--Meier method (GraphPad Prism 8.0.1). Group
frequency data were examined using Chi-squared tests. Multivariate Cox
regression analysis and Log-rank tests were used for survival
correlation factors and inter-group curve comparisons, respectively.

\textbf{2 Results}

In the present study, 140 consecutive patients were screened for
eligibility and 130 patients were enrolled in the clinical trial. Ten
patients were excluded (4 were lost to follow-up and 6 were unbearable
to side effects during concurrent chemoradiotherapy). Patients were
stratified into 3 groups based on the degree of carotid artery
involvement: \textless{}180o, n=37; 180o\selectlanguage{english}[?]IG\textless{}270o, n=32; and
\selectlanguage{english}[?]270o, n=61.

Three patients whose primary tumor located in the nasopharyngeal recess
and carotid artery invasion \selectlanguage{english}[?]270deg died of massive neck hemorrhage (Table
3; Fig.2).They were confirmed by repeated nasal endoscopy (gray-white
necrotic material) and MRI enhancement of nasopharynx (gray-black
necrotic material, non-neoplastic tissue, T1 phase is low signal, T2
phase is slightly high signal) prior to hemorrhage.No radiation-induced
carotid pseudoaneurysms were confirmed by DSA.

The median follow-up time was 25 months (range 5-97 months). During the
follow-up period, 20 patients died, 22 patients progressed (including 3
patients with recurrence, 2 with cervical lymph node metastasis, 16 with
distant metastasis, and 1 with secondary primary cancer). The overall
5-year survival rates were PFS=75.2\%, DMFS=76.8\%, LNRFS=90.0\%,
LRFS=93.9\%, NRFS=95.8\% and OS=87.2\% (Fig.3-1).

Univariate analysis showed that gender, age, pathological type and
degree of carotid artery involvement were not significantly associated
with survival. Clinical stage, induction chemotherapy regimen,
concurrent chemotherapy regimen and EGFR inhibitors were significantly
associated with PFS and DMFS (P\textless{}0.05). Hemoglobin levels
during radiotherapy were significantly associated with DMFS, PFS and OS
(P\textless{}0.05) (Supplementary Table 1).

Multivariate analysis showed that EGFR inhibitor was an independent
prognostic factor for DMFS and PFS (P\textless{}0.05). Hemoglobin level
during radiotherapy was an independent prognostic factor for OS
(P\textless{}0.05) (Supplementary Table 2; Fig3-2\textasciitilde{}4).

Comparison of three degrees of the carotid artery invasion
(\textless{}180deg, 180deg\selectlanguage{english}[?]IG\textless{}270deg, \selectlanguage{english}[?]270deg) suggested that the
5-year PFS was 82.3\%, 72.4\% and 59.5\%, respectively; 5-year DMFS was
85.8\%, 78.0\% and 77.1\%, respectively; 5-year LNRFS was 95.8\%, 90.4\%
and 77.1\%, respectively; 5-year LRFS was 95.8\%, 100\% and 77.1\%,
respectively; 5-year NRFS was 100\%, 90.4\% and 100\%, respectively; and
5-year OS was 92.9\%, 85.2\% and 78.0\%, respectively (Supplementary
Fig.1-6).

\textbf{Acute toxicities}

All possible side effects were documented for each patient. Acute toxic
effects were very mild and did not reach grade 4. The most common grade
1-2 toxicities included oropharyngeal mucositis, RT-related dermatitis,
xerostomia and pharyngo-esophagitis, which were less severe than those
of intensity-modulated radiation therapy (IMRT) (Supplementary Table 3).
Acute toxicities were significantly improved 1 month after radiotherapy
compared to those observed at the end of radiotherapy. Some patients
treated with CCRT showed different degrees of bone marrow toxicity.
After full radiotherapy, patients' average weight loss was 10.6\%,
varying from 0\% to 20.4 \%. Through the analysis between groups, there
is no statistically significant side effect among the degree of carotid
artery invasion.

