Pilot Feasibility Trial of Dose Adjusted Chemoradiotherapy in HPV-Associated Oropharynx Cancer of the Elderly (DACHOC-E)
Phase: NA
Conditions: Oropharynx Cancer, Frailty
Sponsor: Omar Mahmoud

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
PILOT FEASIBILTY TRIAL OF DOSE VOLUME ADJUSTED 
CHEMORADIOTHERAPY IN HPV-ASSOCIATED OROPHARYNGEAL CANCER OF 
THE ELDERLY (DACHOC-E) 
 
 
Principal Investigator/Radiation Oncology  
Omar Mahmoud, MD 
 omar.mahmoud@bmcjax.com 
 
Co-Principal Investigator/Radiation Oncology  
Mark Augspurger, MD 
 Mark.Augspurger@bmcjax.com 
 
 
Head and Neck Surgical Oncology Chair 
Faisal Ahmad, MD 
faisal.ahmad@bmcjax.com 
 
Head and Neck Surgical Oncology  
Erica Mayland, MD 
erica.mayland@bmcjax.com 
 
 
Medical Oncology Chair 
Ian Pinto, MD 
ian.pinto@bmcjax.com 
 
 
 
 
 
 

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
PILOT FEASIBILTY TRIAL OF DOSE VOLUME ADJUSTED 
CHEMORADIOTHERAPY IN HPV-ASSOCIATED OROPHARYNGEAL CANCER OF 
THE ELDERLY (DACHOC-E) 
CONTENTS 
SCHEMA ........................................................................................................................................ 6 
1. 
OBJECTIVES .......................................................................................................................... 7 
1.1 
Primary Objective ............................................................................................................ 7 
1.2 
Secondary Objectives ....................................................................................................... 7 
2. 
BACKGROUND ..................................................................................................................... 7 
2.1 
Oropharynx Cancer: Current State of Practice and Purpose of This Trial ....................... 7 
2.2 
Rationale for Lower Dose Radiation ................................................................................ 8 
2.3 
Rationale for Reduced Size of Radiation Fields .............................................................. 9 
2.4 
Rationale for Hypofractionated Regimen ...................................................................... 10 
2.5 
Rationale for Frailty Index Selection and Stratification................................................. 11 
2.6 
Toxicity and Quality of Life (QOL) ............................................................................... 12 
2.6.1 
Schedule of Toxicity Assessments ................................................................................. 13 
2.6.2 
Clinician-reported Toxicity Assessment Tools ............................................................ 13 
2.6.3 
Swallowing Function ....................................................................................................... 13 
2.6.4 
Acute and Late Toxicity Profiles.................................................................................... 13 
3. 
ELIGIBILITY AND INELIGIBILITY CRITERIA .............................................................. 15 
3.1 
Eligibility Criteria .......................................................................................................... 15 
3.2 
Ineligibility Criteria ........................................................................................................ 16 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP .............. 16 
4.1 
Assessments: Pre-Treatment: ......................................................................................... 16 
4.2 
Assessments: On Treatment ........................................................................................... 17 
4.3 
Assessments: Follow Up ................................................................................................ 18 
5. 
TREATMENT PLAN............................................................................................................ 19 
5.1 
Systemic Therapy: Cisplatin .......................................................................................... 19 
5.1.1 
Intravenous Cisplatin Administration Concurrent with Radiation ............................ 19 
5.1.2 
Cisplatin Concurrent with Radiation Administration Guidelines .............................. 20 
5.2 
Radiation Therapy .......................................................................................................... 22 

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5.2.1 
Treatment Technology ..................................................................................................... 22 
5.2.2 
Immobilization and Simulation ...................................................................................... 22 
5.2.3 
Imaging for Structure Definition, Image Registration/Fusion and Follow-up ......... 22 
5.2.4 
Definition of Target Volumes and Margins .................................................................. 22 
5.2.5 
Definition of Organs at Risk ........................................................................................... 26 
5.2.6 
Planning Target Volumes ................................................................................................ 27 
5.2.7 
Dose Prescription ............................................................................................................. 28 
5.2.8 
Treatment Planning Priorities and Instructions ............................................................ 28 
5.2.9 
Doses to Normal Structures ............................................................................................ 29 
5.2.10 
Dose Compliance Criteria ............................................................................................... 30 
5.2.11 
Delivery Compliance Criteria ......................................................................................... 31 
5.2.12 
Dose Calculations ............................................................................................................. 31 
5.2.13 
Daily Treatment Localization/IGRT .......................................................................... 3132 
5.2.14 
Replanning ........................................................................................................................ 32 
5.2.15 
Radiation Therapy Adverse Events ............................................................................ 3233 
5.3 
Surgery ........................................................................................................................... 33 
5.3.1 
Post-Treatment Imaging/Timing .................................................................................... 33 
5.3.2 
Post-Treatment Surgical Salvage of Residual Disease ................................................ 34 
5.4 
General Concomitant Medication and Supportive Care Guidelines .......................... 3435 
5.4.1 
Permitted Supportive/Ancillary Care and Concomitant Medications ................... 3435 
5.4.2 
Participation in Other Trials ............................................................................................ 35 
5.5 
Duration of Therapy ....................................................................................................... 35 
5.6 
Measurement of Response/Progression ......................................................................... 35 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT ........................................................ 37 
6.1 
Chemotherapy Dose Modifications:............................................................................... 37 
6.1.1 
Cisplatin Dose Modifications during Concurrent Radiation ...................................... 37 
6.1.2 
Cisplatin Dose Modifications for Hematologic Adverse Events during Concurrent 
Radiation ............................................................................................................................................ 37 
6.1.3 
Cisplatin Dose Modifications for Non-Hematologic Adverse Events during 
Concurrent Radiation ....................................................................................................................... 38 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS ..................................................... 40 

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7.1 
Adverse Events (AE) ...................................................................................................... 40 
7.2 
Serious Adverse Events (SAEs) ..................................................................................... 40 
8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES .................. 41 
8.1 
Site Registration Requirements ...................................................................................... 41 
 
Radiotherapy Specific Requirements .......................... Error! Bookmark not defined.41 
8.1.1 
Radiotherapy Plan Evaluation and Storage ............................................................... 4142 
8.2 
Patient enrollment ...................................................................................................... 4142 
9. 
DRUG THERAPY ............................................................................................................ 4142 
9.1 
Investigational Study Agent ....................................................................................... 4142 
9.2 
Commercial Agent: Cisplatin ..................................................................................... 4143 
10. 
DATA COLLECTION .................................................................................................. 4143 
10.1 Data Management/Collection and Storage ................................................................. 4143 
10.2 Data Submission ......................................................................................................... 4243 
11. 
STATISTICAL ANALYSIS ......................................................................................... 4344 
11.1 Study Design .............................................................................................................. 4344 
11.1.1 
Stratification .................................................................................................................. 4344 
11.1.2 
Accrual Number ........................................................................................................... 4344 
11.3Study Endpoints ............................................................................................................. 4344 
11.3.1 
Primary Endpoint ......................................................................................................... 4344 
11.3.2 
Secondary Endpoint ..................................................................................................... 4344 
11.4 Primary Objectives Study Design .............................................................................. 4344 
11.4.1 
Primary Hypothesis and Endpoints ............................................................................ 4344 
11.4.2 
Definitions of Primary Endpoint ................................................................................ 4345 
11.4.3 
Study Monitoring of Primary Objectives .................................................................. 4345 
11.4.4 
Accrual Logistics .......................................................................................................... 4445 
11.4.5 
Secondary Elements Statistical Analysis .................................................................. 4445 
REFERENCES: ........................................................................................................................ 4445 
APPENDICES .......................................................................................................................... 4849 
APPENDIX 1:G8 SCREENING TOOL ............................................................................... 4849 
APPENDIX 2: STAGING SYSTEM .................................................................................... 4950 
APPENDIX 3: RTOG DENTAL EFFECTS HEALTH SCALE .......................................... 5051 

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APPENDIX 4: MANAGEMENT OF DENTAL PROBLEMS IN IRRADIATED PATIENTS
 ............................................................................................................................................... 5152 
APPENDIX 5: DENTAL TOOTH COUNT DIAGRAM..................................................... 5455 
 
 
 
 

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SCHEMA 
Register 
P16 Positive 
Stratify 
Frailty G8 score < 14 vs. >14 
ENROLL 
RT 55Gy in 25 fractions to GTV 
42.5 Gy to 3cm marginal region 
+ weekly Cisplatin 40 mg /m2 in 5 
weeks 
 
 Any T stage (T1, T2, T3, T4) 
 N positive (any N stage with 
positive regional lymph nodes: 
N1, N2, N3) 
>65-<75 vs. >75 
Smoking History: < 10 PY vs. >10 
PY 
 
 
 

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
 
1. OBJECTIVES 
1.1 
Primary Objective  
1.1.1 To determine non-inferiority of hypofractionated short radiotherapy regimen in 
elderly patients in term of 2 years progressive free survival compared with published 
outcomes. 
1.2 
Secondary Objectives  
1.2.1 To establish frailty index as a good discriminator on the patient who cannot tolerate 
aggressive long term chemoradiotherapy with its association to the need of PEG tube, 
hospitalization and treatment breaks compared with published outcomes. 
1.2.2 To compare patterns of failure (locoregional vs. distant) with published outcomes.  
1.2.3 To compare acute toxicity profiles (and overall toxicity burden) with published 
outcomes. 
1.2.4 To compare long term toxicity CTCAE, v. 4 late toxicity at 1, 2 years with published 
outcomes. 
 
2. BACKGROUND  
2.1 
Oropharyngeal Cancer: Current State of Practice and Purpose of This Trial 
The recent rapid rise in the incidence of oropharyngeal human papilloma virus-associated 
carcinoma (HAOPC) and the increased prevalence in elderly patients above 65 years old have 
prompted the evaluation of treatment intensity de-escalation [1].   
While the 3-year survival in low risk patients in RTOG 0129 was 93%, [2] the standard of care 
platinum based chemoradiotherapy with large radiation fields endorsed by NRG [2]and 
GORTEC [3] are associated with very high level of acute and long term toxicities as well as 
fatalities[4, 5]. 
First set of deintensification studies, DeESCALaTE and RTOG 1016, confirmed that Cisplatin 
cannot be substituted with Cetuximab without jeopardizing local control [6, 7]. University of 
Florida and North Carolina phase II studies reported 3-year locoregional control and survival of 
100% and 93% with radiation dose reduction (60Gy to gross disease and 48-54Gy to elective 
neck)[8]. Currently, NRG-HN002 and HN005 are investigating 60Gy in 6 weeks. 
More importantly, the evidence to treat elderly patients (> 65) and those with frailty is lacking. 
Frailty indices were shown to offer an important prognosticator for overall survival and overall 
tolerance to treatment [9]. 

