Definitive Concurrent Hypofractionated Radiotherapy With Weekly Cisplatin in Locally Advanced Squamous Cell Carcinoma Head and Neck (SCCHN)
Conditions: Squamous Cell Carcinoma of the Head and Neck
Sponsor: Assiut University

COVER PAGE 
Title: 
Definitive concurrent hypo fractionated radiotherapy with weekly cisplatin in locally advanced 
SCCHN in COVID-19 era 
 NCT03880396 
 DATE OF THE DOCUMENT : 20TH JULY,2022 
Authors: 
Nora Abdelhafiz1, Doaa Mahmoud2, Mohamed O.A.Gad 3, Aiat Morsy2 
 
Affiliations: 
1) Department of Radiotherapy and Nuclear Medicine, South Egypt Cancer Institute, 
Assiut University, Assiut, Egypt. 
2) Department of Clinical Oncology, Faculty of medicine, Assiut University, Assiut, Egypt. 
3) Department of Otorhinolaryngology, Head and Neck surgery, Faculty of medicine, 
Assiut University, Assiut, Egypt 
 
Running title: 
Hypo fractionated radiotherapy with weekly cisplatin in locally advanced SCCHN in COVID-
19 era 
Corresponding Author: 
Nora, Abdelhafiz 
Address: Department of Radiotherapy and Nuclear Medicine, South Egypt Cancer Institute, 
Assiut University, Assiut, Egypt 
Email:  nouralah3@aun.edu.eg 

 
 
Definitive concurent hypofractionated radiotherapy with weekly cisplatin  in locally advanced 
SCCHN  
"
Thesis
"
 
Submitted in partial fulfillment of the MD Degree in
 
Clinical Oncology
 
Presented By
 
Doaa Gamal Abdelnaser Fathy Mahmoud
 
M.B.B.ch, M.sc
 
Supervised by
 
Prof. Hoda Hassan Essa
 
Professor of clinical oncology
 
Faculty of medicine
 
Assiut university
 
Associate Prof.Ola Nabeh
 
Associaate Professor of clinical oncology
 
Faculty of medicine
 
Assiut university
 
Dr.Aiat Morsy Mohamed
 
Lecturer of clinical oncology
 
Faculty of medicine
 
Assiut university 
 
Dr. Mohamed Omar Ahmed Gad
 
Lecturer of ENT surgery 
 
Faculty of medicine
 
Assiut university
 

 
 
 
Introduction
 
 
 
Head and neck cancer is considered the 6th most common cancer all over the world, with 
890,000 new cases and 450,000 deaths in 2018 (1). The histologic type in more than 90% of 
head and neck cancer is squamous cell carcinoma (SCC) (2). The incidence of SCC in head and 
neck (SCCHN) continues to rise and is expected to increase by 30% in 2030, which means about 
1.08 million new cases annually (3). Hospital-based studies in Egypt showed that SCCHN 
represents about 20% of all malignancies. The overall incidence of SCCHN in Egypt from 1999 
to 2006 was approximately twice among males (476,000) than in females (273,000) (4). Males 
are affected significantly more than females, with a ratio ranging from 2:1 to 4:1 (5). 
Tobacco and alcohol consumption are the high-risk factors of SCCHN (6). Human papilloma 
virus (HPV), especially subtypes 16 and 18 are implicated risk factors in oropharyngeal cancer 
(7).  Some studies found an association between HPV and P53 gene mutation, as HPV 
expresses two viral proteins (E6 and E7 proteins) that inactivates P53 and pRB genes, causing 
genomic instability and malignant transformation (8). SCCHN arises from the mucosal 
epithelium of the oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx. HPV 
associated SCCHN arises primarily from the palatine and lingual tonsils of the oropharynx, 
whereas tobacco associated SCCHN arises primarily in the oral cavity, hypopharynx, and 
larynx. 
 
