A Phase I Randomized Controlled Trial of Intratumoral Lidocaine Injection Before Transoral Robotic Surgery (TORS) and Neck Dissection for HPV-Associated Oropharyngeal Squamous Cell Carcinoma
Phase: PHASE1
Conditions: Oropharyngeal Squamous Cell Carcinoma (OPSCCA), Oropharyngeal Cancer, Human Papilloma Virus, Squamous Cell Carcinoma
Sponsor: Ryan Carey

Version Date: 10 January 2025 
 
 
 
1 
 
University of Pennsylvania  
 
 
 
Protocol Design Template © 2005  
Trustees of the University of Pennsylvania 
 
 
A Phase I Randomized Controlled Trial of Intratumoral 
Lidocaine Injection Before Transoral Robotic Surgery (TORS) 
and Neck Dissection for HPV-Associated Oropharyngeal 
Squamous Cell Carcinoma 
 
Regulatory Sponsor: 
Ryan M. Carey, MD 
University of Pennsylvania  
Department of Otorhinolaryngology – Head & Neck Surgery 
5th Floor Ravdin Bldg 
3400 Spruce Street 
Philadelphia, PA  19104 
(610)-790-9202 
Ryan.Carey@pennmedicine.upenn.edu  
 
 
Sub-Investigators: 
Radiation Oncology: Alexander Lin, MD 
Otorhinolaryngology: Robert M. Brody, MD  
Otorhinolaryngology: Gregory S. Weinstein, MD  
Otorhinolaryngology: Devraj Basu, MD, PhD 
Otorhinolaryngology: Karthik Rajasekaran, MD  
Pathology: Timothy Chao, MD, PhD 
 
 
 
 
 
Biostatistics:  
Xingmei Wang, MS 
 
 
Protocol Number: 
 
 
 
UPCC Number: 
 
856397 
 
 
12324 
 
 
 
 
 
CONFIDENTIAL 
 
 
This document is confidential and the property of the University of Pennsylvania.  No part 
of it may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the study sponsor. 

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Table of Contents 
STUDY SUMMARY .................................................................................................................................................... 3 
1 
INTRODUCTION .............................................................................................................................................. 6 
2 
STUDY OBJECTIVES ...................................................................................................................................... 9 
3 
STUDY DESIGN ................................................................................................................................................ 9 
4 
SUBJECT SELECTION AND WITHDRAWAL .......................................................................................... 10 
5 
STUDY PROCEDURES .................................................................................................................................. 13 
6 
STATISTICAL PLAN ..................................................................................................................................... 16 
7 
SAFETY AND ADVERSE EVENTS .............................................................................................................. 17 
8 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 21 
9 
DATA AND SAFETY MONITORING PLAN .............................................................................................. 22 
10 
ETHICAL CONSIDERATIONS .................................................................................................................... 23 
11 
STUDY FINANCES ......................................................................................................................................... 24 
12 
PUBLICATION PLAN .................................................................................................................................... 25 
13 
REFERENCES ................................................................................................................................................. 25 
 
 
 
List of Abbreviations 
 
Oropharyngeal squamous cell carcinoma 
 
OPSCC 
Human papillomavirus  
 
 
 
HPV 
Transoral Robotic Surgery 
 
 
 
TORS 
Chemoradiotherapy 
 
 
 
 
CRT 
 
Intensity-modulated radiation therapy 
 
IMRT 
Perineural invasion 
 
 
 
 
PNI 
Extranodal extension  
 
 
 
ENE 
Quality of Life 
 
 
 
 
QOL 
Bitter taste receptor 
 
 
 
 
T2Rs 
Voltage gated sodium channel 
 
 
VGSC 
Pathologic tumor response 
 
 
 
pTR 

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Study Summary 
Title 
A Phase I Randomized Controlled Trial of Intratumoral Lidocaine 
Injection Before Transoral Robotic Surgery (TORS) and Neck 
Dissection for HPV-Associated Oropharyngeal Squamous Cell 
Carcinoma 
Short Title 
Intratumoral Lidocaine Injection Before Oropharyngeal Cancer Surgery 
Protocol Number 
 
Phase 
Phase I 
Study Duration 
2-years 
Study Center(s) 
Single-center 
Objectives 
Primary: To determine if intratumoral lidocaine injection prior to TORS 
and neck dissection for HPV associated OPSCC is 1) safe and 2) causes 
a major pathologic treatment effect.  
 
Secondary: To determine if intratumoral lidocaine injection prior to 
TORS and neck dissection for HPV associated OPSCC improves the 
locoregional control rates, progression-free survival, metastasis-free 
survival, and overall survival.  
 
Number of Subjects 
30 evaluable subjects 
Diagnosis and Main 
Inclusion Criteria 
- 
≥18 years old with OPSCC undergoing direct laryngoscopy for 
consideration of TORS and neck dissection. 
Study Regimen 
- 
Patients will be randomized and blinded to intratumoral injection 
of 1% lidocaine (intervention arm) or no injection (control arm) 
at the time of direct laryngoscopy and biopsy prior to TORS and 
neck dissection. 
o Intervention arm: While under general anesthesia after 
direct laryngoscopy with biopsy, 1% lidocaine will be 
injected under direct visualization (not exceeding the 
maximum tolerated dose of 4.5 mg/kg body weight) into 
the primary tumor with the aim to distribute the lidocaine 
evenly into the tumor. 
o Control arm: Direct laryngoscopy with biopsy with no 
injection.  
- 
Blood samples will be obtained before and after direct 
laryngoscopy/study intervention. 
- 
Pathologic tumor response (pTR) will be determined from 
surgical specimens. 

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Statistical 
Methodology 
This is a patient-blinded, randomized phase I study assessing safety, 
pathologic treatment effects, and oncologic outcomes from intratumoral 
lidocaine injection vs no injection at the time of direct laryngoscopy 
prior to TORS and neck dissection for HPV associated OPSCC. The 
total sample size is estimated to be 30 patients total (split approximately 
equally between the two groups). The proportion of patients with a 
pathologic tumor response (pTR) ≥50% (pTR-2) in the primary tumor 
following surgical resection will be compared between intervention and 
control arms using a one-sided Fisher’s exact test with a significance 
level of 0.05. The 2-year locoregional control (LRC) rates, progression-
free survival (PFS), metastasis-free survival (MFS), and overall survival 
(OS) will be estimated using the Kaplan–Meier method and compared 
using log-rank test between the two arms. 
 

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Study Schema 
 
  

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1 Introduction 
Based on evidence that lidocaine may activate apoptosis in cancer cells and/or limit 
metastasis, this randomized phase I study will establish the safety and efficacy of 
intratumoral lidocaine injection at the time of direct laryngoscopy prior to TransOral 
Robotic Surgery (TORS) and neck dissection for oropharyngeal squamous cell carcinoma 
(OPSCC). The primary objective of the study is to determine if intratumoral lidocaine 
injection is safe and causes a major pathologic treatment effect in the primary tumor 
following surgical resection. The secondary objectives will be to determine if intratumoral 
lidocaine injection improves locoregional control (LRC) rates, progression-free survival 
(PFS), metastasis-free survival (MFS), and overall survival (OS) compared to no injection 
(standard of care).  
 
Background 
Oral squamous cell carcinomas, which are located in the oral cavity and pharynx, accounted 
for roughly 50,000 new cancer diagnoses in the US in 2020 with an anticipated increase to 
76,000 by 2040.1 The increase in incidence is predominantly attributed to the rise in human 
papillomavirus (HPV)-associated OPSCCs which now represent most OPSCC cases and 
typically occur in the tonsils or base of tongue.2 Compared to HPV-negative OPSCCs, HPV 
associated OPSCCs tend to have relatively higher nodal burden at presentation and generally 
affect younger patients with higher performance status and fewer co-morbid conditions.3, 4 
Treatment for OPSCCs is selected based on the clinical and pathologic features and typically 
includes either definitive chemoradiation or surgery (TORS and selective neck dissection) 
followed by adjuvant radiation (+/- chemotherapy).5-8 Candidacy for TORS is typically 
assessed with direct laryngoscopy (with biopsy when indicated) to help evaluate the tumor 
extent and relevant anatomy. Primary surgery or primary radiation for HPV associated 
OPSCC both allow for favorable disease control (>95% LRC rates) and OS (~90% 3-year 
OS);9-13 however, a subset of patients recur and are unable to be successfully salvaged.13, 14 
Furthermore, the available treatments have associated toxicities including life-threatening 
sequelae or side-effects that impact quality of life (QoL) such as dysphagia, xerostomia, 
dysgeusia, neck fibrosis, and chronic pain.15-18 Several completed and ongoing de-escalation 
trials have sought to limit treatment-related morbidity by de-intensifying therapy for HPV 
associated OPSCC.19-22 However, there is a clear need for novel therapies with low side-
effect profiles to improve disease outcomes while maintaining QoL. 
 