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2.2 
Rationale for Lower Dose Radiation 
As the recent studies demonstrated the superiority of combined chemoradiotherapy, the 
contribution of concurrent chemotherapy may be considered radiobiologically equivalent to 
approximately 8-9 Gy10 of biologic effective dose (BED)[10, 11]. With an effective concurrent 
radiosensitizer, the risks of reducing the radiation dose may be mitigated.  
Phase II studies employing lower radiation dose are ongoing as shown in table 1. Indeed NRG 
HN002 met acceptability criterion of 2-year progression-free-survival exceeding 85% with either 
60Gy in 6 weeks with Cisplatinum as well as 60Gy in 5 weeks without chemotherapy [12].   The 
most recent update confirmed 2-year overall survival of 96.7% for the cisplatin arm meeting both 
end points (PFS and OAS) to be advanced to the phase III arm[13]. 
Even at lower radiation doses (30Gy) investigators at MSKCC demonstrated that 30 Gy may 
result in complete response in selected patients based on response image guided phase II study 
[14]. In this study, PET guidance after 30 Gy allowed de-escalation of the dose from 70 to 30 Gy 
in 15 out of the 18 patients. 
Achieving similar tumor outcome with a reduced dose is expected to be associated with higher 
therapeutic value through reducing grade 2-3 severe acute and late toxicities [4, 5] which in turn 
especially valuable in frail elderly patient population. 
Table 1: Phase II studies employing lower radiation dose. 
Institution 
Name  
Systemic Agent  
Dose to Gross Disease  
Target 
Accrua
l  
Primary Endpoint  
Univ. North 
Carolina, 
Chapel Hill  
Concurrent cisplatin 
30 mg/m2 weekly  
60 Gy  
40  
Pathologic response at 
3 months  
John 
Hopkins 
Univ.  
Concurrent Cisplatin 
40 mg/m2 weekly  
63 Gy to pharyngeal 
constrictors, larynx, parotids, 
mandible, and masticatory 
muscles +8 mm expansion, 
70 Gy to remainder of PTV  
60  
Local-regional control 
≥ 80%, late toxicity at 
2 years  
Long Island 
Jewish 
Hosp.  
Induction TPF x 3, 
then +/- concurrent 
chemotherapy  
Responders: 70 Gy;  
non-responders: 70 Gy (with 
concurrent chemotherapy)  
50  
Response at 3 months  
Dana 
Farber 
Cancer 
Institute  
Induction TPF x 3, 
then concurrent 
chemotherapy  
Responders receive "reduced 
dose"  
50  
Local-regional control 
at 2 and 5 years  
ECOG 
1308  
Induction TP-
cetuximab x 3, then 
Responders: 54 Gy; non-
responders: 70 Gy  
90  
PFS at 2 years in 54 
Gy group  

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concurrent 
chemotherapy  
Memorial 
Sloan 
Kettering  
“Standard 
chemotherapy” 
(concurrent 
regimens)  
70 Gy to primary, 60 Gy to 
nodes followed by neck 
dissection  
100 
HPV+,  
50 
HPV-  
Feasibility of 18F-
MISO PET to detect 
hypoxia, 3-month neck 
control ≥ 80%  
Univ. of 
California, 
Davis  
Induction 
carboplatin-
paclitaxel x 2, then 
concurrent paclitaxel  
Complete response: 54 Gy; 
non-responders: 60 Gy  
50  
PFS at 2 years  
Reduction of radiation dose and volume is expected to reduce the long-term side effects of 
radiation therapy. The ability to reduce the low or intermediate-level doses further may allow 
lesser xerostomia, dysphagia, neuropathy and hypothyroidism through better sparing of salivary 
glands [15], thyroid gland [16], and brachial plexus [17].  
2.3 
Rationale for Reduced Size of Radiation Fields 
Pattern of lymph node metastasis and consequent target volume definition are largely influenced 
by the seminal paper by Dr. Lindberg and Byers et al[18] [19]. However, extensive coverage 
based on risk of lymph node involvement led to excessive head and neck mucosa and organs at 
risk exposure to therapeutic radiation dose with consequent higher toxicity.  
Reduction in target coverage was shown in multiple studies to result in same local control rate 
while reducing toxicity. In Chicago University experience, reducing field to contralateral level II 
and retropharyngeal lymph nodes during three phases of radiation planning (comprising 748 
head and neck cancer patients) showed comparable locoregional control with improvement of 
swallowing scores and reduction of long-term dysphagia [20]. Princess Margret investigators 
updated their experience with the role of ipsilateral radiation in the HPV positive tonsillar cancer 
N0-N2b cases showing contralateral failure rates of 2% [21].  
Similar findings were confirmed in 901 tonsillar cancer patients treated at MDACC where the 
contralateral recurrence was 2% [22]. 
After induction chemotherapy HPV positive oropharyngeal cancer patients were treated to the 
gross disease and the first echelon of lymph nodes with a 2-year PFS of 95% [23]. 
All of these studies confirm that a tighter radiation volume encompassing the primary disease 
with the next echelon of lymph nodes without needing to cover contralateral or low risk 
lymphatics with probability of harboring microscopic disease is less than 5% is justified and, 
more importantly, is expected to be associated with lower toxicity especially in frail elderly 
patient population. 

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2.4 
Rationale for Hypofractionated Regimen 
Hypofractionated radiotherapy was used successfully in laryngeal tumor with limited volume 
disease. The Japanese experience reported superior local control with 56.25 Gy in 25 fractions 
(2.25 Gy/fraction over 39 days compared to 60Gy in 30 fractions (2 Gy/fraction over 46 
days)[24]. The radiobiological rational for this superior outcomes was postulated to be two folds: 
The first is shortening the overall treatment time in a rapidly populating tumor clone as head and 
neck squamous cell carcinoma [25] and the second due to associated increased radiosensitivity 
with higher dose per fraction [26]. 
The importance of overall time was recently validated in the RTOG 0129 study showing that 
72Gy in 6 weeks with 2 cycles of chemotherapy provided the same survival as 70Gy in 7 weeks 
with 3 cycles of chemotherapy postulating that accelerated delivery of radiotherapy counteracted 
the rapid tumor repopulation (addressed by the third cycle of chemotherapy)[27].  
To reduce overall treatment time effect, subsequent standard radiotherapy regimens in head and 
neck studies adopted a mildly hypofractionated dose prescription permitting the therapy to be 
completed in 33 fractions delivering 69.96 Gy, 59.4 Gy and 54.45Gy in 2.12 Gy, 1.8 Gy and 
1.65Gy, respectively. 
In our proposal, 55Gy in 25 fractions to gross tumor disease would be equivalent to 63 Gy in 
2Gy per fraction and 42.5 Gy to subclinical microscopic disease would be equivalent to 41Gy in 
2Gy per fraction adopting 21 day as time to accelerated tumor repopulation and 0.75Gy per day 
as dose of radiation needed to account for prolongation of overall treatment time per day as 
proliferative an alpha beta ratio of 3 and 10 for late reacting tissue and tumor, respectively. Form 
a normal tissue perspective, cell turnover kinetics are not typically included to estimate late 
radiation damage with 55Gy and 42.5Gy would be equivalent to 57.2 and 40 Gy, respectively, 
with standard fraction size [25]. 
A more intense hypofractionation with Cisplatin was shown to be feasible in a recent study 
employing 20 fractions to deliver 55Gy and 46Gy to gross and subclinical disease, respectively 
[28]. Moreover, MSKCC investigators reviewed a more intense hypofractionated regimen with 
fractions size >6Gy showing safety and efficacy of this approach [29]. Especially in elderly frail 
patients, reduction of grade 3 acute toxicity to 36% was observed with 40Gy in 16 factions 
indicating the potential clinical benefit of this approach [30]. 
The study hypothesizes that a dose reduction to sensitive HPV positive malignant clone 
delivered in a slightly hypofractionated regimen with a shorter overall time maybe not only 
feasible but expected to be more convenient with less acute mucosal toxicity and less financial 
toxicity with patient needing to commit to 5 week course instead of the 6 week course currently 
being tested in NRG. Moreover, reducing the radiation course by an extra week may lead to 
significant reduction in overall health expenditure especially for a vulnerable patient population 
highlighting the cost effectiveness of this approach [31].     
 

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2.5 
Rationale for Frailty Index Selection and Stratification  
Frail elderly patient population displays multiple competing mortality hazards ranging from 
cancer related (tumor recurrence and mortality), treatment-related morbidity and mortality 
(mucositis associated infection, immunocompromised infection, aspiration pneumonia, 
malnutrition and dehydration), and increased age intercurrent non-cancer mortality are all well 
known to complicate the interpretation of treatment effects[32]. 
In addition, the magnitude of benefit from treatment intensification is not the same across all age 
strata and such intensification is controversial as survival advantage was not seen in elderly 
individuals[33].  
While Frailty models have been adopted to predict chemotherapy toxicity in the cancer 
management in general [34], the formal adoption in radiation patients in general and in head and 
neck cancer patient in particular has not been formalized or in wide use as expected [35]. 
 Multiple models showed good prediction of frailty in elderly population to identify a patient 
subpopulation that might benefit from selective treatment deintensification [36-38].   
Multiple factors were found to be associated with morbidity and mortality in elderly frail head and 
neck cancer patients undergoing chemoradiotherapy and typically assessed in the comprehensive 
geriatric assessment (CGA) model [39]: 
a. The presence of more than 2 comorbidities [40] on Charlson comorbidity score 
b. Depressed mood with score 9 or more on Geriatric Depression Scale Short form 33(GDS-
SF33)[41]  
c. More than 2 falls in the last 3 months [42] 
d. Lowered cognitive performance on mini mental examination with score 23 or less [42] 
e. Body mass index < 18.5 or loosing > 5% of body weight in the last 6 months [43, 44] 
f. Intake of more than 5 medications [43] 
g. Score 7 or higher in Lawton scale of instrumental activity of daily living (IADL)[41] 
In a prospective cohort of 461 head and neck cancer patients, vulnerable group defined as 
impairment of 2 of more domain in GCA model as defined above- was detected in almost one third 
of the cohort and this group showed lower survival at 12 and 18 months of 76% and 66%, 
respectively versus 89% and 81% observed in the non-vulnerable group [39]. Another study 
confirmed frailty using GCA (present in 43.6% of the patients) was a good predictor of 2 year 
mortality (P=0.27); however incorporating voice handicap index (VHI)>8, MD Anderson 
Dysphagia Inventory (MDADI) <70 were highly significant predictors of mortality and morbidity 
at 2 years [37]. In this study, high risk patients (14% of the patient population) with more than 5 
factors (age >75, >220 PPY smoking, body weight loss, ECOG>2, CCI >1, dental problem, 
VHI>8, MDADI <70 and Beck depression inventory >14) displayed 60% 2-year mortality rate 
compared with 16% in patients with 2 to 4 risk factors. In addition, another study validated a 

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prognostic model based on Karnofsky Performance Status < 70, Charlson Comorbidity Index 
(CCI) > 6 and C-reactive protein (CRP) > 5 and, in this cohort of 284 head and neck cancer patients 
older than 75 year old, the median survival was 9 months versus 130 months (p=0.005) in 
unfavorable versus favorable risk group, respectively [9]. 
While GCA is the gold standard and the most comprehensive, adoption in regular clinic is 
hampered by documentation of 7 domains with some domains involving extensive questionnaire. 
Also, its discrimatory impact on identifying those patients who would benefit from deescalated 
regimen was inferior to newer models [37]. Therefore, alternate more practical assessment tools 
were compared with GCA including vulnerable elders-survey 13 (VES13) and G8 [45]. The G8 
was found to provide superior correlation with GCA in the ONCODAGE study evaluating these 
screening tools in 1435 patients [46]. Although ongoing studies are still employing GCA in 
prospective studies:  ELAN-RT ( NCT01864850 ) testing different definitive radiotherapy 
regimens in older adults aged ≥70 years, G8 practicality was assessed and shown to provide an 
equivalent precision [47, 48]. In anticipating widespread adoption in the clinic is one of the main 
study hypotheses confirming the validity of this screening tool and the 14 cut point used for 
stratification. 
2.6 
Toxicity and Quality of Life (QOL) 
In addition to showing the non-inferiority of radiation dose deescalation in HPHNC elderly 
patients and in addition to establishing the frailty index G8 in identifying those at high risk of 
morbidity and mortality with standard radiation doses, the study aim to show that the reduction 
in radiation dose and fields will substantially reduce the burden of acute toxicity, improve 
swallowing function which will reflect on QOL.  
The protocol-specific Toxicity Assessments are defined as evaluations performed by the clinical 
team and will include clinician-reporting and grading of CTCAE (v. 4) symptoms, findings on 
physical examination, and laboratories.  
The tools and time points selected are designed to capture most of the short- and longer-term 
effects of the treatment. Short term assessments include baseline status, end of treatment at week 
5 or 7 when maximum acute toxicity is expected, as well as tracking of subacute toxicity and/or 
recovery at 3 and 6 months. The late changes usually more obvious between 6 months and 2 
years when certain late effects such as dry mouth, incomplete return of taste, persistent weight 
loss, pain syndromes, soft tissue necrosis and/or, bone necrosis may be predominant. 
 Protocol-specific Toxicity assessments will evaluate and compare events in patients regarding 
the following:  
• Reduction in 10 key acute toxicity rates by > 50%.  
• Reduction in acute high-grade (3-4) dysphagia by > 50%.  
• Reduction in feeding tube usage by > 50%.  

