A Phase II Study on Treatment De-Intensification in Favorable Squamous Cell Carcinoma of the Oropharynx
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of Oropharynx
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Version:  March 4, 2013 
 
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A Phase II Study on Treatment De-Intensification in  
Favorable Squamous Cell Carcinoma of the Oropharynx 
 
 
PrincipaI Investigators:  
 
Harry Quon, M.D. 
 
 
 
 
 
Radiation Oncology 
 
 
 
 
 
 
Arlene Forastiere, M.D. 
Medical Oncology 
Co-Investigators:                                    
Shanthi Marur, M.D., Medical Oncology 
Christine Chung, M.D., Medical Oncology 
Nishant Agrawal, M.D., Head & Neck Surgery 
Ralph P. Tufano, M.D., Head & Neck Surgery 
Christine Gourin, M.D., Head & Neck Surgery 
Jeremy Richmon, M.D., Head & Neck Surgery 
Wayne Koch, M.D., Head & Neck Surgery 
Nafi Aygun, M.D., Radiology 
William Westra, M.D., Pathology 
Heather Starmer MA CCC-SLP, Speech therapy 
Kim Webster, MA MS CCC-SLP, Speech therapy 
Donna Tippett MPH, MA, CCC-SLP, Speech therapy 
Todd McNutt, Ph.D., Physics 
Amanda Blackford, Sc.M., Statistics 
 
 
Research Nurses: 
Kelly Szajna, R.N., B.S.N 
 
Shirl DiPasquale, R.N.  
Beth Griffith, R.N. 
410-502-9242  
 
 
410-614-1598  
 
410-502-9243 
kszajna1@jhmi.edu 
 
 
sdipasq1@jhmi.edu 
 
bgriffit@jhmi.edu  
 
  
 
 
 
 
Study Coordinators: 
Katharine Oteiza 
 
 
Ryan Assadi 
 
 
Helen Kim 
410-614-3158  
 
 
410-955-8652  
 
410-614-3950 
koteiza1@jhmi.edu 
 
 
rassadi1@jhmi.edu 
 
hkim91@jhmi.edu 
 
Other study staff: 
Sarah Bonerigo, P.A.
NCT01088802   
March 29, 2022

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Table of Contents 
1 
BACKGROUND AND RATIONALE ................................................................................... 6 
1.1 
Disease control of contemporary oropharyngeal cancer .................................................. 6 
1.2 
Favorable subgroup of patients with ORO-SCC .............................................................. 7 
1.3 
On systemic treatment for ORO-SCC .............................................................................. 8 
1.4 
Treatment morbidity ......................................................................................................... 9 
1.5 
Strategies to decrease toxicity ........................................................................................ 11 
1.6 
Standard Supportive treatment ....................................................................................... 16 
2 
OBJECTIVES ........................................................................................................................ 17 
3 
SELECTION CRITERIA ...................................................................................................... 17 
3.1 
Eligibility Criteria .......................................................................................................... 17 
3.2 
Ineligibility Criteria ........................................................................................................ 18 
4 
PRETREATMENT EVALUATIONS .................................................................................. 18 
5 
RADIATION THERAPY ...................................................................................................... 19 
5.1 
Treatment Planning, Imaging and Localization Requirements ...................................... 19 
5.2 
Volume and ICRU Reference Point Definitions ............................................................ 20 
5.3 
Target Definition ............................................................................................................ 21 
5.4 
Organ At Risk (OAR) Definitions ................................................................................. 22 
5.5 
PTV and subPTV generation .......................................................................................... 22 
5.6 
Dose prescription ............................................................................................................ 23 
5.7 
Planning .......................................................................................................................... 23 
5.8 
External Beam Equipment and Beam Delivery Methods .............................................. 25 
 
Treatment Verification and daily imaging ......................................................................... 25 
5.9.............................................................................................................................................. 25 
5.10 
Quality Assurance of Target Volumes and Critical Structure Volumes .................... 25 
 
Radiation Therapy Toxicity Adjustments .......................................................................... 26 
5.11............................................................................................................................................ 26 
 
Toxicity Reporting Guidelines ........................................................................................... 26 
5.12............................................................................................................................................ 26 
6 
DRUG THERAPY ................................................................................................................ 26 
6.1 
Cisplatin ......................................................................................................................... 26 
6.2 
Cisplatin Dose Modification for toxicity ....................................................................... 27 
6.3 
Carboplatin ..................................................................................................................... 27 
6.4 
Carboplatin Dose Modification for Toxicity .................................................................. 28 
7 
SURGERY............................................................................................................................. 28 
8 
PATHOLOGY ....................................................................................................................... 28 
9.1 
Patient Assessments ....................................................................................................... 29 
9.2 
Evaluations ..................................................................................................................... 30 
9.3 
Response Criteria ........................................................................................................... 30 
9.4 
Definition of locoregional control .................................................................................. 31 
9.5 
Scoring of toxicity (see also 5.11) .................................................................................. 31 
9.6 
Criteria for Removal from Treatment ............................................................................ 32 
10 
STATISTICAL CONSIDERATIONS............................................................................... 32 
10.1 
Sample Size ................................................................................................................ 32 
10.2 
Monitoring for Efficacy and Toxicity ........................................................................ 33 
10.3 
Analysis of Endpoints ................................................................................................. 33 

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11 
REFERENCES .................................................................................................................. 35 
Appendix 1 CTCAE v4.0 Toxicity ............................................................................................... 39 
Appendix 2 – Head and Neck MD Anderson Symptom Inventory (MDASI-HN) ...................... 48 
Appendix 3 – Xerostomia Questionnaire ...................................................................................... 50 
Appendix 4 – Penetration/Aspiration Scale .................................................................................. 52 
Appendix 5 – Montreal Cognitive Assessment ............................................................................ 53 
Appendix 6 – MD Anderson Dysphagia Inventory (MDADI) ..................................................... 54 
 
 
 

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SCHEMA 
Treatment Plan:  
The protocol combines selective RT dose de-escalation (from 70 Gy to 63 Gy and from 58.1 Gy 
to 50.75 Gy, same number of fractions (N=35) in 7 weeks) in patients with HPV-associated 
cancers of the oropharynx receiving standard of care treatment based on clinical stage. Image 
guided RT with daily cone-beam CT imaging will be used with CTV to PTV margins of 5 mm. 
Outcome will be evaluated both in terms of tumor control (and pattern of failure) and 
toxicity/QoL.Endpoints: Prevalence of grade 3+ toxicity at 2 yrs according to CTCAE 4.0 <15%; 
locoregional control at 2 yrs >85%. 
 