\textbf{3 Discussion}

According to the National Comprehensive Cancer Network (NCCN), carotid
artery invasion is a sign of poor prognosis, such as oral cavity cancer,
P16\textsuperscript{---}oropharyngeal cancer, laryngeal cancer,
hypopharyngeal cancer other than nasopharyngeal cancer. MR images were
used to predict carotid artery invasion {[}9{]}: circumferential
involvement of 270deg or less of the wall meant no invasion, and more than
270deg meant wall invasion. Based on our comparison of the survival rates
in three degrees of carotid artery invasion (\textless{}180deg,
180deg\selectlanguage{english}[?]IG\textless{}270deg, and \selectlanguage{english}[?]270deg), although the difference was not
statistically significant, it showed that the survival rate tended to
decrease with an increase degree of invasion. However, patients with
LANC with carotid artery invasion have a better prognosis, compared with
other head and neck tumors. In this study, 130 LANC patients with
carotid artery invasion were treated with induction chemotherapy
followed by CCRT +- an EGFR inhibitor. Five-year survival rates were:
PFS=75.2\%; DMFS=76.8\%; LNRFS=90.0\%; LRFS=93.9\%; NRFS=95.8\% and
OS=87.2\%. Side effects were mild and well-tolerated; survival rates
were similar to those observed in other studies {[}10-11{]}.

Shen C et al. {[}12{]} showed that anemia is closely related to tumor
hypoxia, which may lead to tumor resistance to radiotherapy and
treatment failure. In this study, we found that the 5-year OS of
patients with the lowest hemoglobin levels (\selectlanguage{english}[?]110 g/L) was significantly
lower than that of patients with hemoglobin levels \textgreater{}110 g/L
during radiotherapy. Therefore, we believe that patients should actively
monitor and treat anemia.

Other studies have shown that patients whose primary tumor located in
the pharyngeal recess, and who experienced inflammation and an opening
incisor tooth distance \textless{}1 cm, had a greater probability of
fatal bleeding after radiotherapy {[}13{]}. Yamazaki et al. {[}14{]} and
Cheng et al. {[}15{]} believed that the pharyngeal recess is part of the
petrosal region of the internal carotid artery where the tumor easily
invades the internal carotid artery and surrounding bone. If the
pharyngeal recess infected, the surrounding tissues may become necrotic,
which may cause rupture of the internal carotid artery and fatal
bleeding.~Similarly, the primary site of the three cases were all the
pharyngeal recess, with more than 270 o carotid artery invasion and
restricted mouth opening.

Fatal bleeding is common in previous studies, Zheng et al. {[}16{]}
found that 1.5\% of nasopharyngeal carcinoma patients with IMRT
experienced fatal bleeding. Wu et al.{[}13{]} showed that 52.9\% (45/85)
of such patients (stage I-IV) occurred fatal bleeding, with 20 patients
died. In our study, all patients were stage III-IV, 32 cases with
carotid artery invasion \textless{}180deg and 37 cases with
180deg\selectlanguage{english}[?]IG\textless{}270deg, no patients suffered fatal neck hemorrhage.

Sixty one patients with carotid artery invasion \selectlanguage{english}[?]270deg, among whom three
patients died of neck hemorrhage, the overall incidence was only 2.3\%
(3/130), which was attributable to nasopharyngeal necrosis (2 of whom
were diabetics and 1 received re-radiation after recurrence). Most
scholars believe that radiation, trauma and infection cause
nasopharyngeal necrosis {[}14{]}. Re-radiation increases the risk of
necrosis of the nasopharynx and neck hemorrhage {[}17{]}. The 2
diabetics had uncontrollable infection with local necrosis. The patient
who received re-radiation was exposed to a cumulative radiation dose of
137.5 Gy and developed osteoradionecrosis of the nasopharynx seven
months after radiotherapy. Another patient with the primary site of the
nasopharyngeal wall was treated with surgery after recurrence, and he
survived without fatal bleeding. Surgery may be a better option than
re-radiation for patients with carotid artery invasion \selectlanguage{english}[?]270deg who
experience recurrence.