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• Reduction in 4 key late effects by > 50%.  
Assuming the primary endpoint (non-inferior 2-year locoregional control) is met, and both 
toxicity outcome goals are met, then concurrent short course radiotherapy would be considered 
an effective and less toxic alternative to concurrent standard arm, in locally advanced HPV-
associated carcinoma of the oropharynx.  
2.6.1 Schedule of Toxicity Assessments  
Toxicity assessments will occur on a limited schedule over the first 2 years. Routine follow up 
and cancer status evaluations will occur as per the traditional follow-up schedule during and after 
completion of the 2-year. Beyond 2 years, CTCAE late effects will revert to standard collection 
methods. 
Toxicity will be collected at only 6 time-points, all follow-up evaluations performed over the 
first 2 years (baseline, end treatment, 1, 3, 6, 9 12, 15, 18, 21, and 24 months) will include the 
same case report forms (CRFs) instructing sites regarding collection of hard coded CTCAE 
terms.  
2.6.2 Clinician-reported Toxicity Assessment Tools 
Toxicity-related tools will be collected and reported by clinical staff. Collectively, completion of 
these forms requires < 30 minutes for the patient-clinician-research associate interaction.  
• CTCAE events (10-15 minutes);  
• Nutrition/feeding tube  
 • Dental status 
 
 
2.6.3 Swallowing Function  
Swallowing limitation heavily impact QOL [49]. Similarly, the persistent need of feeding tube 
support hinders social functioning with its resultant psychological distress, and cost. Measuring 
swallowing toxicity can be performed using diet assessment, video fluoroscopy, and patient 
questionnaires. In the absence of gold standard for barium swallow interpretation [49], several 
measurement methods for swallowing will be used:  
• Hard-coded CTCAE events (Dysphagia);  
• Feeding tube use;  
• Weight loss;  
 
2.6.4 Acute and Late Toxicity Profiles  

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Cisplatin enhances radiation-related epithelial reactions, causes life-threatening neutropenia, and 
carries high gastrointestinal effects. Chemoradiation has been shown to impact QOL and head 
and neck specific domains for up to 1 year. Functional outcomes from chemoradiation (dry 
mouth, dental effects, swallowing disorders, neurosensory, and mood disorders) can persist for 
the remainder of survivorship, which is expected to be > 70% at 5 years in the HPV-associated 
head and neck population.  
Estimated differences in acute toxicity rates extrapolated from RTOG 1016 and RTOG 0522 
(using identical chemoradiation to the standard arm in this study), specifically for a cohort of 
oropharynx cancers treated with IMRT (N=278 for acute, and N= 270 for late toxicity). The 
median follow-up on this cohort is 1.9 years (range: 0.3- 4.0).  
Based on comparative review of these data, detectable reductions are anticipated in 10 specific 
acute effects item: 
-grade 3+ dysphagia (26% versus 61%),  
- pain (28% versus 71%),  
Estimated Difference in Overall Acute Toxicity Burden (T-score) routine reporting of adverse 
events will be performed using the CTCAE v. 4.0 terminology and grading system. Data will be 
reported, including a summary of lower toxicity (grade 1-2) versus higher toxicity (grade 3-4) 
events.  
Early Deaths due to toxicity or within 30 days of completing radiation were reported in RTOG 
0522; 6 patients (2.2%) died from toxicity or within 30 days of completing treatment (2 patients 
died of treatment-related causes and 4 additional patients died within 30 days of treatment from 
other causes). Similar figures were reported in RTOG 0129 (2.8%). Deaths due to toxicity will 
be reported separately as well as G5 side effects. Death from non-related comorbidities or other 
causes will be reported but not counted as treatment related mortality. 
A simple 5-point global health dental scale was created in RTOG 1016 and will be used in this 
study due to absence of global dental instrument: edentulous, excellent, good, fair, or poor (see 
Appendix 4). In addition to overall assessment of dental health changes over time, a dental 
“count” will be performed at each of the designated outcome assessments (Appendix 5) which 
involve simply counting the number of native teeth at each visit, not including bridges or partial 
or full dentures. A diagram of 32 teeth will be provided to assist in dental count. The percent 
change from baseline in number of teeth over time will be reported. Loss of teeth (up to 10 years 
follow up) should give a quantitative measure of changes in dental health in the HPV associated 
population treated with IMRT.  

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3. ELIGIBILITY AND INELIGIBILITY CRITERIA  
For questions concerning eligibility or radiation therapy-related questions, please contact the 
principal investigator. 
3.1 
Eligibility Criteria  
A patient cannot be considered eligible for this study unless ALL the following conditions are 
met. 
3.1.1 Pathologically proven diagnosis of squamous cell carcinoma (not including the 
neuroendocrine phenotype) of the oropharynx (tonsil, base of tongue, soft palate, or 
oropharyngeal walls); cytologic diagnosis from a cervical lymph node is sufficient in 
the presence of clinical evidence of a primary tumor in the oropharynx. Clinical 
evidence should be documented, may consist of palpation, imaging, or endoscopic 
evaluation, and should be sufficient to estimate the size of the primary (for T stage). 
 
3.1.2 Patients must have clinically or radiographically evident measurable disease at the 
primary site or at nodal stations. Simple tonsillectomy or local excision of the primary 
without removal of nodal disease is not permitted, as is excision removing gross nodal 
disease prior to chemoradiotherapy. 
 
3.1.3 P16-positive based on local site immunohistochemical tissue staining (defined as 
greater than 70% strong diffuse nuclear or nuclear and cytoplasmic staining of tumor 
cells). Fine needle aspiration (FNA) biopsy specimens may be used as the sole 
diagnostic tissue. 
 
3.1.4 Clinical stage Any T as long as N+ and M0 AJCC, 8th ed.) including no distant 
metastases based on the following diagnostic workup:  
• General history and physical examination within 56 days prior to registration.  
• Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable) within 
70 days prior to registration.  
• One of the following imaging studies is required within 56 days prior to registration:  
Chest and neck CT with contrast or FDG-PET/CT of the neck and chest (with or without 
contrast); FDG-PET/CT scan is strongly preferred and highly recommended to be used for 
eligibility. 
 
3.1.5 Patients must provide their personal smoking history prior to registration. The 
following formula is used to calculate the pack-years during the periods of smoking in 
the patient’s life; the cumulative total of the number of pack-years during each period 
of active smoking is the lifetime cumulative history.  
Number of pack-years = [Frequency of smoking (number of cigarettes per day) × 
duration of cigarette smoking (years)] / 20 
 

16 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
3.1.6 Age ≥ 65. 
 
3.1.7 Normal organ and marrow function within 14 days prior to registration defined as 
follows: 
      − Absolute neutrophil count ≥ 1,500/mcL  
− Platelets ≥ 100,000/mcL  
− Hemoglobin ≥ 8.0 g/dL (Note: use of transfusion or other intervention to achieve Hgb 
≥ 8.0 g/dL is acceptable)  
− Total bilirubin ≤ 1.5× institutional upper limit of normal (ULN)  
− AST(SGOT) or ALT(SGPT) ≤ 3.0 × institutional ULN  
− Serum creatinine ≤ 1.5× institutional ULN  
3.1.8  Patients with known Human immunodeficiency virus (HIV)-infection on effective 
anti-retroviral therapy with undetectable viral load within 6 months are eligible for this 
trial. 
 
3.2 
Ineligibility Criteria 
3.2.1 Metastatic disease 
3.2.2 Recurrent disease after primary management 
3.2.3 Cancers with center of mass is outside the oropharyngeal boundaries (i.e. laryngeal, 
hypopharyngeal, nasopharyngeal or oral cavity tumors) 
3.2.4 Synchronous double primaries 
3.2.5 Prior radiotherapy for lymphoma or other malignancy 
3.2.6 Prior systemic therapy including immunotherapy 
3.2.7 Severe active comorbidity where life expectancy is <1 year. 
3.2.8 Autoimmune disease 
3.2.9 Patient with known Uncontrolled HIV 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
4.1 
Assessments: Pre-Treatment: 
Time Point 
Procedure 
Notes 
Prior to registration  
 
• Pathologically 
confirmed 
oropharyngeal HPV 
 

17 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
 
4.2 
Assessments: On Treatment 
positive squamous cell 
carcinoma 
• Smoking history 
70 days prior to registration 
Endoscopic evaluation of 
tumor 
 
56 days prior to registration 
• H&P 
• FDG PET Scan 
• Diagnostic CT or MRI 
neck if clinically 
indicated 
 
14 days prior to registration 
CBC 
CMP( NA, K, Ca, Glu, Cr, 
BUN, AST, ALT, Bil, Alb) 
 
Prior to treatment  
• G8 
• MDADI 
Dental assessment VHI 
 
Time Point 
Procedure 
Notes 
 
Cycles 1 to 5 (weekly) 
-CBC +Diff 
-CMP  (NA, K, Ca, Glu, Cr, 
BUN, AST, ALT, Bil, Alb) 
-Physical Exam 
-Weekly RT assessment 
-Adverse events evaluation 
-Cisplatin 40 mg/m2 given 
over 60 minutes 
 

18 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
 
4.3 
Assessments: Follow Up 
 
Definition of Disease Assessments  
• Response versus “Tumor Clearance” versus Cancer Progression  
 
Response and confirmation of local (primary site) or regional (neck) “tumor clearance” are not 
endpoints in this study. Clinical or radiographic evidence of progressive local-regional disease 
beyond 20 weeks should be documented in the clinical record and ideally confirmed by local or 
regional biopsy, neck dissection, or salvage surgery. CT or MRI (of head and neck region, with 
Week 5  
• H&P 
• Adverse events 
evaluation 
PEG tube existence, 
documentation if in active 
use. 
• Weight 
• MDADI 
• VHI 
• G8 
 
Time Point 
Procedure 
Notes 
At 12-16 weeks from RT end  
 
• FDG PET scan 
 
1, 3, 6, 9 12, 15, 18, 21, and 
24 months 
• H&P 
• Adverse events 
evaluation 
• PEG tube existence, 
documentation if in 
active use. 
• Weight 
• MDADI 
• VHI 
• G8 
• Dental assessment if 
medically necessary  
 

19 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
Chest CT), or PET/CT (including chest anatomy) may be used as radiographic evaluation of 
overall cancer status. The primary, neck and chest portions of the scans should be evaluated and 
reported separately. The CT portion of a PET/CT may serve as sufficient radiographic evaluation 
of the chest. If CT or MRI is used for evaluation of the head and neck region, CT of chest will be 
needed to rule out distant disease or second primaries at the designated evaluation intervals.  
 
• Local or Regional Progression  
 
Local (primary site) or regional (neck) progression is defined as clinical or radiographic evidence 
of progressive disease at the primary site or neck. The location of progressive disease should be 
separately distinguished (local vs. neck) to document the precise pattern of failure if possible. 
Progression of local or regional disease should be confirmed by biopsy when possible but may 
be clinically assessed and documented in the clinical record at the judgment of the treating 
clinicians. Suspicion of disease progression exclusively on the basis of indeterminate or positive 
PET/CT scan should be confirmed with continued clinical follow-up or pathologically.  
 
• Distant Metastasis  
 
Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended where 
possible. A solitary, spiculated lung mass/nodule is considered a second primary neoplasm 
unless proven otherwise. 
 
• Second Primary Neoplasm  
Tumor reappearing with the initial and immediate adjoining anatomical region of the primary 
will be considered local recurrence. Multiple lung nodules/masses are considered distant 
metastases from the index cancer unless proven otherwise. 
5. TREATMENT PLAN 
Protocol treatment must begin within 30 days from signing informed consent.  . 
5.1 
Systemic Therapy: Cisplatin 
5.1.1 Intravenous Cisplatin Administration Concurrent with Radiation  
Cisplatin: 40 mg/m2/week, every week during radiation.  
Dose should be based on actual body weight.  
The first cisplatin infusion should be started within 24 hours before or after the first 
scheduled radiation treatment.  
Cisplatin is administered concurrent with radiation therapy.  
Doses of cisplatin that are not given or which are held for toxicities may be made up.  
Aiming to deliver 5 cycles is the preferred goal. 
 
Cisplatin should be administered on Mondays or Tuesdays to maximize overlap of daily 
radiation with cisplatin exposure.  

20 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
Administration on Wednesday prior to that day’s radiation dose is acceptable but not preferred. 
Cisplatin should be administered before or after radiation.  
Investigators should strive to administer cisplatin on schedule, but if the dose is not being held 
for toxicity reasons, a variance of 1 day is acceptable for vacations, holidays, etc.  
If radiation treatments are held for toxicity, cisplatin dosing should also be held.  
5.1.2 Cisplatin Concurrent with Radiation Administration Guidelines  
• Cisplatin is highly ematogenic and can cause both acute and delayed nausea (occurring > 24 
hours after chemotherapy administration).  
- 
Investigators should be prepared to use aggressive prophylactic antiemetics and 
hydration.  
 
- 
Many institutions will have standard guidelines for the administration of cisplatin at 
the doses used in this study.  
 
- 
For purposes of this protocol, individual investigators may use their local 
guidelines for Cisplatin administration.  
 
- 
The anti-emetic and hydration regimen and schedule is to be determined by the local 
investigator medical oncologist.  
  