SCC oropharynx, HPV positive, 
 
Tx, T1-2 and Nx (without ECE), N0-1, N2a (<5 cm)  de-escalated IMRT alone + S for 
residual disease 
 
T3 and/or Nx (with ECE) N2a (>5 cm), N2b-c, N3 (resectable)     de-escalated IMRT + 
conc CDDP + S for residual disease 
 
Eligibility:  
- Confirmed histopathologic diagnosis of oropharyngeal (tonsil, base of tongue, pharyngeal wall, 
soft palate) squamous cell carcinoma; 
- Human papillomavirus (HPV) positive; 
- Stage T1-T3, N0-N3 (resectable), M0; both sides of the neck are judged to be at risk of 
metastatic disease 
- Surgery of the primary tumor is limited to incisional or excisional biopsies; any surgery is 
allowed in the neck; patients with surgery at both primary and nodal sites and without 
macroscopic residual disease (cTxcNx) are excluded) 
- ANC ≥ 1200 /mm3 
- Platelets >100,000/ mm3 
- Adequate hepatic function with bilirubin < 1.5 mg/dl 
- AST < 2x the upper limit of normal 
- ALT < 2x the upper limit of normal 
- Serum creatinine < 1.3 mg/dl 
-  Normal serum calcium (or normal corrected serum calcium) 
(Please note*: Formula for corrected calcium if albumin value is below normal range: Corrected 
calcium (mg/dl) = [ 4 – [patient albumin (g/dl)] x 0.8 + patient calcium (mg/dl) 
- Cannot have Serum creatinine >1.3 or ULN 
- Cannot have CCL < 60 cc/min 
- ECOG performance status 0-1 
- Nutritional condition must be considered compatible with the proposed radiotherapeutic 
treatment (cannot have unintentional and/or surgically unrelated weight loss >20% in the 
preceding 3 months) 
- Patients cannot be a current smoker at time of treatment 
- Patient cannot have a smoking history of > 10 pack years 
- No prior radiotherapy to the head and neck;  
- No prophylactic use of amifostine and/or pilocarpine;  

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- No concurrent enrollment in another therapeutic protocol for the same diagnosis; 
- No active untreated infection; 
- No major medical or psychiatric illness that would preclude treatment compliance; 
- Signed study-specific informed consent form prior to registration; 
- No other malignancy except for non-melanomatous skin cancer, early stage prostate cancer 
(T<2a and PSA<10 and GLS<7) or a carcinoma not of head and neck origin disease free for > 5 
years 
 
Required Sample Size: 60 patients 

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1 
BACKGROUND AND RATIONALE 
1.1 
Disease control of contemporary oropharyngeal cancer 
As for many other primary subsites of the head and neck district, two main options have been 
traditionally employed for the treatment of squamous cell carcinoma of the oropharynx (ORO-
SCC), surgery and radiotherapy (RT). The latter has been shown to be less `invasive` and morbid 
than radical surgery 1 and therefore has gained consensus as first line option in ORO-SCC at 
many Institutions across the country.  
 
Surveillance Epidemiology and End Results (SEER) data from 1975 to 2002 show an 
approximate 5% to 8% improvement in 5-year overall survival for squamous head and neck 
cancer 2. Most of this improvement occurred in oropharyngeal carcinoma. Table 1 summarizes 
results from contemporary series using non-surgical-based approach for ORO-SCC. They 
consistently show that long-term locoregional control rates are in the order of 80-95%. 
 
Table 1.  IMRT+chemotherapy for oropharyngeal SCC: literature data with emphasis on the 
pattern of failure. 
 
 Author  
Period 
# pts # def (%) 
% 
T3-4
% 
N2-3
% 
Chemo
FU (mths) 
2-yr^^ 
Min^ 
Median 
LRC 
OS 
 Wash U 
 1997-2001 74 
31 (42%) 71%
NA 
55% 
24 
33 
77% (4) 
 
 MDACC 
 2000-2002 51  51 (100%) 
0 
53% 
10% 
15 
45 
93%+ 
96% (T) 
94% 
 MSKCC  
 1998-2004 50 
48 (96%) 34%
NA 
86% 
8.4 
18 
98% (T) 
86% (N)+
98% 
  
 1998-2004 41  41 (100%) 39%
75% 
100%
20 
31 
92%(3)+
91% (3) 
 RTOG 0022  2001-2005 67  67 (100%) 
0 
10% 
0 
2.4 
19.2 
95.5% 
 
Univ IOWA 
 2000-2004 66 
62 (94%) 41%
82% 
74% 
11.5 
27.3 
98.8%(3)+ 78.1% (3)
 UTMB 
 2002-2006 50  50 (100%) 38%
60% 
0 
12.1 
32.6 
94% 
(3)(T) 
85% 
(3)(N) 
 