Study Rationale, Preliminary Data, and Significance 
Lidocaine, a commonly used local anesthetic, has potential relevance for OPSCC treatment 
through its activation of bitter taste receptors (T2Rs) and inhibition of voltage gated sodium 
channels (VGSCs). T2Rs are G-protein-coupled receptors (GPCRs) that bind bitter agonists 
and are best known for their gustatory role on the tongue23. These receptors are also 

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expressed in other normal tissues throughout the body where they serve a diverse array of 
chemosensory and immune functions.24-29 More recently, T2Rs have been investigated in 
several cancers including GI,30-36 pancreatic,37, 38 breast,39 thyroid,40 acute myeloid 
leukemia,41 and head and neck squamous cell carcinoma including HPV associated 
OPSCCs.42 T2Rs in head and neck squamous cell carcinoma cells are activated by bitter 
compounds which trigger downstream Ca2+ responses, mitochondrial depolarization, caspase 
activation, and apoptosis.42 T2R expression levels have been shown to correlate with 
survival in head and neck squamous cell carcinomas42 and several other solid tumors 
including lung, prostate, and esophageal cancer.43 Of the 25 T2R isoforms in humans, 
T2R14 is being studied most actively.24 , 44, 45 Interestingly, the local anesthetic lidocaine is a 
bitter agonist for T2R14.46 In head and neck squamous cell carcinoma, lidocaine decreases 
cancer viability, depolarizes the mitochondrial membrane potential, elevates mitochondrial 
reactive oxygen species, induces apoptosis, and can inhibit the proteasome in a T2R14-
dependent manner.47 Furthermore, analysis of The Cancer Genome Atlas (TCGA) data 
suggests that T2R14 expression is increased in HPV associated OPSCCs compared to HPV-
negative OPSCCs.  
In addition to the newly described T2R14-mediated effects and increased receptor 
expression in HPV associated OPSCCs,47 lidocaine has been shown to also have beneficial 
effects in certain cancer types through its inhibitory effects on VGSCs.48-56 VGSCs have 
been shown to be expressed in human cancers including prostate57, breast cancer,58-60 and 
head and neck squamous cell carcinoma.54-56 It has been suggested that VGSCs are involved 
in oncogenic processes and are associated with metastatic behavior.48-56 For example, 
sodium channel protein type 5 subunit alpha, also known as NaV1.5, is highly expressed in 
head and neck squamous cell carcinomas and associated with TNM stage, lymph node 
metastasis, and other clinical features. In vitro inhibition of NaV1.5 promotes apoptosis and 
decreases proliferation, migration, and invasion. Additionally, NaV1.5 is thought to 
potentially be involved in the progression of head and neck squamous cell carcinomas 
through the Wnt/β-catenin signaling pathway.56 To our knowledge, there are no published 
studies evaluating oncologic outcomes for the in vivo clinical use of local anesthetics such as 
lidocaine in patients with OPSCC, though these drugs have been studied in other solid 
tumors including breast cancer.48, 52, 61, 62 
In vitro inhibition of VGSCs in breast cancer has been shown to reduce cell proliferation, 
motility, and invasion while encouraging focal adhesion, potentially reducing the metastatic 
capability of primary tumors.60 Clinical studies in patients undergoing breast cancer tumor 
resection suggested possible improved outcomes with use of local anesthetic, specifically 
lidocaine, at the primary tumor site.63-65 These observations led to the design of a recently 
published randomized controlled trial in the Journal of Clinical Oncology assessing the 
effect of lidocaine infiltration around the primary breast tumor prior to surgical resection in 
women with early breast cancer. This multi-institutional trial of nearly 1600 patients 

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demonstrated significantly increased 5-year DFS (86.6% vs 82.6%) and OS (90.1% and 
86.4%) in the peritumoral lidocaine injection group compared to the no injection group.66  
Surgery for solid tumors is known to modify gene expression and metastatic potential, cause 
dissemination of tumor cells, stimulate growth of micrometastasis, and inhibit the immune 
system.67-72 Simple interventions before or during oncologic surgery that can improve 
outcomes and potentially reduce metastasis are appealing, especially when they are not 
particularly time-consuming or expensive. Injection of local anesthetic such as lidocaine 
(with or without vasoconstrictive agents like epinephrine) is already commonly used during 
head and neck surgery to reduce general anesthetic requirements and provide hemostasis.73 
Therefore, lidocaine injection into the primary tumor in OPSCC would likely be easy to 
implement at the time of direct laryngoscopy while a patient is already under general 
anesthesia. Given the potential oncologic benefits and limited side-effects, intratumoral 
lidocaine injection may be particularly beneficial in HPV associated OPSCC prior to 
definitive TORS and neck dissection. 
Dosing Rationale 
Subcutaneous injection of 1% lidocaine (40 mM) is frequently used for local anesthesia 
during surgical operations and minor procedures.73 Concentrations of lidocaine lower than 
1% or 40 mM (including 10 mM) were sufficient to decrease head and neck SCC viability 
and cell proliferation and induce apoptosis in vitro; this effect was reduced or lost at lower 
concentrations of 5 mM or 1 mM.47 The previously referenced breast cancer randomized 
controlled trial demonstrated that 1% lidocaine injected around the primary tumor was 
associated with ~4% higher DFS and OS compared to no injection.66 Therefore, the current 
study will use 1% lidocaine injected under direct visualization (not exceeding the maximum 
tolerated dose of 4.5 mg/kg body weight) into the primary tumor with the aim to distribute 
the lidocaine evenly into the tumor. The maximum tolerated dose of 1% lidocaine (4.5 
mg/kg body weight) is ~31.5 mL total for a 70 kg person.  
 
Most tumors are stage T1 or T2 with greatest dimension 2 or 4 cm, respectively. A spherical 
tumor with diameter of 2 cm corresponds to a volume of 4.2 mL. A spherical tumor with 
diameter of 4 cm corresponds to a volume of 33.5 mL. However, in our experience injecting 
oropharyngeal tumors or abscesses with lidocaine for anesthetic purposes for biopsy or 
drainage, respectively, it is typically not feasible to inject more than 10 mL before the 
injection begins to extravasate from the tissues, likely due to the anatomic constraints of the 
oropharynx. A total volume of 10 mL is significantly lower than the maximum tolerated 
dose of 1% lidocaine (31.5 mL for a 70 kg individual). Therefore, tumors will be injected 
with 1% lidocaine until the injection appears to be evenly distributed into the tumor and 
begins to extravasate, with a total volume not to exceed 10 mL. The exact volume injected 
will be recorded for each subject. Notably, the previously referenced breast cancer clinical 
trial with 1600 patients reported no adverse events related to lidocaine injection.66 

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Biological Correlate for Early Evaluation of Intervention: Pathologic Tumor Response 
Advancements in neoadjuvant therapies have led to several systems for evaluating the 
pathologic treatment response in tumors following surgical removal. Pathological complete 
response (pCR, eradication of all cancer cells) and major pathologic response (MPR, 
presence of ≤ 10% viable tumor cells) are commonly used as surrogate clinical markers for 
predicting long-term survival.74-77 Despite being regarded as the “gold standard” for 
immunotherapy, pCR and MPR do not fully consider the varying degrees of treatment 
response within the tumor that may influence clinical outcomes. Therefore, some researchers 
have also implemented a metric known as the pathological tumor response (pTR) defined as 
the presence of tumor cell necrosis, keratinous debris, and giant cell/histiocytic reaction, 
quantified as a percentage of the overall tumor bed (area pathologic response/area 
pathologic response plus viable tumor).78, 79 The calculated pTR rate is scored in increments 
of 10% and often grouped into pTR-0 (≤10%), pTR-1 (≤10-49%), and pTR-2 (≥50%) to 
categorize the degree of response. Recent clinical trials in HPV associated OPSCC have 
successfully used pTR rates as primary endpoints for assessing responses to neoadjuvant 
pembrolizumab.78 pTR scoring will serve as an early metric for evaluating the study 
intervention. 
 
2 
Study Objectives 
2.1 Primary Objectives 
Determine if intratumoral 1% lidocaine injection at the time of direct laryngoscopy prior 
to TORS and neck dissection for HPV associated OPSCC is safe and causes a major 
pathologic treatment effect.  
2.2 Secondary Objectives 
Determine if intratumoral 1% lidocaine injection at the time of direct laryngoscopy prior 
to TORS and neck dissection for HPV associated OPSCC improves the locoregional 
control rates, progression-free survival, metastasis-free survival, and overall survival 
compared to no injection. 
 
3 Study Design 
3.1 General Design 
This is a phase I patient-blinded, randomized controlled trial evaluating intratumoral 
lidocaine injection prior to definitive surgery in HPV associated OPSCC. Patients with 
OPSCC undergoing direct laryngoscopy who are being considered for definitive TORS 

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and selective neck dissection, will be eligible. Patients will be randomized and blinded to 
intratumoral injection of 1% lidocaine (intervention arm) or no injection (control arm) at 
the time of direct laryngoscopy. After administration of general anesthesia and biopsy, 
lidocaine will be injected under direct visualization (not exceeding the maximum 
tolerated dose of 4.5 mg/kg body weight) into the primary tumor. The control arm will 
receive no injection.  
 
Blood samples will be obtained prior to direct laryngoscopy/study intervention (pre-
biopsy) and again after the intervention (post-biopsy). The pTR rate (defined above and 
in published literature78, 79) will be determined by the designated study pathologist 
(Timothy Chao, MD, PhD) with head and neck expertise using increments of 10% for the 
biopsy and surgery specimens. The scores will be grouped as pTR-0 (<10%), pTR-1 
(10%–49%), and pTR-2 (≥50%). 
 
Patients will otherwise receive institutional standard of care treatment including TORS 
primary site resection, selective neck dissection, and additional indicated adjuvant 
radiation therapy with or without chemotherapy. All enrolled patients will be assessed for 
safety measured by adverse events. If a patient does not ultimately receive primary 
surgery following their direct laryngoscopy/study intervention (based on surgical 
candidacy, patient preference, or other reasons), then they will not be counted as an 
evaluable subject, as the primary endpoint pTR requires a surgical specimen for 
evaluation. If a patient is determined to have a pathology other than HPV associated 
OPSCC after their direct laryngoscopy, then they will not be counted as an evaluable 
subject.  
3.2 Primary Study Endpoints 
1) Safety measured by occurrence of adverse events. 
 
2) Pathological tumor response (pTR) in the primary tumor following surgical resection. 
3.3 Secondary Study Endpoints 
2-year locoregional control rates, progression-free survival, metastasis-free survival, and 
overall survival. 
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
4.1.1 Patients ³ 18 years old. 