Squamous cell carcinoma of head and neck (HNSCC) is being increasingly treated by 
multimodality approaches combining surgery, radiotherapy, and chemotherapy. 
Randomized controlled trials have demonstrated major improvements in loco-regional 
tumor control from altered fractionation radiotherapy with chemotherapy as compared with 
conventional fractionation (9) 

Altered fractionation schedules reduces tumor repopulation effect and seek to improve the 
therapeutic ratio between tumor cell killing and normal tissue damage. 
 hypo-RT utilizes a small number of fractions with a larger dose per fraction (> 2Gy per 
fraction), shortening overall treatment time compared to a CFRT (9). Although a shorter 
treatment time can be obtained by applying a higher dose per fraction, it might also result in 
an increase in the incidence of late complications 
In a meta-analysis of 50 trials including a total of 9615 patients, the addition of synchronous 
chemotherapy to radiotherapy for locally advanced SCCHN resulted in an overall survival 
benefit of 6.5% at five years (10). However, this is associated with late toxicity and 
questionable improvement in the therapeutic ratio 
The objective of this study was to investigate hypofractionated IMRT CRT with 62.5 Gy in 25 
daily fractions over five weeks (2.5 Gy per fractions biologically equivalent dose to the 
tumor, 70.9Gy 10 and late reacting tissues, 114.6 Gy 3) [20] with synchronous weekly 
cisplatin 40mg/m2 in patients with high-risk stage II (T2N0, excluding glottic laryngeal) 
disease, stage III (T1-3 N1 or T3N0). And stage IV (T1-4N2 orN3)
 
 
 
 
 
Aim of work
 
The primary endpoint will be acute toxicity. Secondary endpoints included: late toxicity and 
quality of life; loco-regional control, disease free survival and overall survival. 
 
 
 
 
 
 
 
 
 

 
Patient and method
 
This will be non-randomized clinical trial study of dose intensiﬁed hypofractionated 3D 
conformal or IMRT with synchronous weekly cisplatin 40 mg/m2 in the period from 2018 to 
2021 in South Egypt Cancer Institute, Assiut, Egypt.   in patients with AJCC high risk stage II 
(T2N0, excluding glottic laryngeal) disease, stage III (T1-3N1 or T3N0)and stage IV (T1-4N2 or 
N3) oropharyngeal, laryngeal  or hypopharyngeal squamous cell carcinoma.  A planned 62 
patients would be recruited and treated with neoadjuvant chemotherapy TPF followed by 
hypo fractionated radiotherapy dose 62.5 Gy in 25 daily fractions  over ﬁve weeks with 
synchronous weekly cisplatin 40mg/m2 
 
Eligibility criteria 
Patients will be enrolled in this prospective study have to fulfill the following criteria: 
Have histologically or cytologically proven oropharyngeal, laryngeal or hypopharyngeal 
squamous cell carcinoma; with AJCC high risk stage II (T2N0, excluding glottic laryngeal) 
disease, stage III (T1-3N1 or T3N0) and stage IV (T1-4N2 or N3) locally advanced non 
metastatic stage II/IV SCCHN according to AJCC stage classification 2018(8th edition 
Age>18 years and <75years 
No previous treatment (neither chemotherapy nor radiotherapy ) 
Eastern Cooperative Oncology Group (ECOG) performance status of <2 
Adequate organ function 
Provide informed oral or written consent 
Exclusion criteria: 
prior surgical curative resection for primary tumor 
 patients with metastatic disease; 
 prior radiotherapy within the treatment field; 
 any relative contraindication to radiotherapy; 
 prior administration of EGFR monoclonal antibodies, signal transduction inhibitors or 
targeted therapies.         
Active severe infection 
Active concomitant malignancy 
Pregnant and or lactating women 