 
^ for living patients 
*6 pts without identification of the origin of primary tumor 
+ including neck dissection for residual neck disease 
^^ unless otherwise specified in parenthesis 
Abbreviations: # def: number of patients treated with definitive intent; chemo: chemotherapy; FU: follow up 
duration; mths: months; Wash U: Washington University; MDACC: MD Anderson Cancer Center; MSKCC: 
Memorial Sloan Kettering Cancer Center; RTOG: Radiation Therapy Oncology Group; UTMB: University of Texas 
Medical Branch; T: tonsillar fossa; BOT: base of tongue; SP: soft palate; PW: pharyngeal wall. For references 
please see3 

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Ameliorations in treatment approach that could have lead to this include: 
1. Introduction of a more sophisticated and precise way to plan and deliver RT or Intensity 
Modulated RT (IMRT). IMRT has been associated with more precise target coverage and 
less long-term toxicity on selected organs such as the parotid glands 4;  
2. Introduction of concomitant systemic chemotherapy (CHT) to RT particularly in 
locoregionally advanced disease (AJCC stage III & IV) 5, 6. Chemotherapy exploits a 
local cooperation with RT.  
3. Better support of patients during treatment in terms of pain control and nutritional status 
that allows more aggressive treatment to be delivered 7; 
4. Wider and wiser use of planned neck dissection after primary RT+CHT and refinement 
of surgical techniques of reconstruction with more salvage options after failure of 
primary chemoradiotherapy. 
 
Finally, nowadays a significant percentage of ORO-SCC is associated with the Human 
Papilloma Virus type 16 (HPV-16) or less frequently, with other types. It has been postulated 
that the biology of HPV-related ORO-SCC may be more benign than the classic alcohol-
tobacco-related cancers 8, and preliminary clinical data seem to confirm this hypothesis 9. 
Currently the prevalence of ORO-SCC which test positive for HPV referred for definitive 
(chemo)radiotherapy at JH is around 80% (unpublished data). 
 
1.2 
Favorable subgroup of patients with ORO-SCC 
Patients with low tumor burden or early stage disease (I-II, T1-2N0-1, primary tumor equal/less 
4 cm in greatest dimension and/or nodal disease up to 3 cm) have a favorable outcome. In the 
MDACC series on 175 patients with stage I-II disease treated from 1970 to 1998 without IMRT 
and systemic treatment, 5-yr local control (LC), regional control (RC) and locoregional control 
rates (LRC) were 85%, 93% and 81%, respectively 10. Recently, RTOG protocol 0022 on IMRT 
alone for early stage (T1-2, N0-1) oropharyngeal carcinoma has produced a 2-yr LRC of 91% 
(95%CI: 97.9-84.2%)11. T-stage is a strong predictor of local control by radiotherapy + 
chemotherapy 12. T4 tumors do significantly and consistently worse than T1-3 13. Interestingly, 
up to T3, oropharyngeal primary tumor staging is based on tumor dimensions, but in two 
separate studies this did not correlate with primary tumor volume as measured before treatment 
on CT 14, 15. Nathu et al. demonstrated a significant variation of oropharyngeal tumor volume for 
a given T-stage. T2 tumors ranged from 0 to 32.5 cm3, T3 from 0 to 48 cm3, and T4 from 6.5 to 
99.9 cm3. The variation in tumor volume appears to be greater for tumors of the oropharynx than 
tumors of other head and neck subsites14. Therefore, it is not surprising that the predictive role of 
tumor volume on outcome after (chemo)radiotherapy is a controversial issue with both negative 
14-16 and positive 17-19 studies. While this seems to contradict one of basic principles of RT that is 
the number of clonogens in the tumor is directly correlated with the risk of failure 20, other 
radiobiologic factors may well overcome and override the negative effect of clonogen number. 
One possible explanation is that intrinsic radiosensitivity of ORO-SCC is greater than that of 
SCC arising from other subsites of the HN district, which is often reported 15, although this has 
not been documented. Another (more reliable) explanation is that tumors that show an exophytic 
pattern of growth are more sensitive to radiation because of better oxygenation and a smaller 
hypoxic component due to better vascular supply 20. It is not an uncommon observation in the 
clinic that bulky, exophytic tumors `melt` during a course of radiotherapy and show good long 

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term control. This is indirectly supported by the evidence that Hypoxia-Inducible Factor-1- 
(HIF1α) is over-expressed in the vast majority of patients with squamous cell cancer of the 
oropharynx 21, 22. Interestingly, the degree of expression has been found to predict the likelihood 
of success of curative radiation therapy 22. Moreover, in one study HIF-1a expression was a more 
significant adverse prognostic factor in the tonsil (hazard ratio [HR], 23.1; 95% confidence 
interval [CI]. 3.04–176.7) than the tongue-base tumor (HR, 2.86; 95% CI, 1.14–7.19) group (p = 
0.03, test for interaction)21.  
 
Based on these considerations, it is reasonable to consider as having a favorable prognosis those 
ORO-SCC`s that present at an early T stage, T1 and T2, and thus radiotherapy alone is a 
reasonable option. For T3`s, combined chemoradiotherapy is the treatment of choice as discussed 
below in 1.3. 
 
Regarding N stage, despite excellent locoregional control rates with RT alone followed by neck 
dissection for residual/persistent nodal disease12, combined chemoradiotherapy is the treatment 
of choice for patients with single nodes greater than 3 cm (N2a, N3) or multiple nodes (N2b-c) in 
attempt to minimize the need for post treatment neck dissection.  
 
Finally, preliminary clinical data from two separate controlled studies support the concept that 
viral-related as opposed to tobacco/alcohol-related ORO-SCC`s have a better prognosis after 
definitive chemoradiotherapy 9, 23. While the positive effect of HPV-associated disease on 
outcome may be somewhat mitigated by a previous history of smoking, evaluation of HPV-status 
appears to identify a group of patients with a better prognosis to IMRT.  
 