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4.1.2 Histologically confirmed diagnosis of squamous cell carcinoma of the 
oropharynx or neck.  
4.1.3 Clinical T1, T2, T3, or T4 stage disease of the oropharynx (per AJCC 
8th Ed). 
4.1.4 Any clinical N stage disease (per AJCC 8th Ed). 
4.1.5 Patients must be undergoing direct laryngoscopy +/- biopsy at the 
University of Pennsylvania as part of their work-up for consideration 
of definitive TORS and selective neck dissection. 
4.1.6 Patients must sign an informed consent document that indicates they 
are aware of the investigational nature of the treatment in this 
protocol as well as the potential risks and benefits. 
4.1.7 Ability to understand and the willingness to provide written informed 
consent.  
4.2 Exclusion Criteria 
4.2.1 Prior external beam radiation therapy to the head and neck. 
4.2.2 Prior chemotherapy for head and neck cancer. 
4.2.3 Tumor invades lateral pterygoid muscle, pterygoid plates, lateral 
nasopharynx, or skull base or encases carotid artery (i.e. AJCC 7th Ed. 
T4b for OPSCC). 
4.2.4 Presence of distant metastatic disease. 
4.2.5 Uncontrolled inter-current illness including, but not limited to, 
symptomatic congestive heart failure, unstable angina pectoris, 
connective tissue disease or psychiatric illness/social situations that 
would limit compliance with study requirements. 
4.2.6 Known history of hypersensitivity to lidocaine or other amide local 
anesthetics. 
4.2.7 Pregnant or breastfeeding. 
4.3 Patient Selection and Inclusion 
OPSCC is now the most common head and neck cancer diagnosed in the United States 

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with most cases attributed to HPV. HPV associated OPSCC is most frequently seen in 
middle-aged, white males (not Hispanic or Latino). We expect to have similar eligibility 
and enrollment demographics as other published trials on HPV associated OPSCC. For 
reference, RTOG 1016, which compared radiotherapy with cetuximab vs cisplatin, is the 
largest published randomized trial of HPV associated OPSCC in the United States with 
the following study demographics:80  
 
4.4 
Subject Recruitment and Screening 
Subjects will be recruited from the practices of Otorhinolaryngology and Radiation 
Oncology at the University of Pennsylvania. The study CRC will verify eligibility using 
the criteria outlined in Section 4.1 and 4.2. Patients will be consented either in clinic or in 
the hospital.  
4.5 
Clinical Evaluation and Staging Criteria 
• History and physical examination:  
o Primary tumor extent will be documented by the head and neck surgeon, with 
a particular focus on the degree (if any) of involvement of the soft palate 
and/or base of tongue. 
• Laboratory studies:  
o HPV 
status 
will 
be 
determined 
based 
on 
p16-positivity 
by 
immunohistochemistry or HPV-positivity by in-situ hybridization. 
o Research blood tests will be drawn 1) prior to direct laryngoscopy/study 
intervention and 2) after the direct laryngoscopy/study intervention (but 
before definitive treatment).  
• Pathologic evaluation 
o In addition to standard pathologic evaluation of biopsy and surgical 

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specimens, pTR will be calculated and categorized as pTR-0 (≤10%), pTR-1 
(≤10-49%), and pTR-2 (≥50%) by the designated study pathologist (Timothy 
Chao, MD, PhD). 
• Staging imaging studies will be dictated by standard of care.  
• Eligibility for this study will be according to AJCC 7th and 8th Edition staging. AJCC 
7th Edition staging data will be collected and recorded in the electronic medical 
record (Epic) for all patients as this staging is currently being used clinically to 
determine indications for adjuvant radiotherapy. 
4.6 
Off-Study Criteria 
• Extraordinary Medical Circumstances: If at any time the constraints of this protocol 
are detrimental to the subject’s health, the subject will be removed from protocol 
therapy.  In this event, the reasons for withdrawal will be documented if possible.   
• Subject’s refusal to continue treatment or decision for non-surgical treatment: In this 
event, the reasons for withdrawal or decision for non-surgical treatment will be 
documented if possible.  
• Patients may be taken off study at any time at the discretion of the Principal 
Investigator. 
4.7 
Study Duration 
With an estimated accrual of 1-2 patients per month, it is anticipated that accrual will 
continue for approximately 2-years. The anticipated accrual rate is based on accrual to 
our prior TORS trial protocols. We find that most of our patients with HPV associated 
OPSCC are highly motivated to enroll on clinical trials, as they are often referred to Penn 
Medicine specifically for that reason.  
  
5 
Study Procedures 
5.1 
General study design 
Patients will be enrolled to reach 30 evaluable subjects on this phase I patient-blinded, 
randomized controlled trial investigating the feasibility and safety of intratumoral 1% 
lidocaine injection at the time of direct laryngoscopy prior to definitive surgery in HPV 
associated OPSCC patients. Patients with a clinically apparent primary tumor (i.e. clinical 
T1-T4), any clinical N stage, and M0 disease (per AJCC 8th Edition) undergoing direct 
laryngoscopy who are being considered for definitive TORS and selective neck 
dissection, will be eligible. Patients will be blinded to the intervention which will be 
administered as dictated by the protocol, according to Section 3.1 above. Randomization 
will be performed using the “Clinical Trial Randomization Tool” from The National 
Cancer Institute's Division of Cancer Prevention.81 

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Clinical evaluations will be performed according to routine clinical care, which is left to 
the discretion of the treating physician. This will include a baseline evaluation prior to 
direct laryngoscopy/study intervention.  
 
All patients will be asked to take a short survey about pain (2 questions) at their follow 
up appointment after their direct laryngoscopy and biopsy. 
 
Locoregional recurrence will be defined as biopsy-proven recurrent squamous cell 
carcinoma at the original, primary tumor site, or in the neck.  
5.2 
Surgery 
Surgery will be performed per standard of care consisting of TORS primary site 
resection, selective neck dissection, and external carotid artery vessel ligation. The 
decision to stage the neck dissection and TORS will be determined at the discretion of the 
head and neck surgeon. Intraoperative continuous monitoring of circulation and 
respiration will be performed. 
5.3 
Radiation Therapy  
Patients who have indications post-operative radiation therapy per NCCN guidelines5 will 
be referred to a radiation oncologist who specializes in the treatment of head and neck 
cancer within the University of Pennsylvania Health System, with the decision on 
whether to treat with radiation therapy determined at the discretion of the consulting 
radiation oncologist. 
 
If the patient meets eligibility criteria for the published AVOID trial which is institutional 
standard of care for HPV associated OPSCC,19 then the primary site will be spared, 
without compromising coverage to the neck volumes. The eligibility for this approach is 
patients with pT1-T2, negative margins (defined as ≥2 mm), no perineural invasion 
(PNI), and no lymph-vascular space invasion (LVSI).  
 
Simulation for treatment is required. CT-based treatment planning is required. Treatment 
with either IMRT or PBT is allowed. All fields will be treated every session.  
Interruptions in therapy should be discussed with the principal investigator but will be 
instituted at the discretion of the treating radiation oncologist. Dose calculation should be 
performed using inhomogeneity corrections to account for differences in tissue density 
across the head and neck region.  Patients may miss up to three treatments a week due to 
illness, travel, etc.  

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5.4 
Chemotherapy 
Patients who have indications for the use of concurrent chemotherapy in the 
postoperative setting (ENE or positive margins)82  will be referred to a medical 
oncologist who specializes in the treatment of head and neck cancer within the University 
of Pennsylvania Health System, with the decision on whether to treat with chemotherapy 
determined at the discretion of the consulting medical oncologist. 
5.5 
Blood Draws 
Research blood draws will be obtained at the following time points: 
1) Prior to direct laryngoscopy/study intervention on the day of surgery. This will 
typically be performed in the preoperative area or operating room when obtaining 
an IV for surgery. 
2) After direct laryngoscopy/study intervention (but before definitive surgery or 
radiation). This will typically be performed on the day of the post-laryngoscopy 
clinic visit to discuss the results of the direct laryngoscopy. 
 
Other blood draws will be obtained according to institutional standard of care. 
 
5.6 
Sample Storage 
Tumor tissue from biopsy and surgery or other collected samples (e.g., blood, serum) 
may be used or stored for any other future relevant analysis. Specific technical studies in 
the future could include pathology, immunohistochemical, genetic, genomic, proteomic, 
or transcriptomic analyses. The tissue may include paraffin blocks or fresh tissue that is 
frozen.  
5.7 
Study Visit Schedule 
 
An outline of the typical study visit schedule is provided below. There will be no 
planned additional study visits compared to routine, standard of care (SOC). Clinical 
research procedures are underlined in the table for clarification purposes.  
 
Visit 
Number 
Visit Procedures 
Visit 1 
Come to the clinic for a routine (SOC) clinic visit(s).  
 
Decide if you want to participate in the study, ask questions, sign the consent form 
if you do want to participate. 
 
Visit 2 
Have a pre-operative research blood draw with blood sample storage on the day of 
your direct laryngoscopy with biopsy. 
 

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Study Intervention: 
Participants will be randomly assigned to two groups. 
• Group 1 (Intervention Arm) – Biopsy and injection of lidocaine into tumor 
while you are under general anesthesia for your direct laryngoscopy. 
• Group 2 (Control Arm) – Biopsy without injection of lidocaine while you are 
under general anesthesia for your direct laryngoscopy. 
 
 
Visit 3 
Routine (SOC) clinic visit to discuss the results of your direct laryngoscopy with 
biopsy and have a research study blood draw with blood sample storage. You will 
also be asked to take a short survey. 
 
Visit 4 
Routine (SOC) treatment with primary surgery or primary radiation with storage of 
tumor tissue for research. This will allow researchers to study leftover tissue 
removed during your routine care. 
 
Visit 5 
Routine (SOC) follow up for cancer surveillance per National Comprehensive 
Cancer Network guidelines. 
 
6 
Statistical Plan 
This study is considered exploratory because, to our knowledge, no prior published data 
exists on the effects of lidocaine injection on pathologic tumor response, survival, and 
recurrence in HPV associated OPSCC. The planned sample size for this phase I trial is 30 
evaluable subjects split equally between the intervention and control arms. Subjects will 
need to have a definitive diagnosis of HPV associated OPSCC and undergo surgery (TORS 
and neck dissection) to be considered evaluable.  
 
The co-primary objectives of this study are to determine safety and if the proportion of 
patients with pTR-2 in the primary tumor is different in the intervention group compared to 
the control arm. All enrolled participants, regardless of HPV status or final pathology, will 
be included in the primary safety analysis. Thus, any adverse events or dose-limiting 
toxicities observed in participants will contribute to the overall safety assessment of 
intratumoral lidocaine. 
 
For the pathologic response primary endpoint, H0 is that there is no difference in the 
proportions of patients with pTR-2 between the intervention or no intervention (control) 
groups; Ha is that the intervention arm is associated with a higher proportion of pTR-2. The 
proportion of pTR-2 will be compared between the intervention and control arms using a 
one-sided Fisher’s exact test with a significance level of 0.05. A 95% confidence interval 
will be used. We estimate that a sample size of 30 patients is needed to allow us to detect 

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with 80% power at the one-sided alpha level of 0.05 a major pathologic treatment rate of 
30% in the intervention arm compared to 0% in the control arm. 
 