• All patients receiving cisplatin chemotherapy should be offered a combination of anti-
emetics. Examples of appropriate anti-emetic choices are provided.  
o Neurokinin 1 (NK1) receptor antagonist  
• Aprepitant 125 mg PO on day of cisplatin and 80 mg PO on days 2 and 3, or  
• Fosaprepitant 150 mg IV on day of cisplatin  
 
o Serotonin (5-HT3) receptor antagonist  
• Granisetron 1 mg IV on day of cisplatin, or  
• Ondansetron up to 16 mg IV on day of cisplatin, or  
• Palonosetron 0.25 mg IV on day of cisplatin  
 
o Steroid  
• Dexamethasone up to 20 mg IV on day of cisplatin 
o Olanzapine  
• 10 mg PO on day of cisplatin  
 
• Dexamethasone (up to 8 mg PO daily) and olanzapine may be continued on days 2 to 4 
of cisplatin administration to prevent delayed nausea.  
• A 5-HT3 receptor antagonist may also be used as needed for delayed nausea.  
• Cisplatin pre-hydration guidelines: Pre-hydration with 1 liter D5 ½ NS and 40 meq 
KCL/ liter x 1 liter prior to cisplatin. Mannitol 12.5 gm IV immediately prior to cisplatin.  
• Cisplatin administration: Cisplatin, 100 mg/m2 over 30-60 minutes IV in 250 cc NS. 
Infusion rate not to exceed 2 mg/min. See Section 6.2 for dose modifications. See above 
discussion on scheduling and number of doses concurrent with radiation.  

21 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
• Cisplatin post-hydration guidelines: Following the end of the cisplatin administration, 
an additional liter of ½ NS with 10 meq KCL/L, 8 meq MgSO4/L, and 25 g mannitol 
should be infused over 2 hours. On the second- and third-day following cisplatin, patient 
should be encouraged to take at least 2 liters of fluid per day orally. Patients unable to 
orally self-hydrate should be considered for additional IV hydration on these days with 
normal saline.  
 
• Low-dose Cisplatin pre-hydration guidelines: 
Pre-hydration with 1 liter D5 ½ NS and 40 meq KCL/ liter x 1 liter prior to cisplatin should 
be given.  
Mannitol 12.5 gm IV immediately prior to cisplatin may be given. Use of mannitol is left to 
the   discretion of the investigator.  
 
•    Low-dose Cisplatin administration:  
Standard administration is cisplatin, 40 mg/m2 over 30-60 minutes IV in 250 cc NS. 
Infusion rate not to exceed 2 mgs per min.   
 
•    Low-dose Cisplatin post-hydration guidelines:  
Following the end of the cisplatin administration, an additional liter of D5½ NS with 10 meq 
KCL/L, 8 meq MgSO4/L, and 25 g mannitol should be infused over 2 hours.  
On the second- and third-day following cisplatin, patient should be encouraged to take at 
least 2 liters of fluid per day orally.  
Patients unable to orally self-hydrate should be considered for additional IV hydration on 
these days with NS.  The amount of pre- and post-hydration is left to the discretion of the 
investigator.  
 

22 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
5.2 
Radiation Therapy 
Intensity Modulated Radiation Therapy (IMRT) and Image-Guided Radiation Therapy (IGRT) 
are mandatory for this study. 
Arm 1: 55 Gy radiation in 5 weeks using 5 fractions per week + Cisplatin every week 
5.2.1 Treatment Technology  
Megavoltage energy photon beam irradiation with energy ≥ 4MV is required (6MV energy is 
preferred).  
Proton therapy is not allowed.  
IMRT techniques including static field IMRT, and VMAT are allowed.  
Matched conventional anterior neck field is not allowed.  
Treatment machine must be equipped to provide daily kV, or MV image guidance.  
The minimum requirements for image guidance are given in Section 5.2.10. 
5.2.2 Immobilization and Simulation  
Patients will be treated supine and must have a secure head and neck immobilization (e.g. 
aquaplast mask) made prior to the treatment planning CT scan.  
The treatment planning CT scan should be performed with IV contrast or fused with IV contrast 
CT images with a slice thickness of 3 mm or less.  
5.2.3 Imaging for Structure Definition, Image Registration/Fusion and Follow-up  
A diagnostic CT or MRI for structure delineation is recommended. These may be fused to the 
planning CT scans to facilitate target and structure definition. 
 
When available FDG PET/CT images may also be fused to the planning CT data set.  
5.2.4 Definition of Target Volumes and Margins  
All specified target volumes and organs-at-risk (OAR) will be contoured on the planning CT 
scan data sets and named according to the nomenclature described below. For the purposes of 
contouring, MRI and PET images, if available and clinically indicated, may be fused with the 
planning CT data set.  
Target volumes and OARs will be labeled according to published guidelines: 
- 
Gross Tumor Volume (GTV)  
The GTV represents clinically or radiographically grossly involved regions of primary tumor or 
involved nodes designated GTVp_5500 and GTVn_5500, respectively.  
These volumes are defined based on physical exam and review of available imaging.  

23 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
FDG-PET may assist in GTV identification, but specific GTV border delineation should not rely 
exclusively on PET signal given the known variable association between gross tumor extent and 
PET signal cutoff and image fusion uncertainty.  
- 
Nodal Definitions  
▪ Clinicians are highly encouraged to request radiologist review if the determination is 
unclear. 
▪ Grossly Positive Nodes (GTVn_5500) are defined as those greater than 1.5 cm in long axis 
and/or > 1 cm in short axis, a cluster of 3 or more borderline size nodes, radiographic 
evidence of extracapsular extension (ECE), or a node of any size with evidence of necrosis.  
▪ Smaller nodes may be determined to be gross disease objects depending on clinical 
suspicion (based on proximity to the primary site or other involved nodes) or demonstration 
of significant uptake of FDG on PET scanning.  
▪ Extracapsular extension (ECE): is defined as radiographic evidence of irregular borders 
and/or perinodal fat stranding, invasion of adjacent structures, or both. Any areas of 
potential involvement should be included within the GTV.  
▪  Matted Nodes: Three or more abutting nodes with loss of the intervening fat planes.  
 
- 
Clinical Target Volume (CTV)  
▪ CTVs are defined and contoured in relation to the targets they are intended to encompass 
and the dose they are intended to receive. For gross targets (GTVs), the CTVs are defined 
by 3D isotropic expansions that should then be limited by potential barriers to tumor spread 
such as air cavities, external contours and bony or fascial planes through which tumor 
spread is not possible or apparent. Similarly, CTVs may be expanded beyond the limits 
defined in this protocol in order to cover areas deemed at risk of tumor extension (e.g. neck 
musculature invaded by nodal disease, or pterygoid regions of infratemporal fossa in 
superiorly extending tonsillar cancers). For nodal regions of potential microscopic 
involvement CTVs are defined according to normal anatomic landmarks. 
 
▪ CTV_5500: Primary Tumor and Involved Nodes  
• 
A CTV_5500 will be defined for primary tumor and involved nodes as a 0.5 
cm isotropic expansion of the GTVs defined for these structures.  
 
▪ CTV: High-Risk conventional can be contoured but not mandatory per protocol. This 
volume will not be prescribed any dose and can be used for future dosimetric 
comparative studies 
- 
High-risk subclinical sites are defined as:  
i) 
Areas of potential subclinical tumor infiltration beyond the primary site 
CTVp_5500  
ii) 
The first echelon node levels to the primary site irrespective of gross nodal 
involvement and all node levels containing gross nodes.  

24 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
 
- 
The value of this intermediate dose level is questionable in HAOPC typically defined 
as:  
i)  1.0 cm isotropic expansion of GTVp_5500 
ii) 1st echelon node levels based on standard anatomic definitions. In most cases 1st 
echelon would be ipsilateral level II, but in cases of midline primary site involvement 
this should include bilateral level II. In cases with soft palate or posterior pharyngeal 
wall involvement this should include the lateral retropharyngeal lymph nodes.  
iii) All node levels containing a CTVn_5500 that has been assigned to involved nodes 
(all grossly involved nodal levels).  
iv) Other high-risk subclinical sites may include nodes < 1cm not thought to harbor 
gross disease yet thought to be at risk of containing more than  
 
 
• CTV_4250: Node Levels at risk of microscopic spread  
- 
CTV_4250 will be defined to treat node levels without evidence of gross disease yet 
at risk of microscopic spread. These levels are defined anatomically according to 
published Intergroup consensus guidelines [50]. The levels to be treated will depend 
on the site and extent of the primary tumor and any grossly involved lymph nodes and 
are indicated in Table 2. It will only include 3cm superior and inferior expansion of 
the CTV5500 and the radial extension will respect fat plan. Committing to entire 
nodal level is not recommended and contralateral delineation of nodal region is not 
indicated in contralateral N0 disease. The probability of neck failure outside of that 
3cm boundary is typically below 5% and typically addressed with the tumoricidal 
effect of chemotherapy while permitting more sparing of organs at risk. 
 
 

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
 
• Contralateral Neck not required for N0 
- 
It is recognized that the evidence as to the efficacy and safety of a unilateral neck 
radiotherapy approach within specific patient groups is largely retrospective, yet 
increasingly compelling evidence has led some centers to consider unilateral 
radiotherapy standard practice. 
- 
Unfortunately, the data for patients with selected N2b or lateralized tongue base 
cancers is less well defined in the literature than that for N0-N2a tonsillar cancer, and 
additionally, substantial disparities in opinions remain related to the effect of 
extracapsular extension [51]. Although unilateral or bilateral radiation is optional to 
the discretion of treating physician, 3 groups of patients with respect to laterality of 
neck irradiation were defined: 
a) Group 1: Unilateral treatment is recommended.  
T1 to T3 tonsil primaries with < 1cm clinical or radiographic extension into tongue base and/or 
palate, no posterior pharyngeal wall extension, N0-N2a (no ECE)  
b) Group 2: Unilateral treatment is optional in standard therapy but required per 
protocol 
T1 to T3 tonsil primaries with < 1cm clinical or radiographic extension into tongue base and/or 
palate, no posterior pharyngeal wall extension, N2b (no ECE) with involved adenopathy 
confined to ipsilateral level 2 of the neck  
 
Table 3: Clinical Target Volume Nomenclature and Description. 
Standard Name  
Description  
Detailed Specification  
GTVp_5500  
GTV to receive 55 
Gy at the primary site 
Required  
Equivalent to GTVp as defined above  
Table 2: Nodal Levels to 
Receive Prophylactic 
Microscopic Dose Not 
required per protocol  
Ipsilateral Neck  
Contralateral Neck**  
N0-1 (in level II – IV)  
 
• Ib (for primary oral cavity 
extension),  
• II-IV  
• RP (lateral retropharyngeal 
LN) for primary extension to 
posterior pharyngeal wall or 
soft palate  
 
 
• II-IV  
• RP (lateral retropharyngeal 
LN) for primary extension to 
posterior pharyngeal wall or 
soft palate  
 
N2a-b  
 
• Ib, II, III, IV, V, RP  
 
 
• II-IV  
• RP (lateral retropharyngeal 
LN) for primary extension to 
posterior pharyngeal wall or 
soft palate  
 

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
GTVn_5500 
GTV to receive 55 
Gy at involved nodes  
Required  
Equivalent to GTVn as defined above  
CTVp_5500 
CTV to receive 55 
Gy at the primary site  
Required  
0.5 cm isotropic expansion of GTVp_55 limited by potential 
anatomic barriers to tumor spread such as air cavities, external 
contours and bony or fascial planes through which tumor spread 
is not possible or apparent  
CTVn_5500   
CTV to receive 55 
Gy at involved nodes  
Required  
0.5 cm isotropic expansion of GTVn_55 limited by potential 
anatomic barriers to tumor spread such as air cavities, external 
contours and bony or fascial planes through which tumor spread 
is not possible or apparent  
CTV_4250 
CTV to receive 42.5 
Gy at low-risk 
volume at the 
primary site and 
applicable node 
levels  
Required  
Arm1: Defined anatomically according to consensus guidelines 
[50].  The levels to be treated will depend in the site and extent of 
the primary tumor and any grossly involved lymph nodes.  
more  
Arm2: Defined as 3cm isotropic expansion around CTV5500 
limited by potential anatomic barriers to tumor spread such as air 
cavities, external contours and bony or fascial planes through 
which tumor spread is not possible or apparent 
 