1.3 
On systemic treatment for ORO-SCC 
Systemic treatment is part of the initial management of patients with locally advanced ORO-
SCC`s based on results obtained from randomized controlled trials in all subsites [summarized 
by 24] and specifically for the oropharynx 6. At JH, cisplatin-based chemotherapy concomitant 
with RT is usually recommended for stage III-IV disease that includes patients with T3 disease 
and/or advanced nodal disease (N2-3). Patients with a single node equal/less than 3 cm, even if 
technically assigned to stage III according to AJCC, have a good prognosis with RT alone10. 
However, Cisplatin and other systemic therapies enhance radiation cytotoxicity by a number of 
mechanisms leading to better control of local and regional disease that has translated into 
significantly improved survival in the majority of randomized controlled trials and in 4 meta-
analyses. Other potential benefits include a lessening of the need for salvage surgery, better 
functional, cosmetic and quality of life outcomes.  Principles of treatment that correlate with 
outcome and apply to radiotherapy, such as the overall duration of treatment time and the total 
dose of radiotherapy, may not apply when RT is delivered with concomitant chemotherapy.  
 
Other situations in which cisplatin concurrent with RT is recommended are positive resection 
margins at the primary tumor site and extracapsular nodal extension25. However, whether 
previous excisional biopsy in the form of wide local excision, radical or simple tonsillectomy, or 
just  `shaving off` the tumor has any role in the management of patients with ORO-SCC is 
unclear with advocates on both sides: `debulking` certainly reduces the number of clonogens, but 
whether it translates into a better outcome is not proven; on the other hand, surgery usually  

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leaves a scarred, potentially hypoxic bed that is less likely to respond to RT or to be reached by 
drugs. While this is an unresolved issue, it has been reported that patients who undergo an 
excisional biopsy (thus staged as cTx before definitive local treatment if no residual macroscopic 
disease is present) have a good outcome after postoperative radiotherapy regardless of their 
margin status10. Moreover, we doubt that a positive microscopic margin at the primary tumor 
after a simple excisional biopsy carries the same predictive value as after a radical, oncologic 
procedure (such a `commando` procedure). Therefore, we advocate the use of concomitant 
CDDP only for those cases were ECE is present, and the use of radiotherapy alone for a 
microscopic mucosal margin after excisional biopsy. In the latter case, a `full dose` of RT at the 
surgical site (70 Gy) is currently delivered. 
 
A new class of drugs targeting the Epidermal Growth Factor Receptor (EGFR) has been 
developed based on  evidence that the receptor is over expressed in most head and neck SCC 
(although constitutive EGFR activation can occur in the absence of increased expression). Many 
studies have reported antitumor effects when EGFR targeting strategies were used in preclinical 
head and neck SCC models 26. Several therapeutic approaches have been developed including 
monoclonal antibodies, tyrosine kinase–specific inhibitors, ligand-linked immunotoxins, and 
antisense approaches. Cetuximab is a monoclonal antibody that targets the extracellular domain 
of the EGFR. A phase III study has shown that cetuximab added to RT reduced the relative risk 
of death with locoregional failure and all-cause mortality by 32% and 26%, respectively 5. Most 
(≈60%) of the patients enrolled in this trial had oropharyngeal cancer and in subset analyses, this 
patient group showed the most benefit. At present, there is no data on how cetuximab plus IMRT 
compares with IMRT and concomitant chemotherapy. Therefore, for tumors at high risk of 
locoregional failure (T3-4`s, N2, N3 disease and/or presence of extracapsular extension after 
surgery) chemoradiotherapy is still the treatment of reference. For patients without these 
unfavorable risk features treatment with IMRT alone is supported by the data previously shown 
(1.1, table 1).  
 
1.4 
Treatment morbidity 
While contemporary results for ORO-SCC are improved compared to historical controls7, 
treatment morbidity on selected organs/tissues may have increased as well, bringing into 
question the real advantage in terms of therapeutic index. 
 
Attention has been focused on organs and structures involved in swallowing that are in close 
proximity to ORO-SCC27. Several papers have reported deterioration of swallowing function 
after RT+CHT (summarized by28). In one study, the incidence of severe aspiration was 11% 
(7/63 pts) before radiotherapy and 38% (24/63 pts) afterwards, with 6 pts dying from 
complications of aspiration29. In another report on 96 pts after radiotherapy, 31 (32%) had 
clinically significant aspiration and 36 (37%) developed a stricture30. Altogether the results show 
that a more aggressive approach may yield better oncologic outcome but at a greater expense in 
terms of both sub-acute and late toxicity. Currently up to 15% of patients are long-term PEG 
tube dependent after combined chemotherapy and IMRT for advanced oropharyngeal cancer31. 
In another study of sequential therapy (induction chemotherapy followed by chemoradiation), 
Goguen et al periodically assessed the swallowing status of 54 head and neck cancer patients30.  

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At one year follow up, 80% were able to eat either a regular or a soft diet and 19% still had their 
gastrostomy feeding tube. 
 
In addition to the salivary glands and those structures involved in swallowing function (including 
the larynx), several other structures can potentially be affected: mandible-osteonecrosis, brachial 
plexus-palsy, thyroid gland-hypothyroidism, masticator muscles and temporomandibular joints –
trismus, oral mucosa-mucositis, ears-deafness, sternocleidomastoid muscles-fibrosis, carotid 
arteries-stroke. 
 
Late toxicity after (chemo)radiotherapy for head and neck SCC is, in general, poorly 
documented, but unfortunately quite prevalent. A retrospective analysis of patients treated with 
concomitant radiotherapy (3D conformal) and chemotherapy for advanced head and neck cancer 
within 3 RTOG studies (RTOG 91-11, 97-03, and 99-14) showed that 43% of assessable patients 
had a severe late toxicity defined as chronic grade 3 to 4 pharyngeal/laryngeal toxicity and/or 
requirement for a feeding tube >or= 2 years after registration and/or potential treatment-related 
death (eg, pneumonia) within 3 years32.  
 