In addition to hypothesis testing for the pathologic response primary outcome, we will use 
within-between interaction models to account for the effects of the treatment and the 
interaction between treatment and patient and disease factors including age, sex, disease 
stage, and adverse pathologic features (e.g. tumor grade, perineural invasion, 
lymphovascular invasion). We will estimate means and standard deviations for each group 
and the correlation within subjects to better understand the relationship between repeated 
measures. We will use mixed-effects models to handle within-subject correlations and 
between-subject comparisons. 
 
The secondary endpoints include 2-year locoregional control (LRC) rates, progression-free 
survival (PFS), metastasis-free survival (MFS), and overall survival (OS). PFS will be 
defined as time from random assignment to disease progression or death from any cause. 
MFS will be defined as time from random assignment to first evidence of distant metastatic 
disease or death from any cause. OS will be defined as the time from random assignment 
and death due to any cause. 95% confidence intervals will be used. LRC rates, PFS, MFS, 
and OS will be estimated using the Kaplan–Meier method, and log-rank test will be used to 
compare the two groups using a significance level of 0.05. 
 
Due to distinct biological differences between HPV associated and HPV-negative OPSCC 
and evidence suggesting that lidocaine’s anticancer effects may be more relevant to HPV 
associated tumors, any HPV-negative tumors will be evaluated separately from HPV 
associated tumors for primary and secondary efficacy endpoints. 
 
An interim analysis is not planned due to the well-established safety data associated with 
injectable lidocaine.  
7 
Safety and Adverse Events 
7.1 
Definitions 
Adverse Event 
Adverse events (AE) and Serious Adverse Events (SAE) will use the descriptions and 
grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE). This study will utilize the CTCAE v5.0 for adverse event reporting.  
All appropriate treatment areas will have access to a copy of the CTCAE v5.0 and 
adverse events will only be collected up until 30 calendar days after completion of the 
injection. Any AE’s which remain unresolved at 30 days post-injection will be assessed 
for resolution at subsequent standard of care follow-up visits. Intercurrent illnesses or 

Version Date: 10 January 2025 
 
 
 
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injuries should be regarded as adverse events. Abnormal results of diagnostic procedures 
are considered to be adverse events if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a Serious Adverse Event (SAE) 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
 
AEs Not to Include: 
• Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition 
that leads to the procedures is an AE 
• Situations where an untoward medical occurrence did not occur (elective and/or 
convenience admission to hospital) 
• Anticipated day-to-day fluctuation of pre-existing disease(s) or condition(s) 
present or detectable at the start of the study that do not worsen in grade or 
severity.  
• The disease/disorder being studied, or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
subject’s condition.  
• Grade 1 adverse events that are expected and related for radiotherapy and 
chemotherapy, if indicated (listed in the radiation and chemotherapy 
protocol/consent). 
• Abnormal lab values 
• Adverse events in patients receiving chemotherapy or radiation therapy for 
metastasis and/or additional cancers will not be collected.     
 
7.2 
Expedited Adverse Event Reporting 
Common Toxicity Criteria 
Toxicity will be evaluated with the NCI Common Toxicity Criteria (CTCAE) v. 5.0. 
 
Serious Adverse Events 
A SAE is defined as any of the following: 
- Fatal or life-threatening (real risk of dying) event 
- Requires or prolongs hospitalization 
- Causes persistent or significant disability/incapacity 
- Results in a birth defect or congenital anomaly 
- Causes cancer 
 

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All hospitalizations or prolongation of existing hospitalization for medical events 
regardless of phase of study, expected or unexpected attributions are SAE’s.  
 
Serious, unexpected drug-related adverse events will be reported to the University of 
Pennsylvania IRB, and the University of Pennsylvania Cancer Center Data and Safety 
Monitoring Committee (DSMC) using the expedited reporting guidelines as is required 
by each board.  
 
The toxicities that develop during the standard chemotherapy portion of this trial will not 
require reporting in an expedited manner. 
7.3 
Lidocaine Safety and Adverse Reactions 
The clinical adverse event profile, pharmacokinetics, pharmacodynamics, and toxicology 
for injectable lidocaine is well-establish and readily available from the manufacturer(s) 
(https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=76176d50-a987-c9f9-
e053-2991aa0aea0f&type=display). Lidocaine is one of the most commonly used local 
anesthetics with well-established safety data for its use as an anesthetic but does not have 
proven safety data for use as a cancer therapy. The most common side effects of lidocaine 
injection are swelling, bruising, or soreness at the injection site, and temporary rapid 
heartbeat. Lidocaine overdose can cause central nervous system (CNS) effects such as 
confusion, seizure, or unconsciousness, respiratory depression and/or respiratory arrest, 
and cardiovascular effects such as cardiac arrythmias. Reactions to lidocaine may result 
from intra-arterial injection of lidocaine with retrograde flow to the cerebral circulation. 
Less common side effects include damage to nerves resulting in temporary or possibly 
permanent numbness or tingling and severe and possibly life-threatening allergic 
reactions.  
 
Monitoring and Management of Adverse Events 
Participants will be closely monitored for any adverse events, particularly those 
potentially related to lidocaine administration. As defined above, the total injected 
volume of lidocaine will not exceed the established maximum tolerated dose, minimizing 
the risk to participants. The following precautions and monitoring procedures will also be 
implemented: 
 
Intraoperative and Postoperative Monitoring: 
• In accordance with our standard of care peri-operative management, all participants 
will undergo continuous electrocardiographic (ECG) monitoring during surgery and 
immediately postoperatively to detect any arrhythmias or other cardiovascular events. 
• Vital signs, including heart rate, blood pressure, and oxygen saturation, will be 
recorded at regular intervals throughout the procedure and in the recovery period. 

Version Date: 10 January 2025 
 
 
 
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• Participants will be monitored in the recovery area for at least 1-hour post-injection, 
with extended monitoring if signs of toxicity are noted. 
 
Management of Specific Adverse Events: 
• Arrhythmias: Anti-arrhythmic medications and defibrillators are readily available in 
the operating room and recovery areas. Any significant arrhythmias will be managed 
according to our standard clinical protocols, including potential transfer to an 
intensive care unit if needed. 
• Lidocaine Central Nervous System Toxicity: CNS toxicity will be managed with 
supportive measures, including supplemental oxygen, and antiepileptics, per our 
standard clinical protocols. If required, intravenous lipid emulsion (ILE) therapy, the 
established treatment for severe local anesthetic systemic toxicity, will be 
administered. Airway protection, including intubation, will be provided if necessary. 
• Hypersensitivity and Allergic Reactions: Epinephrine, antihistamines, and 
corticosteroids will be available in the perioperative period to treat any severe allergic 
reactions. 
 
This monitoring and management plan will ensure that any adverse reactions are 
identified and treated promptly, thereby minimizing risks to participants. 
 
7.4 
Dose-Limiting Toxicities and Stopping Rules  
Dose-limiting toxicities (DLTs) will be defined as any of the following adverse events 
occurring after intratumoral lidocaine injection: 
• 
Grade 3 or higher cardiac arrhythmia, seizure, or other central nervous system 
toxicity attributed to lidocaine, as graded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 
• 
Any other Grade 3 or higher adverse event directly attributed to lidocaine that, in 
the judgment of the Medical Monitor and Study Sponsor, poses a significant risk to 
participant safety. 
Stopping Rules for Safety 
A stopping rule for safety will halt accrual to the study if risks to subjects unexpectedly 
outweigh the benefits due to unexpected severe adverse events (SAEs). This 
determination will be made by the DSMC, Medical Monitor, and Study Sponsor. The 
specific stopping rules are as follows: 
• 
Cohort-Based Pausing: If 2 or more participants within a cohort of 5 experience 
DLTs, the study will be paused. An independent safety review will be conducted by 
the DSMC and Medical Monitor. The study will only resume if the DSMC concludes 
it is safe to proceed. 

Version Date: 10 January 2025 
 
 
 
21 
• 
Overall Study Pausing: If more than 10% of participants across the study 
experience a DLT or Grade 3 or higher adverse event related to lidocaine, the 
study will be paused. The DSMC, Medical Monitor, and Study Sponsor will re-
evaluate the safety profile of intratumoral lidocaine injection to determine if 
modifications to the protocol or dosing are required or if the study should be 
permanently discontinued. 
Reporting and Adjustments 
Any unexpected SAEs will be reported to the IRB promptly, and study procedures will be 
adjusted as necessary to mitigate further risk. 
8 
Data Handling and Record Keeping 
8.1 
Records 
All patients must have a signed Informed Consent Form. Confirmation of study eligibility 
will be completed by a participating investigator via the electronic medical record (EPIC) 
prior to entering the study. 
Confidential research charts will be kept in locked cabinets at each participating 
institution.  Subjects will be assigned a study number at the time of study enrollment.  
This study number and not the subject’s name will be used on all case report forms. 
HIPAA Compliance:   
Prior to direct laryngoscopy and randomization to the intervention vs control, each 
subject will sign a study informed consent, which also includes consent acknowledging 
the uses and disclosures of protected health information (PHI) in this study as required by 
The Health Insurance Portability and Accountability Act (HIPAA).  PHI will not be 
shared with any outside institution except as required by law.  Any reporting of the 
results of this study will be done only with de-identified patient data.  Confidentiality will 
be protected as outlined below. 
• Each subject will sign a study informed consent electronically prior to direct 
laryngoscopy and randomization to the intervention vs control 
 
8.2 
Data Collection and Management 
All patients must have a signed Informed Consent Form and an On-study (confirmation 
of eligibility) form filled out and signed by a participating investigator prior to entering 
the study. 
A case report form will be used to standardize data keeping and allow entry to a 
computerized data base. 

Version Date: 10 January 2025 
 
 
 
22 
• Each subject will be assigned a study number.  All research-related material will 
be labeled with the subject study number and the subject’s initials.  
• A list of the subject names with the associated subject numbers will be maintained 
in a locked cabinet and computer by the principal investigator and study 
coordinator. 
• All research subject records will be kept in a study chart or patient binder. 
• An electronic, password protected database will be maintained. PHI and patient 
IDs will be used.  Research members outside of those who need to have PHI, will 
only have the Patient ID (Coded information) to follow UPHS limited data policy. 
 