5.2.5 Definition of Organs at Risk 
Table 4: Organ at Risk Nomenclature  
OAR Standard Name  
Description  
SpinalCord  
Spinal cord  
Required  
SpinalCord_05  
PRV = 5 mm expansion on spinal 
cord  
Required  
BrainStem  
Brain stem  
Required  
BrainStem_03  
PRV= 3 mm expansion on brainstem  
Required  
Lips  
Lips  
Required  
OralCavity  
Oral cavity  
Required  
Parotid_R  
Right parotid gland  
Required  
Parotid_L  
Left parotid gland  
Required  
Mandible  
Mandible  
Required  
Esophagus_Up  
Cervical esophagus  
Required  
Larynx  
Larynx  

27 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
Required  
 
• Spinal Cord: The cord begins at the cranial-cervical junction (ie, the top of the C1 vertebral 
body). Superior to this is brainstem and inferior to this is cord. The inferior border of the 
spinal cord volume will be defined at approximately T3-4 (ie, just below the lowest slice 
level that has PTV on it). The spinal cord shall be defined based on the treatment planning 
CT scan. In addition, however, a Planning Risk Volume (PRV) spinal cord shall be defined 
as: SpinalCord_05 = cord + 5 mm in each dimension.  
• Brain Stem: The inferior most portion of the brainstem is at the cranial-cervical junction 
where it meets the spinal cord. For the purposes of this study, the superior most portion of the 
brainstem is approximately at the level of the top of the posterior clinoid. The brainstem shall 
be defined based on the treatment planning CT scan. In addition, however, a Planning Risk 
Volume (PRV) brainstem shall be defined as: BrainStem_03 = brainstem + 3 mm in each 
dimension.  
• Lips: The definition of lips is self-explanatory.  
• Oral Cavity: The oral cavity will be defined as a composite structure posterior to lips 
consisting of the anterior ½ to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and 
superiorly the palate, and inferiorly to the plane containing the tip of the mandible.  
• Parotid Glands: Parotid glands will be defined in their entirety (superficial and deep lobes) 
based on the treatment planning CT scan.  
• Esophagus: This will be defined as the cervical (upper) esophagus, a tubular structure that 
starts at the bottom of pharynx (cricopharyngeal inlet) and extends to the thoracic inlet.  
• Larynx: This will be defined as the glottic and supraglottic larynx, including the tip of the 
epiglottis, the aryepiglottic folds, arytenoids, false cords, and true cords, bounded by the 
thyroid cartilage laterally, anteriorly including the anterior edge of the pre-epiglottic fat, and 
posteriorly bounded by the anterior edge of the pharyngeal wall or the posterior edge of the 
arytenoid and/or cricoid cartilage. 
• Mandible: This includes the entire bony structure of the mandible from TMJ through the 
symphysis. 
5.2.6 Planning Target Volumes  
All CTVs will have associated PTVs which represent the volumes to which radiation dose will 
be prescribed, delivered, and evaluated.  
The PTVs are isotropic expansions of the CTVs to account for internal motion and residual set-
up error.  
PTVs are defined as a 3 mm expansion of the CTV in all planes  
 
The PTVs may be modified in the following situations:  
1) When a PTV overlaps a critical OAR (spinal cord and/or brainstem) and its associated PRV, 
the PTV should be modified to exclude the PRV so as to limit the dose delivered to the PRV 
within constraints defined in table 5. 
2) The PTVs should be constrained 3 mm within the external contour. The multiple beam entry 
tangential angles characteristic of intensity modulated arc therapy is typically delivering higher 
than calculated surface dose not accounted with planning software algorithms. These software 
dose calculation algorithms model tissue air interface overestimating the skin sparing effects of 

28 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
electronic equilibrium which may give the impression of dose undercoverage and/or not meeting 
planning dosimetric goals. 
 
Table 5: Planning Target Volume Nomenclature and Description  
Standard Name  
Description  
Detailed Description  
PTVp_5500 
PTV to receive 55Gy at the 
primary site Required  
3-5mm expansion of 
CTVp_5500 
PTVn_5500 
PTV to receive 55 Gy at 
involved nodes Required  
3-5mm expansion of 
CTVn_5500  
PTV_5500 
PTV to receive 55 Gy 
Required  
Sum of PTVp_5500 and 
PTVn_5500 
PTV_4250 
PTV to receive 42.5 Gy at 
the primary site and 
applicable node levels 
Required  
3-5mm expansion of 
CTV_4250  
 
5.2.7 Dose Prescription 
The prescribed radiotherapy dose to gross disease for all patients will be 55Gy over 25 fractions 
delivered once daily, 5 fractions per week Monday to Friday for 25 consecutive treatment days 
(5 weeks), with weekly concurrent cisplatin at 40 mg/m2. 
 
The primary tumor and involved nodes will receive 55 Gy (2.2 Gy per fraction for 25 fractions), 
and low-risk subclinical sites will receive 42.5 Gy (1.7Gy per fraction for 25 fractions).  
Doses prescribed are indicated in Table 6 below. All PTVs are to be treated concurrently within 
a single IMRT plan of 25 fractions. 
 
Table 6: Doses Prescribed to PTVs 
 
5.2.8 Treatment Planning Priorities and Instructions 
IMRT Dose Prescription to PTVs  
Target 
Standard 
Name  
Dose (Gy)  
Fraction  
Size (Gy)  
# of 
fractions  
Dose 
specificatio
n technique  
PTV_5500 
55 
2.2  
25 
Covering ≥ 
95% of 
PTV_5500  
PTV_4250  
42.5 
1.7 
25 
Covering ≥ 
95% of 
PTV_4250  

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
Doses are prescribed to PTVs as outlined in Table 6. The treatment goal is that 95% of the 
volume of all PTVs must receive the prescribed dose with a minimum dose (defined as dose to 
99% of PTVs) greater than 93% of the prescription dose and a maximum dose (defined as dose 
encompassing 0.03 cc of the PTV) less than 110-115% of the highest prescription dose.  
 
It is recognized that portions of PTVs close to the skin or critical PRVs (spinal cord and 
brainstem) may receive significantly less than the prescription doses. This is acceptable in these 
regions if cold spots within these PTVs do not exist within the GTV.  
 
It is also recognized that PTVs abutting or enclosing higher dose PTVs will have regions of 
maximum dose that may exceed their prescribed dose to achieve acceptable minimal doses to the 
higher dose PTVs which are considered a higher priority target.  
 
 
Prioritization for IMRT Planning  
1. Spinal Cord  
2. Brainstem  
3. PTV_5500 
4. PTV_4250 
5. Parotid gland contralateral to primary tumor site  
6. Larynx  
7. Oral Cavity  
8. Esophagus 
9. Parotid gland ipsilateral to primary tumor site  
10. Mandible  
5.2.9 Doses to Normal Structures 
Dose limitations to normal structures are described below. For the critical structures of spinal 
cord and brainstem these are mandatory. For other structures recommended limits are provided, 
but the doses delivered should always be as low as reasonably achievable without compromising 
doses to PTVs.  
• Spinal Cord: The PRV for spinal cord (SpinalCord_05) should not exceed 48 Gy to any 
volume more than 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the 
spinal cord PRV should be given the highest priority.  
• Brainstem: The PRV for brainstem (BrainStem_03) should not exceed 50 Gy to any volume 
more than 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the 
BrainStem_03 should be given less priority than the SpinalCord_05, but more than the critical 
structures listed below.  
• Oral Cavity: Reduce the dose as much as possible. The mean dose should be < 32 Gy for the 
oral cavity. Efforts should also be made to avoid hot spots (> 60 Gy) within the non-involved 
oral cavity.  
• Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The 
treatment planning goal will be for this individual parotid gland to receive a mean dose of < 26 
Gy, but efforts should be made to reduce this further if possible without compromising dose to 
PTVs.  

30 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
• Esophagus: Reduce the dose as much as possible; recommended (but not mandatory) treatment 
goal: mean dose < 30 Gy.  
• Larynx: Reduce the dose as much as possible. The larynx mean dose is recommended to be ≤ 
35 Gy if whole-neck IMRT is used.  
• Mandible: Reduce the dose as much as possible. Hot spots within the mandible should be 
avoided. It is recommended that maximum dose within the mandible be < 63 Gy.  
 
5.2.10 Dose Compliance Criteria 
The compliance criteria listed in Table7 will be used to evaluate each case.  
The Per Protocol and Variation Acceptable categories are both considered to be acceptable.  
The Per Protocol cases can be viewed as ideal plans, and the Variation Acceptable category can 
include more challenging plans that do not fall at or near the ideal results.  
A final category, called Deviation Unacceptable, results when cases do not meet the 
requirements for either Per Protocol or Variation Acceptable.  
Plans falling in this category are suboptimal and additional treatment planning optimization is 
recommended to avoid protocol deviation. 
Table 7: Planning Target Volume and Critical OAR Constraints and Compliance Criteria 
Name of Structure  
Dosimetric 
parameter*  
Per Protocol  
Dose (Gy)  
Variation 
Acceptable  
PTV_5500  
D95%*(Gy)  
D99%(Gy)  
Dmax**(Gy)  
55  
> 55 and ≤ 58  
≥ 51  
≥ 50 
≤ 60 
≤ 63  
CTV_5500  
V55 Gy (%)  
≥ 99 %  
95 to 99 %  
PTV_4250  
D95%*(Gy)  
D99%(Gy)  
Dmax**(Gy)  
≥ 42.5  
≥ 39.5 
≤ 52  
≥ 40  
≥ 38  
≤ 56  
CTV_4250 
V42.5 Gy (%)  
99 %  
95 to 99 %  
SpinalCord_05  
Dmax**(Gy)  
≤48  
≤50  
Spinal Cord  
Dmax**(Gy)  
≤45  
≤48  
BrainStem_03  
Dmax**(Gy)  
≤ 50  
≤52  
Recommended dose acceptance criteria for other normal tissue,  
but not to be used for plan score 
Parotid  
Mean dose to one parotid ≤ 26 Gy  
Larynx  
Mean dose ≤ 35 Gy  
OralCavity (excluding PTV’s)  
Mean dose ≤ 32 Gy  
Esophagus_Up  
Mean dose ≤ 30 Gy  
Mandible  
D0.03cc < 63 Gy  
 

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
A Deviation Unacceptable will be scored when the Variation Acceptable limits are not met.  
*D95%(Gy) = dose to 95% of volume  
**Dmax = maximum dose to 0.03 cc of the volume 
5.2.11 Delivery Compliance Criteria 
Protocol treatment must begin within 30 days of signing informed consent. Treatment breaks 
must be clearly indicated in the treatment record along with the reason(s) for the treatment 
break(s). Treatment breaks, if necessary, should not exceed 3 treatment days at a time and 5 
treatment days total. 
 
Treatment breaks should be allowed only for resolution of severe acute toxicity and/or for 
intercurrent illness and not for social or logistical reasons. Any treatment break(s) exceeding 2 
treatment days for reasons other than toxicity/illness will be considered a protocol deviation.  
 
Given the importance of timeliness of treatment delivery in this study, it is strongly 
recommended that patients receive twice-daily treatments with a minimum 6-hour inter-fraction 
interval to compensate for missed days including holidays and those for toxicity or illness once 
sufficiently recovered with the goal of keeping the overall treatment time within the limits 
defined in Table 8. 
 
Table 8: Delivery Compliance Criteria 
 
Per Protocol 
Variation Acceptable  Deviation Unacceptable  
Overall Treatment 
time  
<37 days  
38-42 days  
>42 days without a medically 
appropriate indication for delay  
Interruptions (without 
medical indication)  
0-2 days  
2-4 days  
>4 days  
5.2.12 Dose Calculations 
The primary data set for dose calculation is CT. In the case in which contrast is present during 
the treatment planning CT, the density of the contrast should be overridden to a representative 
background electron density. The dose grid size should be ≤ 3 mm in all directions, which means 
that the CT slice thickness should be ≤ 3 mm.  
 