In our study, 127 patients without massive hemorrhage benefited from the
application of induction/concurrent chemotherapy and HT. Induction
chemotherapy can reduce tumor load, enlarge the space between the
carotid artery and the tumor body and produce a greater safety margin,
thereby reducing damage to important tissues and organs caused by
radiotherapy. Dionisi et al. {[}18{]} showed that CCRT could further
shrink the tumor body, accelerate blood supply to surrounding tissues,
and reduce the incidence of mucosal necrosis. HT has many dosimetric
advantages, such as delivering a more precise dosage to the target
tissue(s) and reducing radiation exposure to critical surrounding
organs, thereby improving local control with less radiation damage
{[}19{]}. In addition, multivariate analysis showed that use of an EGFR
inhibitor was an independent prognostic factor for PFS and DMFS.
Previous studies have shown that adding CTX/NTZ to CCRT may improve OS,
DFS and DMFS {[}20-24{]}, which is consistent with our results. EGFR
inhibitors also have been shown to have significant anti-proliferation,
pro-apoptosis and anti-angiogenesis effects, which may further control
the recurrence of tumors and improve the sensitivity of tumors to
radiotherapy and chemotherapy {[}25{]}.

In conclusion, 130 patients with LANC surrounding the carotid artery
were treated with a comprehensive treatment regimen, 95.7\% of the
patients successfully completed the entire courses, producing desirable
outcomes and a low incidence of fatal hemorrhage. Improved outcomes may
be possible with the application of new proton and other radiotherapy
technologies and new PD-1 immuno-targeted drugs in patients with
nasopharyngeal carcinoma. The primary site located in the pharyngeal
recess with more than 270 o carotid artery invasion and restricted mouth
opening, especially diabetics, should actively control blood glucose
levels and prevent infection. Nasopharyngeal necrosis should be actively
treated by antibiotics and hyperbaric oxygen, removing by oxygen nasal
endoscope regularly.

\textbf{Abbreviations:} Arrowheads indicate the ICA; LANC, Locally
advanced nasopharyngeal carcinoma; MRI, magnetic resonance imaging; ICA,
internal carotid artery; T1WI, T1-weighted imaging

EGFR, epidermal growth factor receptor inhibitor; PFS, progression-free
survival; DMFS, distant metastasis-free survival; LNRFS, local nodal
recurrence-free survival; LRFS, local recurrence-free survival; NRFS,
nodal recurrence-free survival; OS, overall survival

T: docetaxel; P: cisplatin; F: 5-fluorouracil; G: Gemcitabine; D:
Doxorubicin

HR3, Nimotuzumab; C-225, Cetuximab; HT, helical tomography

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{[}25{]}. Diaz Miqueli~A,~~Rolff~J,~~Lemm~M, et al. Radiosensitisation
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monoclonal antibodies. Br J Cancer. 2009; 100(6):950-958.\selectlanguage{english}
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\textbf{Hosted file}

\verb`Table 1.doc`  available at \url{https://authorea.com/users/740634/articles/713410-efficacy-of-helical-tomography-ht-with-concurrent-chemoradiotherapy-ccrt-epidermal-growth-factor-receptor-egfr-inhibitor-in-locally-advanced-nasopharyngeal-carcinoma-lanc-patients-invading-carotid-artery-and-risk-of-fatal-bleeding}

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\verb`Table 2.doc`  available at \url{https://authorea.com/users/740634/articles/713410-efficacy-of-helical-tomography-ht-with-concurrent-chemoradiotherapy-ccrt-epidermal-growth-factor-receptor-egfr-inhibitor-in-locally-advanced-nasopharyngeal-carcinoma-lanc-patients-invading-carotid-artery-and-risk-of-fatal-bleeding}

\textbf{Hosted file}

\verb`Table 3.doc`  available at \url{https://authorea.com/users/740634/articles/713410-efficacy-of-helical-tomography-ht-with-concurrent-chemoradiotherapy-ccrt-epidermal-growth-factor-receptor-egfr-inhibitor-in-locally-advanced-nasopharyngeal-carcinoma-lanc-patients-invading-carotid-artery-and-risk-of-fatal-bleeding}

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