9 Data and Safety Monitoring Plan 
9.1 Overview 
The University of Pennsylvania Cancer Center (UPCC) has a formal plan for Data Safety 
and Monitoring of Clinical Trials.  The clinical trial, “A Phase I Randomized Controlled 
Trial of Intratumoral Lidocaine Injection Before Transoral Robotic Surgery (TORS) and 
Neck Dissection for HPV associated Oropharyngeal Squamous Cell Carcinoma” is a trial 
that is subject to oversight of the UPCC through the Data and Safety Monitoring 
Committee (DSMC). DSMC role is to ensure that the rights and well-being of all subjects 
are protected and that subjects are treated in full compliance with the study treatment and 
parameters specified in the protocol. The DSMC is responsible for overseeing the process 
of monitoring of studies and the conduct of audits.  The investigators on this study are 
responsible for the continuous, close monitoring of subjects enrolled on this trial. 
9.2 Study Audits 
A DSMC audit of this trial will be performed twice a year for as long as the trial remains 
open for accrual.  The principal investigator will be notified in advance of the selection of 
their protocol for review.  Three randomly selected patients or 10% of the total accrual, 
whichever is higher will be audited.  A written report is provided to the principal 
investigator following this audit.  Any rating less than satisfactory would warrant a repeat 
full review at the time of the next scheduled audit or sooner, depending upon the extent 
of the deficiencies found.  Substantial protocol deviations will be reported to the Director 
of the Cancer Center and the Associate Director for Clinical Research for consideration 
of appropriate administrative action, such as suspending accrual to the protocol. 

Version Date: 10 January 2025 
 
 
 
23 
9.3  Study Monitoring 
A Medical Monitor, who is not directly involved in this trial and is not collaborating with 
the Sponsor-investigator in any other trials, has been selected for this trial. The Medical 
Monitor for this trial is Noam Cohen, MD, PhD. The Medical Monitor will review 
adverse events, safety data, and activity data observed in the ongoing clinical trial. The 
Medical Monitor may recommend reporting of adverse events and relevant safety data 
not previously reported and may recommend suspension or termination of the trial. 
Meetings with the Medical Monitor will occur biannually or more frequently if 
necessary. The meetings will take place in person or via telephone. The summary reports 
of all discussions of adverse events will be submitted to the DSMC on a biannual basis or 
more frequently if appropriate. 
 
The Principal Investigator or his/her designee of the trial will present to the Medical 
Monitor all serious adverse events observed in patients, any activity data obtained, and 
whether those data invoked any stopping criteria in the clinical protocol. Adverse event 
reporting will follow the NCI guidelines. Results of the data from toxicology or other 
animal studies that are relevant will be discussed. Other information related to the safety 
and efficacy of the clinical study will be discussed. This includes information of similar 
investigational materials used in different studies. 
 
10 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB 
concerning the conduct of the study will be made in writing to the investigator and a copy of 
this decision will be provided to the sponsor before commencement of this study. The 
investigator should provide a list of EC/IRB members and their affiliate to the sponsor. 
10.1 
Risks 
As part of the research study, subjects will be asked to have blood samples collected in 
addition to any blood samples that will be drawn as part of the routine clinical care. The 
risk of having additional blood samples collected is minimal, and includes pain, redness, 
swelling, and/or bruising where the needle enters the body. Rare instances of fainting, 
excess bleeding, blood clotting, or infection have happened. 

Version Date: 10 January 2025 
 
 
 
24 
10.2 
Benefits 
The potential benefits of participating in this study are improved survival and decreased 
rate of cancer recurrence if subjects are assigned to the group that receives the lidocaine 
injection. However, these benefits have NOT yet been established in the type of cancer 
being studied. If subjects are assigned to the group that receives the lidocaine injection, 
they may also have the benefit of temporarily (i.e. ~2 hours) decreased pain from the 
biopsy site, as lidocaine is a local anesthetic. The benefits of participating in research using 
tissue include improving our knowledge of the causes of head and neck disease and other 
diseases, how to prevent them, how to treat them, and how to cure them. Patients may not 
get any benefit from being in this research study. 
10.3 
Risk / Benefit Assessment 
The risks of participating in the study are outweighed by the potential benefits of 
participating in the study.  
10.4 
Informed Consent Process / HIPAA Authorization  
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study. The potential risks and benefits of participation on the study will 
be discussed with each subject, with risk-benefit assessment. All subjects will be informed 
that participation is voluntary, and that treatment on study is investigational.  This consent 
form will be submitted with the protocol for review and approval by the IRB for the study.  
The formal consent of a subject, using the IRB-approved consent form, must be obtained 
before that subject is submitted to any study procedure.  This consent form must be signed 
by the subject or legally acceptable surrogate, and the investigator-designated research 
professional obtaining the consent.  
 
11 Study Finances 
11.1 Funding Source 
This study will be financed through the Department of Otorhinolaryngology – Head & 
Neck Surgery at the University of Pennsylvania using academic development funds.  
11.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must have the conflict reviewed by a properly constituted Conflict of Interest Committee 
with a Committee-sanctioned conflict management plan that has been reviewed and 

Version Date: 10 January 2025 
 
 
 
25 
approved by the study sponsor prior to participation in this study.  All University of 
Pennsylvania investigators will follow the University conflict of interest policy. 
 
12 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, 
nor any of the information provided by the sponsor for the purposes of performing the study, 
will be published or passed on to any third party without the consent of the study sponsor 
(PI).  Any investigator involved with this study is obligated to provide the sponsor (PI) with 
complete test results and all data derived from the study. 
 
13 References 
1. 
Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated Projection of US Cancer 
Incidence and Death to 2040. JAMA Netw Open. 2021;4(4):e214708. Epub 2021/04/08. doi: 
10.1001/jamanetworkopen.2021.4708. PubMed PMID: 33825840; PMCID: PMC8027914. 
2. 
Gooi Z, Chan JY, Fakhry C. The epidemiology of the human papillomavirus related to 
oropharyngeal head and neck cancer. Laryngoscope. 2016;126(4):894-900. doi: 
10.1002/lary.25767. PubMed PMID: 26845348. 
3. 
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman 
D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in 
GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-86. doi: 10.1002/ijc.29210. PubMed PMID: 
25220842. 
4. 
Chai RC, Lambie D, Verma M, Punyadeera C. Current trends in the etiology and 
diagnosis of HPV-related head and neck cancers. Cancer Med. 2015;4(4):596-607. doi: 
10.1002/cam4.424. PubMed PMID: 25644715; PMCID: PMC4402074. 
5. 
Network NCC. Head and Neck Cancers (Version 2.2023) 2023 [May 28, 2023]. 
Available from: https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. 
6. 
Cramer JD, Burtness B, Ferris RL. Immunotherapy for head and neck cancer: Recent 
advances and future directions. Oral Oncol. 2019;99:104460. doi: 
10.1016/j.oraloncology.2019.104460. PubMed PMID: 31683169. 
7. 
Weinstein GS, O'Malley BW, Jr., Cohen MA, Quon H. Transoral robotic surgery for 
advanced oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 2010;136(11):1079-85. 
doi: 10.1001/archoto.2010.191. PubMed PMID: 21079160. 
8. 
Weinstein GS, Quon H, O'Malley BW, Jr., Kim GG, Cohen MA. Selective neck 
dissection and deintensified postoperative radiation and chemotherapy for oropharyngeal cancer: 
a subset analysis of the University of Pennsylvania transoral robotic surgery trial. The 
Laryngoscope. 2010;120(9):1749-55. Epub 2010/08/19. doi: 10.1002/lary.21021. PubMed 
PMID: 20717944. 
9. 
Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, 
Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML. 
Human papillomavirus and survival of patients with oropharyngeal cancer. The New England 
journal of medicine. 2010;363(1):24-35. Epub 2010/06/10. doi: 10.1056/NEJMoa0912217. 
PubMed PMID: 20530316; PMCID: PMC2943767. 

Version Date: 10 January 2025 
 
 
 