In one other recent prospective study, the actuarial prevalence of grade 3+ CTC AE v3.0 toxicity 
after altered fractionated IMRT for oropharyngeal SCC was 30.9% and 26.1% at 2 and 3 years, 
respectively 33. 
 
At UTMB, 58 patients with ORO-SCC were treated with IMRT alone (conventional 
fractionation to 70 Gy, 24 pts; hypofractionation to 66 Gy, 9 pts; hyperfractionation to 78 Gy, 25 
pts) from 09/02 to 09/06. At a median follow up of 22 months (range: 3-53.4 months), the 
actuarial prevalence of selected grade 3+ CTCAE 3.0 toxicity is 35.1% (Figure 1)(unpublished 
data). 
 
Time (yrs)
proportion of pts
1
2
25%
50%
75%
100%
 
Figure 1. 
 
The actuarial prevalence curve shows two `waves` of toxicity: the first one, corresponding to 
acute toxicity during and after treatment, which subsides by 6 months and a late wave due to late 
toxicity.  
 
This increase in toxicity seems  contradictory because it is well recognized that IMRT allows for 
sparing of selected structures (i.e. parotid glands) and thus fewer complications (i.e. 

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xerostomia)34. However, the dose to other organs at risk (OAR- such as the swallowing 
structures and the larynx) remains high due to their proximity or even `embedding` to the target. 
Another intrinsic limitation of IMRT is that about 25-30% of the prescribed dose is distributed 
across all structures surrounding the target. The resulting `dose bath` may be high enough to 
have clinical implications 35.  
 
Therefore, besides the few organs at risk (cord, brain, brainstem, parotids, mandible, larynx) 
whose sparing is usually prioritized, this sparing is usually not possible for the remaining 
structures in the context of standard IMRT planning. This is due to both physical (unless the dose 
comes from inside the pt, as in the case of brachytherapy, it has to go through the patient) and 
clinical reasons (proximity of the tumor to the organ at risk).   
 
The addition of chemotherapy to IMRT has been shown to increase acute mucosal damage 
compared to RT alone, and thus increases the risk of acute toxicity (intensity and duration of 
mucositis, pain, need and duration of PEG tube…). More importantly, acute toxicity can lead to 
subacute and late toxicity (so called `consequential late toxicity`)36. It has been reported that 
bone exposure and osteo- necrosis may result as consequence of overlying mucosal denudation 
36; more recently it has been postulated that pharyngeal constrictor muscle damage may result 
from a breakdown of the overlying mucosa, leading to edema, inflammation and ultimately 
fibrosis of the muscles 37.  
 
1.5 
Strategies to decrease toxicity 
There are several steps that can potentially reduce or mitigate the risk of toxicity. Regarding 
IMRT, there are several levels of intervention as illustrated in table 2.  
  
Table 2.  Examples of radiation treatment de-intensification strategies 
 
Strategy 
Feature 
Example 
Dose reduction 
To high dose volume  
Lower Px dose (S1) 
 
To low dose volume 
Lower Px dose (S3) 
 
To organs at risk 
To PTV-OAR overlap (S2) 
 
 
SF-IMRT 
 
 
Surgical transfer of submandib gland 
Volume reduction 
Contoured                 
CTV3 
Avoid medial RP nodes 
 
                     
CTV3 
Avoid anterior part of ipsi lv IB  
 
                     
CTV3 
Avoid controlat lvs IB & V 
 
                     
CTV3 
Allow unilateral tmt only 
 
                     
CTV2 
Reduce volume 
 
                     
CTV1 
Limit to metabolically active 

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Irradiated 
Reduce CTV to PTV exp – IGRT 
 
 
Brachytherapy boost 
 
Dashed: strategies exploited in the current protocol 
 
We have identified a solution that involves several individual strategies, as extensively discussed 
elsewhere38.  Briefly, in the context of dose painting IMRT (where CTV1 covers the gross tumor 
volume, CTV3 the volume at low (<10%) risk of microscopic disease, and PTV1-3 represent an 
expansion of CTV1-3 to account for set-up errors and tissue deformation), we plan a reduction of 
the prescription dose from 70 Gy equivalent dose at 2 Gy per fraction (ED2) for PTV1 and from 
50 Gy ED2 for PTV3 to 60 Gy ED2 and 44 Gy ED2, respectively. The rationale of the entity in 
dose reduction is reported in table 3. How these `experimental` doses compare to standard ones 
is reported in table 4. 
 
Table 3. Radiobiologic considerations on dose de-escalation 
 
Subclinical disease 
Gross disease 
General 
assumptions 
and 
definitions 
1. 10 fold reduction of cell population means 1 Log or elimination of 
90% of cells;  
2. D10 is defined as the dose necessary to depopulate by 1 Log; 
3. D10=D0 x 2.3; 
4. Typical value of D0 is 1.5-2.5 Gy (3 Gy if only hypoxic cells were 
present); here we consider 2.5 Gy; 
5. According to Poisson statistics, 90% of local control means that the 
average number of cells surviving is about 0.1 or 10-1; 99% means 
0.01 or 10-2; 
6. If a tumor is composed by 1010 cells to begin with, in order to achieve 
a LC of 90%, 10-11 cells need to be killed (from 10 to -1 Logs, thus 11) 
Specific 
assumptions 
1. In `high` risk areas at containing 
microscopic disease, tumor 
population is 107 cells; 
2. To achieve 90% of local 
control, 8 Logs of cells need to 
be killed; 
1.Subtotal resection, leaving 1% or 
0.01 of cells, depopulates by 2 
Logs; 
 