Pre-existing motor or sensory neurotoxicity >Common Terminology Criteria of Adverse 
Events (CTCEA) grade 2 
Percutaneous endoscopic gastrotomy tube will be placed in case of compromised nutritional 
status (significant weight loss due to dysphagia at time of presentation . 
Evaluation and follow up: 
Pretreatment evaluation must include the following : 
Full medical history and physical examination 
Assessment of performance status 
All patients had dental evaluation at baseline 
Complete blood cell count with differential 
Liver function tests, kidney function tests and 24 h urine creatinine clearance 
Baseline pretreatment assessment of tumor will be required within 4weeks before start of 
treatment as measured by computed tomography or magnetic resonance and direct 
endoscopy 
During the treatment period, the patients will undergo weekly physical examination and 
toxicity assessment 
CBC and serum creatinine will be performed weekly, while 24h urine creatinine clearance 
have to be performed every 3 weeks 
Assessment of tumor response by clinical examination and head and neck MRI or CT will be 
performed 6-8 weeks after completion of treatment 
Endoscopy will be done at 8-12 weeks after the end of concurrent chemo radiation for 
pathological conformation of response 
Patients have to be followed up by clinical examination every 2months during the first year, 
every 3 months for the subsequent 2 years and every 6months thereafter 
Tumor response will be assessed according to Response Evaluation Criteria in Solid Tumors 
(RECIST) criteria. Toxicity from treatment will be graded according to (CTCEA) and Radiation 
Therapy Oncology Group (RTOG) criteria. Clinically significant toxicity will be defined as any 
grade 3 or 4 toxicity probably or definitely attributable to therapy 
Radiotherapy and chemotherapy protocol: 
All patients will receive neoadjuvant chemotherapy TPF given in 21 day cycle for 3 cycles   in 
the form of Docetaxel 75mg/m2 IV on day 1 , cisplatin 100 mg/m2 IV on day 1, 5-FU 1000 
mg/m2 by continuous IV infusion over 24 hours on day 1 through day 4  then hypo 
fractionated radiotherapy  

All patients will undergo simulation, and treatment will be delivered through the megavoltage 
beam with linear accelerator with 6M using 3D-CRT or IMRT with head immobilization using 
thermoplastic head and neck mask. contrast enhanced CT images for treatment planning at 
2-5mm intervals from vertex to below the carina. the clinical target volume (CTV) and organs 
at risk (OAR) will be outlined on the axial images. Delineation of target volume will be aided 
with a radiologist in difficult cases. A 5-10mm expansion margin will be applied to the (CTV) 
to obtain the planning target volume (PTV)  
The gross tumor volume (GTV) will be deﬁned as the primary tumor and involved lymph nodes, 
determined by clinical, endoscopic and imaging investigations. Involved lymph nodes will be 
deﬁned as those > 10 mm in short axis diameter or presence of a necrotic center. The clinical 
target volume (CTV) will be the GTV and areas deemed at risk of microscopic disease. Three 
CTVs were delineated: CTV1, the GTV with an isotropic expansion of 10 mm (edited for natural 
barriers to disease spread including bone, air, fascia); CTV2, the remainder of the involved 
sub-site and nodal levels and uninvolved first echelon nodal levels; and CTV3, nodal levels 
deemed at lower risk of microscopic disease spread. Three planning target volumes (PTV1, 
PTV2, PTV3) will be deﬁned by an isotropic expansion of 3 mm from CTV1, CTV2 and CTV3, 
respectively.  Radiation doses to PTV1, PTV2 and PTV3 will be 62.5 Gy, 55 Gy and 50 Gy over 
ﬁve weeks, respectively, prescribed to the mean of the PTV. The planning targets included 
that minimum and maximum dose to the PTV will be within 95– 105% of the prescription dose 
and less than 5% of the volume outside the PTV  
The concurrent chemotherapy will be weekly cisplatin 40mg/m2 with proper premedication 
and good hydration  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Statistics: 
All statistical calculations were done using SPSS (statistical package for the social science; SPSS 
Inc., Chicago, IL, USA) version 22. Data were statistically described in terms of mean ± standard 
deviation (±SD), or median and range when not normally distributed, frequencies (number of 
cases) and relative frequencies (percentages) when appropriate. For comparing categorical 
data Exact test was used instead of Chi square (χ2) as the expected frequency was less than 5. 
OS, PFS and DFS were estimated using the Kaplan-Meier method. P-value is always 2 tailed 
set significant at 0.05 level. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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