26 
10. 
O'Sullivan B, Huang SH, Siu LL, Waldron J, Zhao H, Perez-Ordonez B, Weinreb I, Kim 
J, Ringash J, Bayley A, Dawson LA, Hope A, Cho J, Irish J, Gilbert R, Gullane P, Hui A, Liu 
FF, Chen E, Xu W. Deintensification candidate subgroups in human papillomavirus-related 
oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol. 
2013;31(5):543-50. doi: 10.1200/JCO.2012.44.0164. PubMed PMID: 23295795. 
11. 
Cohen MA, Weinstein GS, O'Malley BW, Jr., Feldman M, Quon H. Transoral robotic 
surgery and human papillomavirus status: Oncologic results. Head & neck. 2011;33(4):573-80. 
Epub 2011/03/23. doi: 10.1002/hed.21500. PubMed PMID: 21425382. 
12. 
Quon H, Cohen MA, Montone KT, Ziober AF, Wang LP, Weinstein GS, O'Malley BW, 
Jr. Transoral robotic surgery and adjuvant therapy for oropharyngeal carcinomas and the 
influence of p16 INK4a on treatment outcomes. The Laryngoscope. 2013;123(3):635-40. Epub 
2012/05/17. doi: 10.1002/lary.22172. PubMed PMID: 22588642. 
13. 
Carey RM, Brody RM, Shimunov D, Shinn JR, Mady LJ, Rajasekaran K, Cannady SB, 
Lin A, Lukens JN, Bauml JM, Cohen RB, Basu D, O'Malley BW, Jr., Weinstein GS, Newman 
JG. Locoregional Recurrence in p16-Positive Oropharyngeal Squamous Cell Carcinoma After 
TORS. Laryngoscope. 2021;131(12):E2865-e73. Epub 2021/06/03. doi: 10.1002/lary.29659. 
PubMed PMID: 34076275. 
14. 
Brody RM, Shimunov D, Cohen RB, Lin A, Lukens JN, Hartner L, Aggarwal C, Duvvuri 
U, Montone KT, Jalaly JB, LiVolsi VA, Carey RM, Shanti RM, Rajasekaran K, Chalian AA, 
Rassekh CH, Cannady SB, Newman JG, O'Malley BW, Weinstein GS, Gimotty PA, Basu D. A 
benchmark for oncologic outcomes and model for lethal recurrence risk after transoral robotic 
resection of HPV-related oropharyngeal cancers. Oral Oncol. 2022;127:105798. Epub 
2022/03/05. doi: 10.1016/j.oraloncology.2022.105798. PubMed PMID: 35245888; PMCID: 
PMC9288202. 
15. 
Lazarus CL. Effects of chemoradiotherapy on voice and swallowing. Curr Opin 
Otolaryngol Head Neck Surg. 2009;17(3):172-8. doi: 10.1097/MOO.0b013e32832af12f. 
PubMed PMID: 19337126; PMCID: PMC2745635. 
16. 
Jethwa AR, Khariwala SS. Tobacco-related carcinogenesis in head and neck cancer. 
Cancer Metastasis Rev. 2017;36(3):411-23. Epub 2017/08/13. doi: 10.1007/s10555-017-9689-6. 
PubMed PMID: 28801840; PMCID: PMC5709040. 
17. 
Suh Y, Amelio I, Guerrero Urbano T, Tavassoli M. Clinical update on cancer: molecular 
oncology of head and neck cancer. Cell Death Dis. 2014;5:e1018. Epub 2014/01/25. doi: 
10.1038/cddis.2013.548. PubMed PMID: 24457962; PMCID: PMC4040714. 
18. 
Murphy BA, Ridner S, Wells N, Dietrich M. Quality of life research in head and neck 
cancer: a review of the current state of the science. Crit Rev Oncol Hematol. 2007;62(3):251-67. 
Epub 2007/04/06. doi: 10.1016/j.critrevonc.2006.07.005. PubMed PMID: 17408963. 
19. 
Swisher-McClure S, Lukens JN, Aggarwal C, Ahn P, Basu D, Bauml JM, Brody R, 
Chalian A, Cohen RB, Fotouhi-Ghiam A, Geiger G, Gershowitz J, Livolsi V, Mitra N, Montone 
K, Newman J, Ojerholm E, O'Malley B, Jr., Rajasekaran K, Tan E, Weinstein G, Lin A. A Phase 
2 Trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): 
Omission of the Resected Primary Tumor Bed After Transoral Robotic Surgery for Human 
Papilloma Virus-Related Squamous Cell Carcinoma of the Oropharynx. Int J Radiat Oncol Biol 
Phys. 2020;106(4):725-32. doi: 10.1016/j.ijrobp.2019.11.021. PubMed PMID: 31785337. 
20. 
Ferris RL, Flamand Y, Holsinger FC, Weinstein GS, Quon H, Mehra R, Garcia JJ, Hinni 
ML, Gross ND, Sturgis EM, Duvvuri U, Méndez E, Ridge JA, Magnuson JS, Higgins KA, Patel 
MR, Smith RB, Karakla DW, Kupferman ME, Malone JP, Judson BL, Richmon J, Boyle JO, 

Version Date: 10 January 2025 
 
 
 
27 
Bayon R, O'Malley BW, Jr., Ozer E, Thomas GR, Koch WM, Bell RB, Saba NF, Li S, Sigurdson 
ER, Burtness B. A novel surgeon credentialing and quality assurance process using transoral 
surgery for oropharyngeal cancer in ECOG-ACRIN Cancer Research Group Trial E3311. Oral 
Oncol. 2020;110:104797. Epub 2020/07/18. doi: 10.1016/j.oraloncology.2020.104797. PubMed 
PMID: 32679405; PMCID: PMC7771718. 
21. 
Ma DJ, Price KA, Moore EJ, Patel SH, Hinni ML, Garcia JJ, Graner DE, Foster NR, 
Ginos B, Neben-Wittich M, Garces YI, Chintakuntlawar AV, Price DL, Olsen KD, Van Abel 
KM, Kasperbauer JL, Janus JR, Waddle M, Miller R, Shiraishi S, Foote RL. Phase II Evaluation 
of Aggressive Dose De-Escalation for Adjuvant Chemoradiotherapy in Human Papillomavirus-
Associated Oropharynx Squamous Cell Carcinoma. J Clin Oncol. 2019;37(22):1909-18. Epub 
2019/06/05. doi: 10.1200/jco.19.00463. PubMed PMID: 31163012; PMCID: PMC7098832. 
22. 
Ferris RL, Flamand Y, Weinstein GS, Li S, Quon H, Mehra R, Garcia JJ, Chung CH, 
Gillison ML, Duvvuri U, O'malley BW, Ozer E, Thomas GR, Koch W, Kupferman ME, Bell 
RB, Saba NF, Lango M, Mendez E, Burtness B. Transoral robotic surgical resection followed by 
randomization to low- or standard-dose IMRT in resectable p16+ locally advanced oropharynx 
cancer: A trial of the ECOG-ACRIN Cancer Research Group (E3311). Journal of Clinical 
Oncology. 2020;38(15_suppl):6500-. doi: 10.1200/JCO.2020.38.15_suppl.6500. 
23. 
Bachmanov AA, Bosak NP, Lin C, Matsumoto I, Ohmoto M, Reed DR, Nelson TM. 
Genetics of taste receptors. Current pharmaceutical design. 2014;20(16):2669-83. Epub 
2013/07/28. doi: 10.2174/13816128113199990566. PubMed PMID: 23886383; PMCID: 
PMC4764331. 
24. 
Hariri BM, McMahon DB, Chen B, Freund JR, Mansfield CJ, Doghramji LJ, Adappa 
ND, Palmer JN, Kennedy DW, Reed DR, Jiang P, Lee RJ. Flavones modulate respiratory 
epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor. J 
Biol Chem. 2017;292(20):8484-97. Epub 2017/04/05. doi: 10.1074/jbc.M116.771949. PubMed 
PMID: 28373278; PMCID: PMC5437252. 
25. 
Carey RM, Lee RJ. Taste Receptors in Upper Airway Innate Immunity. Nutrients. 
2019;11(9). doi: 10.3390/nu11092017. PubMed PMID: 31466230; PMCID: PMC6770031. 
26. 
Clark AA, Dotson CD, Elson AE, Voigt A, Boehm U, Meyerhof W, Steinle NI, Munger 
SD. TAS2R bitter taste receptors regulate thyroid function. Faseb j. 2015;29(1):164-72. Epub 
2014/10/25. doi: 10.1096/fj.14-262246. PubMed PMID: 25342133; PMCID: PMC4285546. 
27. 
Kinnamon SC. Taste receptor signalling - from tongues to lungs. Acta Physiol (Oxf). 
2012;204(2):158-68. Epub 2011/04/13. doi: 10.1111/j.1748-1716.2011.02308.x. PubMed PMID: 
21481196; PMCID: PMC3704337. 
28. 
Janssen S, Laermans J, Verhulst PJ, Thijs T, Tack J, Depoortere I. Bitter taste receptors 
and alpha-gustducin regulate the secretion of ghrelin with functional effects on food intake and 
gastric emptying. Proceedings of the National Academy of Sciences of the United States of 
America. 2011;108(5):2094-9. Epub 2011/01/20. doi: 10.1073/pnas.1011508108. PubMed 
PMID: 21245306; PMCID: 3033292. 
29. 
Wu SV, Rozengurt N, Yang M, Young SH, Sinnett-Smith J, Rozengurt E. Expression of 
bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 
cells. Proceedings of the National Academy of Sciences of the United States of America. 
2002;99(4):2392-7. Epub 2002/02/21. doi: 10.1073/pnas.042617699. PubMed PMID: 11854532; 
PMCID: PMC122375. 

Version Date: 10 January 2025 
 
 
 
28 
30. 
Choi JH, Lee J, Choi IJ, Kim YW, Ryu KW, Kim J. Genetic Variation in the TAS2R38 
Bitter Taste Receptor and Gastric Cancer Risk in Koreans. Sci Rep. 2016;6:26904. Epub 
2016/06/02. doi: 10.1038/srep26904. PubMed PMID: 27245112; PMCID: PMC4887993. 
31. 
Yamaki M, Saito H, Isono K, Goto T, Shirakawa H, Shoji N, Satoh-Kuriwada S, Sasano 
T, Okada R, Kudoh K, Motoi F, Unno M, Komai M. Genotyping Analysis of Bitter-Taste 
Receptor Genes TAS2R38 and TAS2R46 in Japanese Patients with Gastrointestinal Cancers. 
Journal of nutritional science and vitaminology. 2017;63(2):148-54. Epub 2017/05/30. doi: 
10.3177/jnsv.63.148. PubMed PMID: 28552880. 
32. 
Carrai M, Steinke V, Vodicka P, Pardini B, Rahner N, Holinski-Feder E, Morak M, 
Schackert HK, Görgens H, Stemmler S, Betz B, Kloor M, Engel C, Büttner R, Naccarati A, 
Vodickova L, Novotny J, Stein A, Hemminki K, Propping P, Försti A, Canzian F, Barale R, 
Campa D. Association between TAS2R38 gene polymorphisms and colorectal cancer risk: a 
case-control study in two independent populations of Caucasian origin. PLoS One. 
2011;6(6):e20464. Epub 2011/06/16. doi: 10.1371/journal.pone.0020464. PubMed PMID: 
21674048; PMCID: PMC3107225 Genetisches Zentrum, Munich. This does not alter the authors' 
adherence to all the PLoS ONE policies on sharing data and materials. 
33. 
Barontini J, Antinucci M, Tofanelli S, Cammalleri M, Dal Monte M, Gemignani F, 
Vodicka P, Marangoni R, Vodickova L, Kupcinskas J, Vymetalkova V, Forsti A, Canzian F, 
Stein A, Moreno V, Mastrodonato N, Tavano F, Panza A, Barale R, Landi S, Campa D. 
Association between polymorphisms of TAS2R16 and susceptibility to colorectal cancer. BMC 
gastroenterology. 2017;17(1):104. Epub 2017/09/17. doi: 10.1186/s12876-017-0659-9. PubMed 
PMID: 28915899; PMCID: PMC5603047. 
34. 
Choi JH, Kim J. TAS2R38 Bitterness Receptor Genetic Variation and Risk of 
Gastrointestinal Neoplasm: A Meta-Analysis. Nutrition and cancer. 2019;71(4):585-93. Epub 
2019/01/22. doi: 10.1080/01635581.2018.1559935. PubMed PMID: 30663393. 
35. 
Schembre SM, Cheng I, Wilkens LR, Albright CL, Marchand le L. Variations in bitter-
taste receptor genes, dietary intake, and colorectal adenoma risk. Nutrition and cancer. 
2013;65(7):982-90. Epub 2013/10/03. doi: 10.1080/01635581.2013.807934. PubMed PMID: 
24083639; PMCID: PMC3836614. 
36. 
Choi JH, Lee J, Choi IJ, Kim YW, Ryu KW, Kim J. Variations in TAS1R taste receptor 
gene family modify food intake and gastric cancer risk in a Korean population. Molecular 
nutrition & food research. 2016;60(11):2433-45. Epub 2016/06/21. doi: 
10.1002/mnfr.201600145. PubMed PMID: 27321875. 
37. 
Stern L, Giese N, Hackert T, Strobel O, Schirmacher P, Felix K, Gaida MM. Overcoming 
chemoresistance in pancreatic cancer cells: role of the bitter taste receptor T2R10. Journal of 
Cancer. 2018;9(4):711-25. Epub 2018/03/21. doi: 10.7150/jca.21803. PubMed PMID: 29556329; 
PMCID: PMC5858493. 
38. 
Gaida MM, Mayer C, Dapunt U, Stegmaier S, Schirmacher P, Wabnitz GH, Hänsch GM. 
Expression of the bitter receptor T2R38 in pancreatic cancer: localization in lipid droplets and 
activation by a bacteria-derived quorum-sensing molecule. Oncotarget. 2016;7(11):12623-32. 
Epub 2016/02/11. doi: 10.18632/oncotarget.7206. PubMed PMID: 26862855; PMCID: 
PMC4914309. 
39. 
Singh N, Chakraborty R, Bhullar RP, Chelikani P. Differential expression of bitter taste 
receptors in non-cancerous breast epithelial and breast cancer cells. Biochemical and biophysical 
research communications. 2014;446(2):499-503. Epub 2014/03/13. doi: 
10.1016/j.bbrc.2014.02.140. PubMed PMID: 24613843. 