Estimates 
If each Log is depopulated with 
5.75 Gy (2.5 Gy x 2.3), then: 
 8 Logs would need 46 Gy 
(5.75 Gy x 8); 
 9 Logs, 51.75 Gy 
 12 Logs would require 69 Gy 
 11 Logs, 63.25 Gy 
 10 Logs, 57.5 Gy  
Comments 
These estimates would be 
consistent with the standard dose 
of 50 Gy for regions treated 
electively or at `low ` risk; 
Consistently, after tonsillectomy 
with 108-9 Logs left, the Px dose is 
between 60 Gy and 66 Gy; 
Role of 
concomitant 
chemotherapy 
Concomitant chemotherapy equals to a biological equivalent dose (BED) 
of 10 Gy39;  
 in presence of chemotherapy, a BED10 10 Gy lower than needed 
would be expected from RT;  

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a BED10 of 8-12 Gy corresponds to 8-10 Gy or 1-2 Logs; 
Estimates 
In presence of concomitant 
chemotherapy, the dose of RT 
for microscopic disease would 
drop to ≈40 Gy for areas at low 
risk and to ≈50 Gy for areas at 
high risk 
The dose of radiation would drop 
to ≈60 Gy 
Comments on 
disease 
control 
44 Gy at 2 Gy per fraction is 
allowed by NCCN guidelines to 
treat electively the neck in 
presence of chemotherapy 40 
 
Clinical data obtained combining 
`reduced dose RT` and concomitant 
chemotherapy seems to be 
consistent to these estimates 41.  
Comments on 
toxicity 
Structures that are expected to benefit from less than 70 Gy (due to their 
proximity to the target), include the mandible, the constrictor mm, the 
larynx, the brachial plexus;  
Structures that benefit from an intermediate dose level reduction include 
the parotids, the submandibular glands, great vessels in the neck, 
masticatory mm, thyroid gland, esophagus  
 
Table 4. Equivalency of schedules in terms of radiobiological parameters 
 
Treatment parameters 
ACUTE TOXICITY 
TUMOR RESPONSE
LATE TOXICITY
 
D 
(Gy) 
d 
(Gy) # fxs OTT
(dd) 
BED10
† 
(Gy) 
LDED210
† 
(Gy) 
BED3
* 
(Gy) 
LDED23
* 
(Gy) 
Micro low risk 
(CTV3) 
 
 
Standard 3FT 
50 
2 
25 
33 
55.2 
50 
83.3 
50 
IMRT 
58.1 
1.66 
35 
47 
57.4 
≈52 
90.2 
≈54 
Experimental 50.75 1.45 
35 
47 
47.8 
≈42 
(-16%)^ 
75.3 
≈45 
(-10%)^ 
Micro high risk 
(CTV2) 
 
 
Standard 3FT 
60 
2 
30 
40 
64.5 
60 
100 
60 
IMRT 
63 
1.8 
35 
47 
64 
≈60 
100.8 
≈60 
Macro-GTV (CTV1) 
 
 
Standard 3FT 
70 
2 
35 
47 
73.7 
70 
116.7 
70 
IMRT 
Experimental 
63 
1.8 
35 
47 
64 
≈60 
(-14%)^ 
100.8 
≈60 
(-14%)^ 
 
Abbreviations: D, total dose of RT (Gy); d, dose per fraction (Gy); OTT: overall treatment time 
BED3 = biologically effective dose considering α/β of 3 Gy; LQED23 = linear quadratic equivalent 
dose in 2 Gy fractions considering α/β of 3 Gy; Standard 3FT = conventional fractionation at 2 Gy 
per fraction using sequential phases and standard 3 field technique; BED10 = biologically effective 
dose considering α/β of 10 Gy; LQED210 = linear quadratic equivalent dose in 2 Gy fractions 
considering α/β of 10 Gy and time factor. 

Version:  March 4, 2013 
 
14 
 
* no time factor applied; assuming complete repair of sublethal damage between fractions for late 
responding tissues; α/β = 3 Gy for late effects. 
† time correction applied; α/β =10 Gy for tumor; α = 0.35 Gy-1; Tk = 21 days; Tp = 5 days;  
^ % reduction compared to standard 3FT RT 
 
It should be noted that the reduction in the prescription dose does not apply to the whole volume 
but only selected parts as follow: 
1. to part(s) of PTV1 and PTV3 that are close (within 8 mm) or overlapping with selected 
organs at risk, such as the constrictor muscles, the parotids…. (for a complete list please 
refer to section 5.4); 
2. to part(s) of PTV3 that cover the ipsilateral (to primary tumor) level IV if ipsilateral level 
III is clinically and radiologically uninvolved 42 (for criteria of nodal involvement please 
refer to section 5.3.2); 
3. to part(s) of PTV3 that cover the contralateral levels III and IV if contralateral level II is 
negative (as defined at 2 above);  
4. to part(s) of PTV3 that cover the contralateral level IV if contralateral level III is negative 
regardless level II status. 
 
Moreover, most (>85%) of each PTV is still adequately `covered` by a standard dose, while there 
is a significant dosimetric benefit on almost each OAR considered 38 as shown in table 5 in terms 
of absolute difference in mean dose compared to a reference plan. 
 