 
5.2.13 Daily Treatment Localization/IGRT 
Daily image guidance (IGRT) of IMRT is required to meet PTV margins of 0.3 cm, and IGRT 
credentialing is also required. (Section 8.3).  
IGRT may be achieved using any one of more of the following techniques:  

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
• Orthogonal kilovoltage (KV) images, e.g. ExacTrac;  
• Linear accelerator mounted kV and MV cone beam CT images;  
 
 
The institution’s procedure to register the treatment day imaging dataset with the reference 
dataset should comply with the following recommendations:  
• Region-of-interest (ROI) or “clip box” for fusion should be set to encompass the high dose 
PTV and adjacent spinal cord;  
• If the fusion software allows the user to create an irregular ROI (e.g. ExacTrac), treatment 
room objects seen on in-room X-rays should be excluded from the registration;  
• Both manual (e.g. based on bony anatomy) and automatic (e.g. based on mutual information) 
types of registration can be used; the result of the fusion must be visually checked for the 
alignment of the bony anatomy, such as vertebral bodies and applicable surgical clips and soft 
tissue structures (e.g. optic nerves and/or optic chiasm);  
• Following the registration, the translational and (if the appropriate technology is available) 
rotational corrections should be applied to the treatment couch. If all the variances are less than 
2.5 mm (this typically corresponds to one half of the usual PRV margin), the treatment can 
proceed without correction (however, the physician/team may elect to perform adjustments even 
for a variance < 2.5 mm).  
If one or more corrections are 2.5-5 mm, adjustment is necessary prior to treatment; however, 
reimaging is not mandatory.  
 
If one or more of the corrections are larger than 5 mm, the imaging must be repeated in addition 
to performing table/positioning adjustments.  
 
5.2.14 Replanning 
In cases of weight loss > 10% or substantial shrinkage of lymphadenopathy during therapy, it is 
recommended that the immobilization mask be adjusted or re-made to preserve adequate 
immobilization, and that a repeated simulation CT be performed to assess the dose distributions 
in the current anatomy.  
Whether or not a new IMRT plan will be generated is at the discretion of the treating physician. 
If a new plan is made, the targets should be the same as those used for the initial plan and not 
adjusted in cases of disease regression, except to respect clear anatomic barriers such as skin or 
fascial or muscle planes initially uninvolved by disease.  
The new CT dataset should be used for IGRT image registration when the patient’s shape 
changes significantly. 
5.2.15 Radiation Therapy Adverse Events 
Grade 3-4 (CTCAE, v. 4) therapy-induced mucositis and/or dysphagia, which are enhanced by 
cisplatin, are expected to develop in about two thirds of patients.  
 

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Nutritional evaluation prior to the initiation of therapy to decide on the use of a prophylactic 
gastrostomy (PEG) tube placement is recommended, but in the absence of significant 
pretreatment dysphagia and associated weight loss of < 10% body weight the insertion of a 
prophylactic PEG is not recommended.  
If done the placement of a feeding tube should be recorded, as should proportion of use of a 
feeding tube during and after treatment (e.g. greater than or less than 50% of nutrition by tube).  
 
Other common radiation adverse events include fatigue, weight loss, regional alopecia, 
xerostomia, hoarseness, transient ear discomfort, dysgeusia, and skin erythema and 
desquamation within the treatment fields.  
 
Less common long-term treatment adverse events include hypothyroidism, loss of hearing, 
chronic swallowing dysfunction requiring permanent feeding tube, and cervical fibrosis. Much 
less common radiation adverse events include mandibular osteoradionecrosis (< 5% incidence 
with attention to the dental recommendations provided in Appendix V), and cervical myelopathy 
(< 1% with restriction of spinal cord dose to ≤ 45 Gy). 
5.3 
Surgery 
Surgery is expected to play only a limited role in the favorable risk HPV-associated cancers 
included in this study. Locoregional progression is expected in <10% of patients. The role of 
neck dissection has been declining in recent years, in part due to a high rate of negative 
specimens when planned neck dissections are performed in cancers of the oropharynx. 
5.3.1 Post-Treatment Imaging/Timing 
While centers are allowed to follow their institutional policies in conducting earlier post-
treatment imaging evaluations, the major initial post-radiation imaging evaluation for the 
purposes of this study is required at 12-14 weeks after the completion of radiotherapy with 
diagnostic quality, contrast-enhanced CT or MRI of the neck.  
 
PET/CT may be conducted in this timeframe as well, based on the preference of treating 
clinicians, but does not substitute for the mandatory anatomic imaging. The required diagnostic 
CT may be performed as part of the integrated PET/CT but only if the CT is considered 
diagnostic quality and is contrast enhanced.  
 
PET/CT may facilitate pre-and post-treatment evaluation of metabolic response and the need for 
post-treatment neck dissection.  
 
If physical examination and imaging suggest residual disease at the primary site, a biopsy will be 
performed to confirm residual disease; otherwise, patients will undergo serial follow up.  
 
Annual chest imaging is required to a maximum of 3 annual imaging sets and thereafter should 
be performed based on clinical judgment.  
 

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5.3.2 Post-Treatment Surgical Salvage of Residual Disease 
Treatment of residual disease at the primary site will be determined by the treating clinicians and 
the clinical situation, and surgical resection, re-irradiation, chemotherapy, or palliative care will 
be done.  
If the primary site is cleared of residual disease yet residual disease at the cervical nodal basin is 
strongly suggested by imaging/clinical evaluation, then selective neck dissection will be 
performed unless a cytologic sampling (biopsy) of the node is negative.  
Post-treatment “planned” neck dissection will be defined as being performed for residual disease 
and within 20 weeks (140 days) of completion of radiotherapy.  
Positive neck specimens removed within 140 days will be considered part of the initial treatment 
plan and not considered as failures of initial management; positive specimens upon neck 
dissection beyond 140 days will be considered regional failures.  
Note that this is relaxed from the traditional definition of 105 days (15 weeks) to permit 
resolution of HPV-associated adenopathy, which is commonly cystic and may have a somewhat 
slower regression rate.  
Such post-treatment consolidation neck dissections will encompass only the areas (typically only 
levels 2 and 3) initially involved in the side of the neck in question.  
The extent of neck dissections performed for nodal recurrence, nodal progression, or salvage of 
disease at the primary ultimately will be determined by the treating surgeon.  
In the case of negative PET/CT in patients who did not achieve clinical or CT/MRI-based 
radiological nodal CR, a minimum of careful clinical examination is required at 3 months, and 
further imaging is highly recommended, such as follow-up imaging every 3-4 months for at least 
24 months, as well as careful recording of the clinical dimensions of the residual abnormality. 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
5.4.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
each site’s source documents as concomitant medication.  
These may include analgesics, antiemetics, topical mouth rinses, skin creams/ointments, etc. In 
general, HIV-positive patients who are on a stable Highly Active Anti-Retroviral Therapy 
(HAART) regimen should continue HAART while receiving chemotherapy.  
However, for patients who are newly diagnosed with HIV but with laboratory parameters 
meeting the eligibility criteria, it is preferable to defer initiation of HAART until after 

35 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
chemotherapy is completed. HAART regimens containing zidovudine and stavudine should be 
avoided during chemotherapy due to concerns for overlapping toxicity with chemotherapy. In 
addition, the protease inhibitor atazanavir (Rayataz) can cause a physiologically unimportant 
hyper-hyperbilirubinemia; however, in the setting of chemotherapy, some experts suggest 
switching that drug for another equally effective one.  
If HAART is withheld during chemotherapy, it should be resumed promptly after conclusion of 
the last cycle of chemotherapy. 
5.4.2 Participation in Other Trials 
Patients may not participate in other clinical trials that are intended to treat the diagnosed 
oropharyngeal cancer or intended to reduce toxicity of therapy. 
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as specified 
in the above treatment modality sections or until one of the following criteria applies:  
• Disease progression,  
• Intercurrent illness that prevents further administration of treatment,  
• Unacceptable adverse event(s),  
• Patient decides to withdraw from the study, or  
• General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator.  
 
5.6 
Measurement of Response/Progression 
• Response versus “Tumor Clearance” versus Cancer Progression  
Response and confirmation of local (primary site) or regional (neck) “tumor clearance” are not 
endpoints in this study.  
Clinical or radiographic evidence of progressive local-regional disease beyond 20 weeks should 
be documented in the clinical record and ideally confirmed by local or regional biopsy, neck 
dissection, or salvage surgery.  
CT or MRI (of head and neck region, with Chest CT), or PET/CT (including chest anatomy) may 
be used as radiographic evaluation of overall cancer status. The primary, neck and chest portions 
of the scans should be evaluated and reported separately.  
The CT portion of a PET/CT may serve as sufficient radiographic evaluation of the chest. If CT 
or MRI is used for evaluation of the head and neck region, CT of chest will be needed to rule out 
distant disease or second primaries at the designated evaluation intervals.  
 
 
• Local or Regional Progression  
Local (primary site) or regional (neck) progression is defined as clinical or radiographic evidence 
of progressive disease at the primary site or neck. The location of progressive disease should be 
separately distinguished (local vs. neck) to document the precise pattern of failure if possible. 

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
Progression of local or regional disease should be confirmed by biopsy when possible but may 
be clinically assessed and documented in the clinical record at the judgment of the treating 
clinicians. Suspicion of disease progression exclusively on the basis of indeterminate or positive 
PET/CT scan must be pathologically confirmed.  
 
• Distant Metastasis  
Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended where 
possible. A solitary, spiculated lung mass/nodule is considered a second primary neoplasm 
unless proven otherwise.  
• Second Primary Neoplasm  
Tumor reappearing with the initial and immediate adjoining anatomical region of the primary 
will be considered local recurrence. Multiple lung nodules/masses are considered distant 
metastases from the index cancer unless proven otherwise. 
 
 

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6. TREATMENT MODIFICATIONS/MANAGEMENT 
6.1 
Chemotherapy Dose Modifications:  
If adverse events prevent the administration of chemotherapy, the patient may continue to 
receive radiation therapy. 
 
6.1.1 Cisplatin Dose Modifications during Concurrent Radiation 
 
Note: Substitution of carboplatin for cisplatin during adverse events is NOT allowed.  
 
Patients will be examined and graded for subjective/objective evidence of developing toxicity 
weekly according to CTCAE, v. 4 while receiving concurrent cisplatin with radiotherapy.  
Treatment interruptions are allowed if there is symptomatic mucositis or skin reaction that, in the 
judgment of the clinician, warrants a break. For chemotherapy-attributable AEs requiring a break 
in treatment, resumption of concurrent cisplatin may begin when AEs have recovered to the 
levels specified below. Chemotherapy should be discontinued in the event of more than 2 events 
requiring dose reduction (e.g. if grade 3 or greater non-hematologic or hematologic event occurs 
at the reduced dose of cisplatin, at 23 mg/m2/week.  
 
If an AE does not resolve to the levels specified in the sections below prior to the calendar week 
of the last radiation treatment (See Section 5.1 for details concerning parameters for timing of 
last allowable concurrent cisplatin dose), then chemotherapy should be discontinued.  
 
There will be no dose re-escalation for concurrent cisplatin.  
 
Chemotherapy dosage modifications are based upon lab values obtained within the 24 hours 
prior to cisplatin and interim non-hematologic toxicities during the week prior to a particular 
cisplatin dose.  
 
The dose modifications for cisplatin (below) are intended to be permanent (i.e., if the patient’s 
dose is reduced to dose level -1, it remains at the reduced dose level). 
6.1.2 Cisplatin Dose Modifications for Hematologic Adverse Events during 
Concurrent Radiation 
 
Starting Dose  
Dose Level -1  
Dose Level -2  
40 mg/m2  
30 mg/m2  
23 mg/m2  
 
Chemotherapy must not be administered until the ANC is ≥ 1,000 mm3 and platelets are ≥ 
75,000 mm3. If not, delay 7 days. Cisplatin should be held every week until the above ANC and 

38 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
platelet parameters are met. Dose reductions when cisplatin is resumed after delay for low ANC 
or platelets will be as follows, based upon counts at time cisplatin was held. 
ANC  
Platelets  
Reduction  
< 1000 mm3  
or  
< 75,000  
One dose level  
Note: Hematologic growth factors for neutropenia or anemia are not allowed during 
concurrent cisplatin and radiation treatment.  
Neutropenic Fever: Grade 3 (CTCAE, v 4) neutropenic fever (ANC < 1000/mm3 with a single 
temperature of > 38.3 degrees C [101 degrees F] or a sustained temperature of ≥ 38 degrees C 
[100.4 degrees F] for more than 1 hour) is an expected potential complication of concurrent 
chemotherapy and radiotherapy or chemotherapy alone. If neutropenic fever is noted, the 
chemotherapy dose reduction will be determined by the weekly blood counts. 
6.1.3 Cisplatin Dose Modifications for Non-Hematologic Adverse Events during 
Concurrent Radiation 
 
Renal Adverse Events: Dose will be modified based on the serum creatinine prior to each 
cisplatin dose. If the serum creatinine is ≤ 1.5 mg/dL, creatinine clearance is not necessary for 
treatment with full dose. If the serum creatinine is > 1.5 mg/dL, a creatinine clearance should be 
obtained by urine collection or nomogram calculation (valid only if serum creatinine is not 
changing rapidly).  
 