Version Date: 10 January 2025 
 
 
 
29 
40. 
Choi JH, Lee J, Yang S, Lee EK, Hwangbo Y, Kim J. Genetic variations in TAS2R3 and 
TAS2R4 bitterness receptors modify papillary carcinoma risk and thyroid function in Korean 
females. Sci Rep. 2018;8(1):15004. Epub 2018/10/12. doi: 10.1038/s41598-018-33338-6. 
PubMed PMID: 30301923; PMCID: PMC6177438. 
41. 
Salvestrini V, Ciciarello M, Pensato V, Simonetti G, Laginestra MA, Bruno S, Pazzaglia 
M, De Marchi E, Forte D, Orecchioni S, Martinelli G, Bertolini F, Méndez-Ferrer S, Adinolfi E, 
Di Virgilio F, Cavo M, Curti A. Denatonium as a Bitter Taste Receptor Agonist Modifies 
Transcriptomic Profile and Functions of Acute Myeloid Leukemia Cells. Front Oncol. 
2020;10:1225. Epub 2020/08/15. doi: 10.3389/fonc.2020.01225. PubMed PMID: 32793492; 
PMCID: PMC7393209. 
42. 
Carey RM, McMahon DB, Miller ZA, Kim T, Rajasekaran K, Gopallawa I, Newman JG, 
Basu D, Nead KT, White EA, Lee RJ. T2R bitter taste receptors regulate apoptosis and may be 
associated with survival in head and neck squamous cell carcinoma. Molecular oncology. 2021. 
Epub 2021/10/31. doi: 10.1002/1878-0261.13131. PubMed PMID: 34717036. 
43. 
Carey RM, Kim T, Cohen NA, Lee RJ, Nead KT. Impact of sweet, umami, and bitter 
taste receptor (TAS1R and TAS2R) genomic and expression alterations in solid tumors on 
survival. Sci Rep. 2022;12(1):8937. Epub 2022/05/28. doi: 10.1038/s41598-022-12788-z. 
PubMed PMID: 35624283; PMCID: PMC9142493. 
44. 
Shaik FA, Jaggupilli A, Chelikani P. Highly conserved intracellular H208 residue 
influences agonist selectivity in bitter taste receptor T2R14. Biochim Biophys Acta Biomembr. 
2019;1861(12):183057. Epub 2019/09/08. doi: 10.1016/j.bbamem.2019.183057. PubMed PMID: 
31493373. 
45. 
Medapati MR, Singh N, Bhagirath AY, Duan K, Triggs-Raine B, Batista EL, Jr., 
Chelikani P. Bitter taste receptor T2R14 detects quorum sensing molecules from cariogenic 
Streptococcus mutans and mediates innate immune responses in gingival epithelial cells. Faseb j. 
2021;35(3):e21375. Epub 2021/02/10. doi: 10.1096/fj.202000208R. PubMed PMID: 33559200. 
46. 
Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, Appendino G, 
Behrens M. The molecular receptive ranges of human TAS2R bitter taste receptors. Chem 
Senses. 2010;35(2):157-70. Epub 2009/12/22. doi: bjp092 [pii] 
10.1093/chemse/bjp092. PubMed PMID: 20022913. 
47. 
Miller ZA, Mueller A, Kim T, Jolivert JF, Ma RZ, Muthuswami S, Park A, McMahon 
DB, Nead KT, Carey RM, Lee RJ. Lidocaine induces apoptosis in head and neck squamous cell 
carcinoma through activation of bitter taste receptor T2R14. Cell Rep. 2023:113437. Epub 
2023/11/24. doi: 10.1016/j.celrep.2023.113437. PubMed PMID: 37995679. 
48. 
Sun D, Li YC, Zhang XY. Lidocaine Promoted Ferroptosis by Targeting miR-382-5p 
/SLC7A11 Axis in Ovarian and Breast Cancer. Front Pharmacol. 2021;12:681223. Epub 
2021/06/15. doi: 10.3389/fphar.2021.681223. PubMed PMID: 34122108; PMCID: 
PMC8188239. 
49. 
Sun M, Huang S, Gao Y. Lidocaine inhibits the proliferation and metastasis of epithelial 
ovarian cancer through the Wnt/beta-catenin pathway. Transl Cancer Res. 2021;10(7):3479-90. 
Epub 2022/02/05. doi: 10.21037/tcr-21-1047. PubMed PMID: 35116652; PMCID: 
PMC8799064. 
50. 
Wall TP, Crowley PD, Sherwin A, Foley AG, Buggy DJ. Effects of Lidocaine and Src 
Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery. Cancers (Basel). 
2019;11(10). Epub 2019/09/25. doi: 10.3390/cancers11101414. PubMed PMID: 31546727; 
PMCID: PMC6826872. 

Version Date: 10 January 2025 
 
 
 
30 
51. 
Sun H, Sun Y. Lidocaine inhibits proliferation and metastasis of lung cancer cell via 
regulation of miR-539/EGFR axis. Artif Cells Nanomed Biotechnol. 2019;47(1):2866-74. Epub 
2019/07/14. doi: 10.1080/21691401.2019.1636807. PubMed PMID: 31299862. 
52. 
Mirshahidi S, Shields TG, de Necochea-Campion R, Yuan X, Janjua A, Williams NL, 
Mirshahidi HR, Reeves ME, Duerksen-Hughes P, Zuckerman LM. Bupivacaine and Lidocaine 
Induce Apoptosis in Osteosarcoma Tumor Cells. Clin Orthop Relat Res. 2021;479(1):180-94. 
Epub 2020/10/04. doi: 10.1097/CORR.0000000000001510. PubMed PMID: 33009230; PMCID: 
PMC7899706 immediate family, has funding or commercial associations (consultancies, stock 
ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of 
interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for 
authors and Clinical Orthopaedics and Related Research(R) editors and board members are on 
file with the publication and can be viewed on request. 
53. 
Zhu J, Han S. Lidocaine inhibits cervical cancer cell proliferation and induces cell 
apoptosis by modulating the lncRNA-MEG3/miR-421/BTG1 pathway. Am J Transl Res. 
2019;11(9):5404-16. Epub 2019/10/22. PubMed PMID: 31632519; PMCID: PMC6789266. 
54. 
Zhang J, Mao W, Dai Y, Qian C, Dong Y, Chen Z, Meng L, Jiang Z, Huang T, Hu J, Luo 
P, Korner H, Jiang Y, Ying S. Voltage-gated sodium channel Nav1.5 promotes proliferation, 
migration and invasion of oral squamous cell carcinoma. Acta Biochim Biophys Sin (Shanghai). 
2019;51(6):562-70. Epub 2019/05/30. doi: 10.1093/abbs/gmz044. PubMed PMID: 31139826. 
55. 
Chiliquinga AJ, Acosta B, Ogonaga-Borja I, Villarruel-Melquiades F, de la Garza J, 
Gariglio P, Ocádiz-Delgado R, Ramírez A, Sánchez-Pérez Y, García-Cuellar CM, Bañuelos C, 
Camacho J. Ion Channels as Potential Tools for the Diagnosis, Prognosis, and Treatment of 
HPV-Associated Cancers. Cells. 2023;12(10). Epub 2023/07/06. doi: 10.3390/cells12101376. 
PubMed PMID: 37408210; PMCID: PMC10217072. 
56. 
Xu X, Dai Y, Feng L, Zhang H, Hu Y, Xu L, Zhu X, Jiang Y. Knockdown of Nav1.5 
inhibits cell proliferation, migration and invasion via Wnt/β-catenin signaling pathway in oral 
squamous cell carcinoma. Acta Biochim Biophys Sin (Shanghai). 2020;52(5):527-35. Epub 
2020/05/14. doi: 10.1093/abbs/gmaa021. PubMed PMID: 32400862. 
57. 
Bennett ES, Smith BA, Harper JM. Voltage-gated Na+ channels confer invasive 
properties on human prostate cancer cells. Pflugers Arch. 2004;447(6):908-14. Epub 2003/12/17. 
doi: 10.1007/s00424-003-1205-x. PubMed PMID: 14677067. 
58. 
Roger S, Besson P, Le Guennec JY. Involvement of a novel fast inward sodium current in 
the invasion capacity of a breast cancer cell line. Biochim Biophys Acta. 2003;1616(2):107-11. 
Epub 2003/10/17. doi: 10.1016/j.bbamem.2003.07.001. PubMed PMID: 14561467. 
59. 
Roger S, Potier M, Vandier C, Besson P, Le Guennec JY. Voltage-gated sodium 
channels: new targets in cancer therapy? Current pharmaceutical design. 2006;12(28):3681-95. 
Epub 2006/11/01. doi: 10.2174/138161206778522047. PubMed PMID: 17073667. 
60. 
Fraser SP, Diss JK, Chioni AM, Mycielska ME, Pan H, Yamaci RF, Pani F, Siwy Z, 
Krasowska M, Grzywna Z, Brackenbury WJ, Theodorou D, Koyutürk M, Kaya H, Battaloglu E, 
De Bella MT, Slade MJ, Tolhurst R, Palmieri C, Jiang J, Latchman DS, Coombes RC, Djamgoz 
MB. Voltage-gated sodium channel expression and potentiation of human breast cancer 
metastasis. Clin Cancer Res. 2005;11(15):5381-9. Epub 2005/08/03. doi: 10.1158/1078-
0432.Ccr-05-0327. PubMed PMID: 16061851. 
61. 
Wall TP, Buggy DJ. Perioperative Intravenous Lidocaine and Metastatic Cancer 
Recurrence - A Narrative Review. Front Oncol. 2021;11:688896. Epub 2021/08/20. doi: 
10.3389/fonc.2021.688896. PubMed PMID: 34408981; PMCID: PMC8365881. 