Table 5. Dose at selected dose point for various OARs: the solution proposed here vs a reference 
plan (modified from38) 
 
 
 
Av
r 
SD 
Avr abs 
gain 
P sign 
Dom parotid 
Mean D 
(Gy) 
48.
4 
6.3 
2.3 
 
Contr parotid 
Mean D 
(Gy) 
35.
6 
3.5 
1.2 
 
Mandible 
Mean D 
(Gy) 
49.
4 
3.2 
2.3 
 
Larynx 
Mean D 
(Gy) 
45.
5 
7.5 
1.4 
 
Esophagus 
Mean D 
(Gy) 
38.
2 
5.1 
2.8 
 
Contr Inner 
Ear 
Mean D 
(Gy) 
35.
7 
8.7 
1.1 
 
Dom Inner 
Ear 
Mean D 
(Gy) 
41.
6 
7.5 
1.8 
 
Dom Brach 
Pl* 
Mean D 
(Gy) 
59.
4 
2.2 
4.4 
 
Contr Brach 
Pl* 
Mean D 
(Gy) 
58.
3 
1.0 
6.5 
 
Mucosa* 
Mean D 
(Gy) 
52.
7 
2.8 
1.4 
 

Version:  March 4, 2013 
 
15 
 
Sup constrict 
m 
Mean D 
(Gy) 
67.
3 
2.1 
3.7 
 
Mid constrict 
m 
Mean D 
(Gy) 
60.
8 
2.2 
3.7 
 
Inf constrict 
m 
Mean D 
(Gy) 
51.
5 
5.9 
2.9 
 
Cricophar m 
Mean D 
(Gy) 
51.
0 
6.7 
3.6 
 
Thyroid 
gland* 
Mean D 
(Gy) 
60.
4 
1.1 
5.5 
 
Dom 
masticat 
Mean D 
(Gy) 
55.
3 
3.7 
2.7 
 
Contr 
masticat 
Mean D 
(Gy) 
41.
6 
2.7 
2.3 
 
Contr TMJ* 
Mean D 
(Gy) 
26.
5 
10.
9 
1.1 
 
Dom TMJ* 
Mean D 
(Gy) 
38.
2 
5.9 
3.2 
 
Dom Subm 
Gl * 
Mean D 
(Gy) 
68.
9 
1.7 
4.6 
 
Contr Subm 
Gl* 
Mean D 
(Gy) 
59.
3 
2.1 
1.9 
 
*: OAR`s not taken into consideration for overlap at planning 
Dashed: OAR not contrained at planning 
  
no sign (p<0.05) difference compared to ref 
   
sign decrease compared to ref 
Abbreviations:  dom: dominant; contr: contralateral; Brach Pl: brachial plexus; sup: superior; mid: middle; inf: 
inferior; m: muscle; cricophar: cricopharyngeous; masticat: masticatory muscles; TMJ: temporomandibular joints; 
Subm Gl: submandibular glands  
 
Finally, the overall duration of treatment will be kept to 7 weeks, in order to avoid an increase in 
acute mucosal toxicity and to reduce the risk of increasing subacute/consequential late toxicity. 
In addition we will enforce a novel set of dose volume objectives for the mucosa (unpublished 
data). According to the retrospective analysis of toxicity data obtained in 59 consecutive patients 
treated with IMRT alone for ORO-SCC at UTMB where a PEG tube was placed only if needed, 
there was a significant correlation between the absolute amount of oral mucosa that received a 
given dose per week and the need for PEG tube. In particular with cut-offs of V9.5<64.5 cc and 
(sensitivity: 95.5, specificity: 59.5) and V10 < 54 cc (sens: 82, spec: 62), only 1 patient needed a 
PEG tube (figure 2).  
 

Version:  March 4, 2013 
 
16 
 
Figure 2. Absolute DVH for the oral mucosa of 59 patients. Red:  pts necessitating PEG –tube 
during treatment; white: patients not needing a PEG tube during treatment. Only 1 patient with 
absolute volume of mucosa <50 cc receiving 9 Gy needed the PEG tube.  
Dmean week vs PEG
0
50
100
150
200
250
300
0
300
600
900
1200
1500
Gy/week
cc mucosa
  
 
Acute toxicity may also translate into subacute and late toxicity as described for the mandible 36 
and hypothesized for the constrictor muscles and the larynx 44,45.  
 
1.6 
Standard Supportive treatment 
Regarding supportive treatment and prophylactic measures to prevent/mitigate toxicity, the 
following ones are generally pursued as standard of care: 
‐ 
Dental evaluation and fluoride prescription/administration; 
‐ 
Speech pathology evaluation including 
‐ 
Baseline swallowing screening with flexible endoscopic evaluation of swallowing 
(FEES) followed by a formal modified barium swallowing study (MBSS) if 
needed. The Penetration/Aspiration Scale (Appendix 4) will be used during 
modified barium swallow studies.  
+ baseline evaluation of jaw opening, premorbid speech disturbance and 
dysphonia.   
+ baseline cognitive/language function screening using the Montreal 
Cognitive Assessment (Appendix 5).  
+ implementation of prophylactic swallowing and trismus prevention 
exercises prior to initiation of treatment46; 
+ education  regarding the role of oral hygiene and aspiration pneumonia, 
products to compensate for xerostomia (e.g., frequent sips of water, oral 
lubricants, saliva substitutes) and dentrifices. 
+ documentation of the presence of a gastrostomy feeding tube, estimated 
percent of oral alimentation/hydration via the feeding tube; estimated 
percentage of PO intake at baseline.  
- Nutritional evaluation with pre-treatment correction of weight loss (nutritional 
impairment is defined as weight loss > 20% in the preceding 3 months or food 

Version:  March 4, 2013 
 
17 
 
intake below 50% of normal requirements in the week preceding enrollment) as 
needed. A PEG-tube will be placed routinely before or shortly after initiation of 
IMRT only in those patients who receive chemotherapy in addition to 
radiotherapy. 
 
2 
OBJECTIVES 
2.1 To achieve a prevalence of grade 3+ late toxicity at 2 yrs <15% while maintaining a 
locoregional tumor control >85+7% at the same time interval (toxicity is scored at 5.11 and 9.5 
and locoregional control at 9.4); 
 
2.2 To determine the nature and prevalence of side effects at different time intervals and describe 
their relationship to pretreatment function and local dose and treated volume.  
 