Cisplatin must not be administered until creatinine is ≤ 1.5 or creatinine clearance ≥ 50. 
Once the creatinine has met the above parameters, cisplatin may be restarted with the below 
modifications based on the creatinine at the time the cisplatin was held: In general, cisplatin 
should be held for weekly intervals (rather than restarting cisplatin later in the same week that a 
dose limiting AE is seen). 
Cisplatin dose modifications for creatinine during concurrent radiation  
Creatinine (mg/dL)  Creatinine clearance, measured or calculated ml/min  Cisplatin dose reduction  
≤ 1.5  
or  
> 50  
No change  
> 1.5  
and  
40-50  
One dose level  
 
< 40  
Hold drug  
 
Neurologic (neuropathy) Adverse Events: 
 
 
 
Ototoxicity: Should patients develop clinical evidence of ototoxicity, further audiometric 
evaluation is required. A neurologic deficit should be distinguished from a conductive loss from 
obstruction of the Eustachian tube leading to a middle ear effusion. Because no AE scale, 
Grade (CTCAE, v. 4)  
Dose Reduction  
0-1  
None  
2  
One dose level  
3-4  
Hold drug  

39 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
including the CTCAE, v. 4, has been validated in terms of correlation with clinically relevant 
hearing loss, there are no protocol mandates requiring dose reduction for audiogram-determined 
sensorineural hearing loss without an analogous clinical high grade ( > grade 2) hearing loss. 
However, for clinical grade 3 or higher hearing loss, cisplatin should be held and for grade 2 
clinical hearing loss, one dose level reduction should be implemented.  
 
All Other Non-Hematologic Adverse Events Attributable to Cisplatin during Concurrent 
Radiation: For all other non-hematologic adverse events in which toxicity is ≥ grade 2 (CTCAE 
v. 4), investigators are advised to evaluate and manage correctable issues promptly to prevent 
worsening of toxicity. For these events in which toxicity is ≥ grade 3, investigators should hold 
cisplatin, with weekly re-evaluation until AE grade falls to 0-1, then restart cisplatin at one lower 
dose level. Note: Grade 3 mucositis is commonly experienced by head and neck cancer patients; 
the investigator generally would not hold the cisplatin dosing in this case, unless there is unusual 
concern for progression to grade 4 mucositis. 
 
 

40 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 for adverse event (AE) reporting. The CTCAE version 4.0 is located on the CTEP 
web site at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
7.1 
Adverse Events (AE)  
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product (attribution of unrelated, unlikely, possible, probable, or definite). 
(International Conference on Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: Adverse  
 
According to Baptist policy, Adverse Events (AEs) must be reported to the IRB, sponsor, and 
regulatory bodies according to the study protocol and regulatory timelines. Serious Adverse 
Events (SAEs) must be reported immediately to the Sponsor, IRB, and regulatory bodies, within 
24 hours if expedited reporting criteria are met. Initial reports should include basic event details, 
followed by more detailed updates as additional information becomes available. 
7.2 
Serious Adverse Events (SAEs)  
Serious adverse events (SAEs) that meet expedited reporting criteria will be reported to the PI 
and IRB via email within 24 hour include the following: 
 Any adverse drug event (experience) occurring at any dose that results in any of the following 
outcomes:  
• Death;  
• A life-threatening adverse drug experience.  
• Inpatient hospitalization or prolongation of existing hospitalization.  
• A persistent or significant disability/incapacity.  
• Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition.  
 
 

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
8. REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES  
8.1 
Site Registration Requirements 
IRB Approval  
IRB approval must be obtained for this protocol and submit IRB approval and supporting 
documentation to the Regulatory Office before they can be approved to enroll patients. 
 
The following documents will be needed: 
-    
- IRB Approved Informed Consent and protocol.  
 
 
8.1.1 Radiotherapy Plan Evaluation and Storage 
 
The radiotherapy plan will be reviewed by radiotherapy principal investigator before patient 
radiotherapy start using direct email communication and deidentified data with final DICOMRT 
plan using unique patient protocol ID stored in BMDA Aria data repository. The same plan can 
still be presented for Peer review committee. 
8.2 
Patient enrollment  
Patient registration can occur only after evaluation for eligibility is complete and documented. 
Patients must have signed and dated all applicable consents and authorization forms. 
9. DRUG THERAPY 
9.1 
Investigational Study Agent  
Not applicable for this study.  
9.2 
Commercial Agent: Cisplatin  
Adverse Events: Sites must refer to the package insert for detailed pharmacologic and safety 
information.  
10. DATA COLLECTION 
10.1 
Data Management/Collection and Storage 
Data collection for this study will be via secured email correspondence with the PI and his 
delegates. 
 
Upon initial site registration approval for the study, all persons with data handling and collection 
roles will be identified as contact persons for this site.  

42 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
 
All the data related electronic communication will be secured in BMDA firewall protected and 
password encrypted server. 
 
10.2 
Data Submission 
Folder 
Item 
Registration 
Subject enrollment form with checklist 1 & 2 
Baseline 
• Consultation note 
• Pathology 
• Labs 
• G8 
RT data 
DICOM RT 
End of RT 
RT specifics 
Supportive care documentation 
Hospitalization 
PEG tube existence, documentation if in 
active use. 
AAdverse events forms (if any) 
Follow up at 3, 6, 9 12, 15, 18, 21, and 24 
months 
Follow up 
PET scan: Disease, new primary 
Supportive care documentation 
Hospitalization 
PEG tube existence, documentation if in 
active use. 
Adverse events forms (if any) protocol or non-
protocol related 
 

43 
 
 
DACHOC-E Protocol V3, Dated 28 January 2025 
 
11. STATISTICAL ANALYSIS 
11.1 
Study Design 
11.1.1 Stratification 
Frailty index using G8 score < 14 versus > 14 will be the main stratifying factor used for this 
study 
11.1.2 Accrual Number 
20 patients 
11.2 
Study Endpoints 
11.2.1 Primary Endpoint  
Two-year progression free survival 
11.2.2 Secondary Endpoint  
• Frailty index G8 score 14 as major determinant of benefit and tolerance to 
treatment through:  
o 2-year overall survival in frail versus non-frail elderly (versus published 
outcomes) 
• Acute and late toxicity in frail versus non-frail elderly (versus published 
outcomes) 
• Acute toxicity (Grade 3 or higher) (versus published outcomes) 
• Late toxicity (Grade 3 or higher) (versus published outcomes) 
• Pattern failure (versus published outcomes) (local in field, local marginal miss, 
local regional failure, distant failure, combination of the above). 
 
11.3 
Primary Objectives Study Design  
11.3.1 Primary Hypothesis and Endpoints  
In HAOPC patients, the favorable risk group will achieve a 2-year progression-free survival 
(PFS) rate of ≥ 85% with standard chemoradiotherapy based on HN002, RTOG 0522 and 
RTOG1016 studies, without unacceptable swallowing toxicity. Although the patient population 
in our study is older, the age is not expected to affect the oncologic outcomes. 
11.3.2 Definition of Primary Endpoint  
Progression free survival is defined as time from day 1 of therapy to local- failure, distant 
metastasis, or deaths due to any causes. PFS rates will be estimated for all treatment arms using 
the Kaplan-Meier method. Multivariate analysis will be performed using the Cox proportional 
hazards model. 
11.3.3 Study Monitoring of Primary Objectives 
Interim Safety Analysis with Early Stopping Rules 

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
At 18 months, the estimated enrollment would be 20 patients. As 10 patients reach 6 months 
follow up period, the interim analysis will be conducted aiming to achieve progression free 
survival of 90% with 90% confidence interval 80- 99.9%.  
The interim analysis is expected to occur at 1.5 years from the start of the study allowing IRB 
approval and 6 months of follow up. If 3 events are encountered among the first 10 patients, the 
study will be suspended. With 2-year progression free survival exceeding 80%, the total number 
of events during the whole study period is 8 events per arm explaining the 3 events cut off in the 
interim analysis. 
11.3.4 Accrual Logistics 
11.3.4.1 
Accrual Rate 
The accrual rate is expected to be 1-2 patients per month 
11.3.4.2 
Accrual Goal 
The total sample size is 20 patients. 
11.3.4.3 
Study Duration 
The accrual is expected to occur in 2 years, allowing for 2 year follow up, the study is expected 
to extend for 4 years. 
11.3.5 Secondary Elements Statistical Analysis 
The Kaplan Meyer curve for 2-year survival and log rank test will compare survival in Frail 
elderly using G8 score 14 cut off.  
Two sample T test will be conducted between mean toxicity scores. 
REFERENCES: 
1. 
Windon, M.J., et al., Increasing prevalence of human papillomavirus-positive 
oropharyngeal cancers among older adults. Cancer, 2018. 124(14): p. 2993-2999. 
2. 
Ang, K.K., et al., Human papillomavirus and survival of patients with oropharyngeal 
cancer. N Engl J Med, 2010. 363(1): p. 24-35. 
3. 
Bourhis, J., et al., Concomitant chemoradiotherapy versus acceleration of radiotherapy 
with or without concomitant chemotherapy in locally advanced head and neck carcinoma 
(GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol, 2012. 13(2): p. 
145-53. 
4. 
Trotti, A., et al., TAME: development of a new method for summarising adverse events of 
cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol, 2007. 8(7): 
p. 613-24. 
5. 
Machtay, M., et al., Factors associated with severe late toxicity after concurrent 
chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin 
Oncol, 2008. 26(21): p. 3582-9. 

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
6. 
Gillison, M.L., et al., Radiotherapy plus cetuximab or cisplatin in human papillomavirus-
positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, 
non-inferiority trial. Lancet, 2019. 393(10166): p. 40-50. 
7. 
Mehanna, H., et al., Radiotherapy plus cisplatin or cetuximab in low-risk human 
papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label 
randomised controlled phase 3 trial. Lancet, 2019. 393(10166): p. 51-60. 
8. 
Chera, B.S., et al., Mature results of a prospective study of deintensified 
chemoradiotherapy for low-risk human papillomavirus-associated oropharyngeal 
squamous cell carcinoma. Cancer, 2018. 124(11): p. 2347-2354. 
9. 
Ruhle, A., et al., Development and validation of a novel prognostic score for elderly 
head-and-neck cancer patients undergoing radiotherapy or chemoradiation. Radiother 
Oncol, 2020. 154: p. 276-282. 
10. 
Lee, I.H. and A. Eisbruch, Mucositis versus tumor control: the therapeutic index of 
adding chemotherapy to irradiation of head and neck cancer. Int J Radiat Oncol Biol 
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Fowler, J.F., Correction to Kasibhatla et al. How much radiation is the chemotherapy 
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Yom SS, T.-S.P., Caudell JJ, Waldron JN, Gillison ML, Truong MT, Jordan R, 
Subramaniam R, Yao M, Chung C, Geiger JL, NRG-HN002: a randomized phase II trial 
for patients with p16-positive, non-smoking-associated, locoregionally advanced 
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13. 
Yom, S.S., et al., Reduced-Dose Radiation Therapy for HPV-Associated Oropharyngeal 
Carcinoma (NRG Oncology HN002). J Clin Oncol, 2021: p. JCO2003128. 
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Riaz, N., et al., A personalized approach using hypoxia resolution to guide curative-
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Gabrys, H.S., et al., Parotid gland mean dose as a xerostomia predictor in low-dose 
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Chyan, A., et al., Dosimetric predictors of hypothyroidism in oropharyngeal cancer 
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Chen, A.M., et al., Dose--volume modeling of brachial plexus-associated neuropathy 
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Byers, R.M., P.F. Wolf, and A.J. Ballantyne, Rationale for elective modified neck 
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Spencer, C.R., et al., Eliminating radiotherapy to the contralateral retropharyngeal and 
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improves quality of life. Cancer, 2014. 120(24): p. 3994-4002. 