Version Date: 10 January 2025 
 
 
 
31 
62. 
Zhang C, Xie C, Lu Y. Local Anesthetic Lidocaine and Cancer: Insight Into Tumor 
Progression and Recurrence. Front Oncol. 2021;11:669746. Epub 2021/07/13. doi: 
10.3389/fonc.2021.669746. PubMed PMID: 34249706; PMCID: PMC8264592. 
63. 
Royds J, Khan AH, Buggy DJ. An Update on Existing Ongoing Prospective Trials 
Evaluating the Effect of Anesthetic and Analgesic Techniques During Primary Cancer Surgery 
on Cancer Recurrence or Metastasis. Int Anesthesiol Clin. 2016;54(4):e76-83. Epub 2016/09/21. 
doi: 10.1097/aia.0000000000000123. PubMed PMID: 27648893. 
64. 
Sessler DI, Pei L, Huang Y, Fleischmann E, Marhofer P, Kurz A, Mayers DB, Meyer-
Treschan TA, Grady M, Tan EY, Ayad S, Mascha EJ, Buggy DJ. Recurrence of breast cancer 
after regional or general anaesthesia: a randomised controlled trial. Lancet. 
2019;394(10211):1807-15. Epub 2019/10/28. doi: 10.1016/s0140-6736(19)32313-x. PubMed 
PMID: 31645288. 
65. 
Cakmakkaya OS, Kolodzie K, Apfel CC, Pace NL. Anaesthetic techniques for risk of 
malignant tumour recurrence. Cochrane Database Syst Rev. 2014(11):Cd008877. Epub 
2014/11/08. doi: 10.1002/14651858.CD008877.pub2. PubMed PMID: 25379840. 
66. 
Badwe RA, Parmar V, Nair N, Joshi S, Hawaldar R, Pawar S, Kadayaprath G, Borthakur 
BB, Rao Thammineedi S, Pandya S, Balasubramanian S, Chitale PV, Neve R, Harris C, 
Srivastava A, Siddique S, Vanmali VJ, Dewade A, Gaikwad V, Gupta S. Effect of Peritumoral 
Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer. J Clin Oncol. 
2023;41(18):3318-28. Epub 2023/04/07. doi: 10.1200/jco.22.01966. PubMed PMID: 37023374. 
67. 
Tohme S, Simmons RL, Tsung A. Surgery for Cancer: A Trigger for Metastases. Cancer 
Res. 2017;77(7):1548-52. Epub 2017/03/24. doi: 10.1158/0008-5472.Can-16-1536. PubMed 
PMID: 28330928; PMCID: PMC5380551. 
68. 
Fisher B, Gunduz N, Coyle J, Rudock C, Saffer E. Presence of a growth-stimulating 
factor in serum following primary tumor removal in mice. Cancer Res. 1989;49(8):1996-2001. 
Epub 1989/04/15. PubMed PMID: 2702641. 
69. 
Holmgren L, O'Reilly MS, Folkman J. Dormancy of micrometastases: balanced 
proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 
1995;1(2):149-53. Epub 1995/02/01. doi: 10.1038/nm0295-149. PubMed PMID: 7585012. 
70. 
Tyzzer EE. Factors in the Production and Growth of tumor Metastases. J Med Res. 
1913;28(2):309-32.1. Epub 1913/07/01. PubMed PMID: 19972114; PMCID: PMC2099742. 
71. 
Hiller JG, Perry NJ, Poulogiannis G, Riedel B, Sloan EK. Perioperative events influence 
cancer recurrence risk after surgery. Nat Rev Clin Oncol. 2018;15(4):205-18. Epub 2017/12/29. 
doi: 10.1038/nrclinonc.2017.194. PubMed PMID: 29283170. 
72. 
Alieva M, van Rheenen J, Broekman MLD. Potential impact of invasive surgical 
procedures on primary tumor growth and metastasis. Clin Exp Metastasis. 2018;35(4):319-31. 
Epub 2018/05/08. doi: 10.1007/s10585-018-9896-8. PubMed PMID: 29728948; PMCID: 
PMC6063335. 
73. 
Safran T, Zammit D, Kanevsky J, Khanna M. Efficacy of Local Anesthesia in the Face 
and Scalp: A Prospective Trial. Plast Reconstr Surg Glob Open. 2019;7(5):e2243. Epub 
2019/07/25. doi: 10.1097/gox.0000000000002243. PubMed PMID: 31333967; PMCID: 
PMC6571352. 
74. 
von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber 
B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, 
Nekljudova V, Mehta K, Loibl S. Definition and impact of pathologic complete response on 
prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin 

Version Date: 10 January 2025 
 
 
 
32 
Oncol. 2012;30(15):1796-804. Epub 2012/04/18. doi: 10.1200/jco.2011.38.8595. PubMed 
PMID: 22508812. 
75. 
Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, 
Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, 
Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, 
Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Geyer CE, 
Jr., Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Minckwitz G. Pathological complete 
response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 
2014;384(9938):164-72. Epub 2014/02/18. doi: 10.1016/s0140-6736(13)62422-8. PubMed 
PMID: 24529560. 
76. 
Weissferdt A, Pataer A, Vaporciyan AA, Correa AM, Sepesi B, Moran CA, Wistuba, II, 
Roth JA, Shewale JB, Heymach JV, Kalhor N, Cascone T, Hofstetter WL, Lee JJ, Swisher SG. 
Agreement on Major Pathological Response in NSCLC Patients Receiving Neoadjuvant 
Chemotherapy. Clin Lung Cancer. 2020;21(4):341-8. Epub 2020/04/14. doi: 
10.1016/j.cllc.2019.11.003. PubMed PMID: 32279936; PMCID: PMC7305995. 
77. 
Junker K, Thomas M, Schulmann K, Klinke F, Bosse U, Müller KM. Tumour regression 
in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer 
Res Clin Oncol. 1997;123(9):469-77. Epub 1997/01/01. doi: 10.1007/bf01192200. PubMed 
PMID: 9341895. 
78. 
Uppaluri R, Campbell KM, Egloff AM, Zolkind P, Skidmore ZL, Nussenbaum B, 
Paniello RC, Rich JT, Jackson R, Pipkorn P, Michel LS, Ley J, Oppelt P, Dunn GP, Barnell EK, 
Spies NC, Lin T, Li T, Mulder DT, Hanna Y, Cirlan I, Pugh TJ, Mudianto T, Riley R, Zhou L, Jo 
VY, Stachler MD, Hanna GJ, Kass J, Haddad R, Schoenfeld JD, Gjini E, Lako A, Thorstad W, 
Gay HA, Daly M, Rodig SJ, Hagemann IS, Kallogjeri D, Piccirillo JF, Chernock RD, Griffith M, 
Griffith OL, Adkins DR. Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally 
Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II 
Trial. Clin Cancer Res. 2020;26(19):5140-52. Epub 2020/07/16. doi: 10.1158/1078-0432.Ccr-20-
1695. PubMed PMID: 32665297; PMCID: PMC7547532. 
79. 
Shibata H, Saito S, Uppaluri R. Immunotherapy for Head and Neck Cancer: A Paradigm 
Shift From Induction Chemotherapy to Neoadjuvant Immunotherapy. Front Oncol. 
2021;11:727433. Epub 2021/09/24. doi: 10.3389/fonc.2021.727433. PubMed PMID: 34552878; 
PMCID: PMC8451593. 
80. 
Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, Jordan RCK, 
Zhao W, Sturgis EM, Burtness B, Ridge JA, Ringash J, Galvin J, Yao M, Koyfman SA, Blakaj 
DM, Razaq MA, Colevas AD, Beitler JJ, Jones CU, Dunlap NE, Seaward SA, Spencer S, 
Galloway TJ, Phan J, Dignam JJ, Le QT. Radiotherapy plus cetuximab or cisplatin in human 
papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, 
multicentre, non-inferiority trial. Lancet (London, England). 2019;393(10166):40-50. Epub 
2018/11/20. doi: 10.1016/s0140-6736(18)32779-x. PubMed PMID: 30449625; PMCID: 
PMC6541928. 
81. 
Prevention TNCIsDoC. Clinical Trial Randomization Tool  [11 December 2024]. 
Available from: https://ctrandomization.cancer.gov. 
82. 
Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, 
Jacobs JR, Jassem J, Ang KK, Lefèbvre JL. Defining risk levels in locally advanced head and 
neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy 

Version Date: 10 January 2025 
 
 
 
33 
trials of the EORTC (#22931) and RTOG (# 9501). Head & neck. 2005;27(10):843-50. Epub 
2005/09/15. doi: 10.1002/hed.20279. PubMed PMID: 16161069.