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21. 
Huang, S.H., et al., Re-evaluation of Ipsilateral Radiation for T1-T2N0-N2b Tonsil 
Carcinoma at the Princess Margaret Hospital in the Human Papillomavirus Era, 25 
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Chronowski, G.M., et al., Unilateral radiotherapy for the treatment of tonsil cancer. Int J 
Radiat Oncol Biol Phys, 2012. 83(1): p. 204-9. 
23. 
Seiwert, T.Y., et al., OPTIMA: a phase II dose and volume de-escalation trial for human 
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Yamazaki, H., et al., Radiotherapy for early glottic carcinoma (T1N0M0): results of 
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25. 
Bentzen, S.M. and M.C. Joiner, The linear-quadratic approach in clinical practice. Basic 
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26. 
Baumann, M. and V. Gregoire, Modified fractionation. Basic clinical radiobiology, 2009. 
4: p. 135-148. 
27. 
Ang, K.K., et al., Randomized phase III trial of concurrent accelerated radiation plus 
cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 
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Jacinto, A.A., et al., Feasibility of concomitant cisplatin with hypofractionated 
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Cancer, 2018. 18(1): p. 1026. 
29. 
Teckie, S., et al., High-dose hypofractionated radiotherapy is effective and safe for 
tumors in the head-and-neck. Oral Oncol, 2016. 60: p. 74-80. 
30. 
Bonomo, P., et al., Elderly patients affected by head and neck squamous cell carcinoma 
unfit for standard curative treatment: Is de-intensified, hypofractionated radiotherapy a 
feasible strategy? Oral Oncol, 2017. 74: p. 142-147. 
31. 
Gupta, T., S. Ghosh-Laskar, and J.P. Agarwal, Resource-sparing curative-intent 
hypofractionated-accelerated radiotherapy in head and neck cancer: More relevant than 
ever before in the COVID era. Oral Oncol, 2020. 111: p. 105045. 
32. 
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Clin Oncol, 2010. 28(1): p. 15-20. 
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NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol, 2009. 
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Adults With Cancer. J Clin Oncol, 2016. 34(20): p. 2366-71. 
35. 
Maggiore, R., et al., The Older Adult With Locoregionally Advanced Head and Neck 
Squamous Cell Carcinoma: Knowledge Gaps and Future Direction in Assessment and 
Treatment. Int J Radiat Oncol Biol Phys, 2017. 98(4): p. 868-883. 
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Kwon, M., et al., An Introduction to a Head and Neck Cancer-Specific Frailty Index and 
Its Clinical Implications in Elderly Patients: A Prospective Observational Study 
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Ruhle, A., et al., Development and validation of a novel prognostic score for elderly 
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Oncol, 2021. 154: p. 276-282. 

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39. 
Chou, W.C., et al., Clinical Significance of Vulnerability Assessment in Patients with 
Primary Head and Neck Cancer Undergoing Definitive Concurrent Chemoradiation 
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40. 
Boje, C.R., Impact of comorbidity on treatment outcome in head and neck squamous cell 
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2017. 65: p. 76-82. 
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Pottel, L., et al., Serial comprehensive geriatric assessment in elderly head and neck 
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(Engl), 2014. 23(3): p. 401-12. 
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Pottel, L., et al., G-8 indicates overall and quality-adjusted survival in older head and 
neck cancer patients treated with curative radiochemotherapy. BMC Cancer, 2015. 15: p. 
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Loser, A., et al., Head and neck cancer patients under (chemo-)radiotherapy undergoing 
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Bellera, C.A., et al., Screening older cancer patients: first evaluation of the G-8 geriatric 
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Soubeyran, P., et al., Screening for vulnerability in older cancer patients: the 
ONCODAGE Prospective Multicenter Cohort Study. PLoS One, 2014. 9(12): p. e115060. 
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Hamaker, M.E., et al., Frailty screening methods for predicting outcome of a 
comprehensive geriatric assessment in elderly patients with cancer: a systematic review. 
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Neve, M., et al., Impact of geriatric assessment on the management of older adults with 
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Langendijk, J.A., et al., Impact of late treatment-related toxicity on quality of life among 
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Gregoire, V., et al., Delineation of the neck node levels for head and neck tumors: a 2013 
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radiation for squamous cell carcinoma of the tonsil. Head Neck, 2012. 34(5): p. 613-6. 
 

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APPENDICES 
APPENDIX 1: G8 SCREENING TOOL 
 
Items 
Possible answers (score) 
A 
Has food intake declined over the past 
3 months due to loss of appetite, 
digestive problems, chewing or 
swallowing difficulties? 
0 : severe decrease in food intake 
1 : moderate decrease in food intake 
2 : no decrease in food intake 
B 
Weight loss during the last 3 months 
0 : weight loss > 3 kg 
1 : does not know 
2 : weight loss between 1 and 3 kgs 
3 : no weight loss 
C 
Mobility 
0 : bed or chair bound 
1 : able to get out of bed/chair but 
does not go out 
2 : goes out 
D 
Neuropsychological problems 
0 : severe dementia or depression 
1 : mild dementia or depression 
2 : no psychological problems 
E 
Body Mass Index (BMI (weight in kg) / 
(height in m²) 
0 : BMI < 19 
1 : BMI = 19 to BMI < 21 
2 : BMI = 21 to BMI < 23 
3 : BMI = 23 and > 23 
F 
Takes more than 3 medications per 
day 
0 : yes 
1 : no 
G 
In comparison with other people of the 
same age, how does the patient 
consider his/her health status? 
0 : not as good 
0.5 : does not know 
1 : as good 
2 : better 
H 
Age 
0 : >85 
1 : 80-85 
2 : <80 
 
TOTAL SCORE 
0 – 17 
 
 
 
 

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APPENDIX 2: STAGING SYSTEM 
 
 
 

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
APPENDIX 3: RTOG DENTAL EFFECTS HEALTH SCALE   
0 Normal: Edentulous, with no gingival disease; native teeth in place with gingiva in 
excellent condition.  
1    Mild changes/good dental health: mild periodontal inflammation-routine cleaning 
indicated; < 5 restorations indicated; no extractions indicated.  
2 Moderate/fair dental health: moderate periodontal inflammation; deep periodontal 
cleaning indicated; 6 or more restorations indicated; less than full mouth extractions 
indicated.  
 
3 Severe changes in dental health: widespread periodontal disease with extensive 
procedure/surgery indicated; full mouth extractions indicated.  
4 Life-threatening dental condition: extensive abscess, extensive soft issue or bone 
infection, sepsis; urgent intervention indicated. 
 
 

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APPENDIX 4: MANAGEMENT OF DENTAL PROBLEMS IN IRRADIATED 
PATIENTS  
Dental Care for Irradiated Patients: 
 Goals for a dental care program include:  
1. To reduce incidence of bone necrosis.  
2. To reduce incidence of irradiation caries.  
3. To allow proper fitting of dentures following treatment.  
 
Pre-irradiation Care and Procedures  
The patients may be grouped into four groups in accordance with the problems they present prior 
to irradiation.  
 
Group 1 
 Includes edentulous patients. They may require surgical removal of any symptomatic cysts, 
infected retained root tips, or alveolar hyperplasia. These patients require hygiene instruction and 
precautionary instruction about trauma with premature use of a prosthesis.  
 
Group 2 
 Includes those with poor dental hygiene, including those patients whose teeth are beyond repair 
by ordinary dental procedure, those with generalized oral sepsis, those with generalized 
periodontal disease, and those with chronic periapical abscesses or granulomas. Procedures 
performed on this group include removal of all remaining teeth prior to irradiation with primary 
closure and surgical preparation of the alveolar ridges to laterally support a prosthesis. There 
should be antibiotic coverage during the healing stage and adequate time prior to the start of 
radiation therapy. These patients need complete hygiene instruction and precautionary 
instruction about premature use of a prosthesis.  
 
Group 3  
Includes those in whom dental condition is fair, including those patients whose teeth are restored, 
ordinary dental procedures, periodontal pockets are less than 3 mm deep, carious lesions are not 
in proximity to the pulp, and no more than 20 restorable carious lesions are present. X-ray 
examinations show at least 1/2 of the bone still present around root surfaces. These patients 
require removal of any teeth that are non-salvageable in accordance with the above and 
restorations of the remaining teeth as required. The patients are instructed for dental prophylaxis 
and the patients utilize custom-made fluoride carriers.  
 
Group 4  
Includes those in whom dental hygiene is good. This includes patients who do not have severe 
malocclusion in whom few carious lesions are present. Carious lesions are not in close proximity 
to the pulp and are correctable by conventional methods. These patients require periodontal 
evaluation and dental prophylaxis training, restorations as needed, no extractions prior to 
radiation therapy, and fitting for custom carriers. Extraction of Teeth If extraction of teeth is 
necessary prior to radiation therapy, the bone must be contoured so that closure at the extraction 
site is possible. All loose spicules and sharp projections must be removed. The approximation of 
the gingival tissue must be such that the closure is neither too loose nor too tight. At least 10 
days are required for adequate healing prior to initiation of therapy.  

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Causative Factors  
The major causative factors appear to be the reduction of the amount of saliva and secondarily, 
reduced pH in the mouth. This occurs following high dose radiation to the major salivary glands 
using parallel opposed fields. The decay process usually occurs in the first year following 
radiation therapy. It tends to occur more quickly in teeth which have a large amount of root 
cementum exposed to those teeth with large amounts of plaque formation present. Doses of 
radiation more than 20 Gy to salivary tissue place the teeth at risk. 
 
Preventive Program  
The rationale behind the use of fluoride treatments is to make the tooth surfaces less susceptible 
to the decay process. This is accomplished by a combination of increasing fluoride concentration 
on the tooth surface and by the effect of fluoride on the plaque and flora that are present in the 
oral cavity. Adequate results are obtained by:  
1) cleansing the teeth thoroughly, followed by a good home care dental prophylaxis program,  
2) construction of fluoride carriers, custom-made mouth guards, which provide local application 
of fluoride solution to the gingiva and tooth surfaces. Fluoride carriers are made individually 
with the use of casts. Material used for making a mouth guard is "Sta-Guard" plastic used in 
conjunction with vacutrole unit produced by Jelrus Technical Products, Corp., both of which are 
available through local dental supply. This material is molded to the cast impression and allowed 
to harden. A fluoride solution prepared at the M.D. Anderson Hospital is now available from the 
Emerson Laboratories, Inc., Dallas, Texas 75221. It has been used to coat the plastic carrier for 
use in the mouth. The patients are instructed to cleanse their teeth prior to placement of the 
carrier. It is then worn in place for 5 minutes each day. The patients are instructed to rinse their 
mouths thoroughly following the use of the carrier. This will be continued for an indefinite 
period of time. Close follow-up is necessary.  
 
Results  
In the 5-1/2 year program at the M.D. Anderson Hospital beginning in 1966, a study of 304 
patients shows that the incidence of necrosis of the jaw was reduced to approximately 21% 
compared to 37% prior to initiation of the study. Groups 3 and 4 patients randomized with and 
without fluoride treatment showed reduction in radiation carries from 67% to 34% among Group 
3 patients, and from 65% to 22% among Group 4 patients.  
 
Failure to Control Decay  
Management of failure to control radiation decay includes silver fillings with continued use of 
fluoride treatments. If the decay process is sufficiently advanced that a filling will no longer stay 
in place, these teeth are merely smoothed so that there will be no sharp, irritating edges. The 
mere existence of such a decayed tooth is not necessarily reason for extraction, for it must be 
remembered that extraction could lead to complications such as bone necrosis. Pulp exposure 
resulting from the decay process can usually be handled by use of antibiotics and/or root-canal 
therapy.  
 
Hypersensitivity of Teeth  
Occasionally, a patient will exhibit extreme sensitivity of the teeth secondary to diminished 
amounts of saliva. This has been shown to be reduced in incidence with the fluoride treatments. 

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DACHOC-E Protocol V3, Dated 28 January 2025 
 
Should this problem become manifest, increasing the fluoride treatment to 10 to 15 minutes 3 
times a day is recommended.  
 
Infections  
Infections occurring in patients under or after radiation therapy are best managed conservatively 
with good oral hygiene, irrigation and flushing procedures, and systemic antibiotics.  
 
Bone Necrosis  
The patients receiving radiation therapy to a high dose to the head and neck region have 
increased susceptibility to bone necrosis for several reasons including impairment of normal 
metabolism, increased susceptibility to infection and severely limited repair process. Bone 
necrosis occurs most often after dental or oral surgery in patients who have been previously 
radiated. Conservative management should be tried first, though in more aggressive lesions a 
more radical approach may ultimately be necessary. 
 
 

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APPENDIX 5: DENTAL TOOTH COUNT DIAGRAM 
Use the diagram below as a guide to count the number of native teeth in place, not including full 
or partial dentures or bridges.  
 
The exact location of teeth does not need to be recorded, only the total number of native teeth in 
place (attached to bone in mandible or maxilla) on the day of evaluation.  
 
 
This exam should be completed by a physician or designee, such as a physician's assistant, nurse 
or nurse practitioner, or a dentist/hygienist. Date of evaluation: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 6: Registration Check List