2.3 To determine the quality of life of surviving patients (5.11 and 9.5)  
 
3 
SELECTION CRITERIA 
3.1 
Eligibility Criteria  
3.1.1 Biopsy-proven SCC of the oropharynx (tonsil, base of tongue, pharyngeal wall or 
 
palate), 
3.1.2 Tumor positive for infection with human papillomavirus (HPV) virus (any subtype) 
as per JH Pathology assessment (section 8.0);  
3.1.3 Negative pregnancy test for women of childbearing potential 
3.1.4  T stage: 1, 2, 3. Surgery of the primary tumor is limited to incisional or excisional 
biopsies (i.e. tonsillectomy) even without macroscopic disease left. Positive resection 
margins and/or gross residual disease at the primary site are allowed; evaluation of 
primary tumor extent may require the use of a flexible fibroscope if deemed clinically 
necessary by the treating physician; any N stage but resectable; lymph nodes in both sides 
of the neck are at risk of metastatic disease, according to clinical judgment, and require 
irradiation; pre-treatment surgery in the neck in the forms of incisional/excisional biopsy 
or a multilevel neck dissection is allowed only if there is gross tumor left at the primary 
site; 
3.1.5 No other malignancy except for non-melanomatous skin cancer, early stage prostate  
cancer (T<2a and PSA<10 and GLS<7) or a carcinoma not of head and neck origin 
disease free for > 5 yrs. 
                             
 
 
 
 
 
3.1.6  - ANC > or = to 1000 /mm3 
 
 
- Platelets >100,000/ mm3 
 
 
- Adequate hepatic function with bilirubin < 1.5 mg/dl 
 
 
- AST < 2x the upper limit of normal 
 
 
- ALT < 2x the upper limit of normal 
 
 
- estimated CCL > 60 cc/min  
- Normal serum calcium (or normal corrected serum calcium) (Please note*: 
Formula for corrected calcium if albumin value is below normal range: Corrected 
calcium (mg/dl) = [ 4 – [patient albumin (g/dl)] x 0.8 + patient calcium (mg/dl) 

Version:  March 4, 2013 
 
18 
 
3.1.7 Cannot have distant metastasis (M0); 
3.1.8 ECOG performance status 0-1 
3.1.9 Patient’s nutritional and general physical condition must be considered compatible 
with the proposed radiotherapeutic treatment (cannot have unintentional and/or surgically 
unrelated weight loss > 20% in the preceding 3 months). *This assessment is a standard 
of care assessment for this patient population. This requirement can be waived by the 
investigator if the subject has an identifiable procedure which is the immediate and sole 
cause for the weight loss without an underlying pathological cause. An example of a 
situation like this would be if a participant is found to need a tonsillectomy during the 
pretreatment evaluations. It’s obvious that this scenario would be a non-pathological 
reason for such a weight loss. The PI will only have this ability to waive this criterion if 
and only if he can substantiate and document that the weight loss does not have a 
pathological etiology and will correct itself within a reasonable and acceptable period of 
time 
3.1.10 Patient is judged to be mentally reliable to follow instructions and to keep 
appointments. (Please note that mental reliability is not determined through any specific 
test rather it is ascertained by the treating physician through conversation at the time of 
consult) 
3.1.11 No concurrent enrollment in another therapeutic protocol for the same diagnosis; 
3.1.12 Signed study-specific informed consent prior to registration.  
3.1.13 Subject must understand that while they are on study they cannot have any 
concurrent curative therapy for their cancer other than what is outlined in the protocol. 
 
3.2 
Ineligibility Criteria 
3.2.1 Evidence of distant metastases. 
3.2.2 Absence of macroscopic disease after upfront surgery, i.e. TxNx and TxN0. TxN+ 
and T1-3Nx are eligible if the T/N stage categories meet the criteria of 3.1.1 
3.2.3 Previous irradiation for head and neck tumor; concurrent chemotherapy other than 
the treatment per protocol; previous chemotherapy ≤ 3 months from start of RT.  
3.2.4 Active untreated infection.  
3.2.5 Major medical or psychiatric illness, which in the investigators’ opinion would 
interfere with either completion of therapy and follow-up or with full and complete 
understanding of the risks and potential complications of the therapy.  
3.2.6 Use of amifostine or pilocarpine before and during radiotherapy is not allowed.  
3.2.7 Serum creatinine >1.3 or ULN, CCL < 60 cc/min, Peripheral neuropathy > grade 1, 
and/or frequency hearing loss that interferes with activities of daily living are 
contraindications to cisplatin but not to carboplatin (6.2.4). 
3.2.8 Patients with > 10 pack years of smoking history and/or currently a smoker at the 
time of treatment. 
 
4 
PRETREATMENT EVALUATIONS  
4.1 Each patient must have completed the following studies prior to irradiation:  
 
4.1.1 Complete history and physical exam including weight and performance status.  

Version:  March 4, 2013 
 
19 
 
 
4.1.2 Complete dental evaluation. Any required dental extractions must be made and 
 
fluoride prophylaxis instituted prior to radiotherapy. 
4.1.3 Speech pathology evaluation including instrumental swallowing assessment or clinical 
assessment of swallowing and administration of pretreatment swallowing and trismus 
exercises (*This assessment is a standard of care assessment for this patient population).  
Completion of pretreatment MD Anderson Dysphagia Inventory (MDADI) and Montreal 
Cognitive Assessment (MCA). Speech therapy evaluation has to take place before 
commencement of treatment.  
 
4.1.4 Nutritional evaluation to be conducted within the first week of starting 
(chemo)radiation therapy.  
4.1.5 Completion of the following laboratory studies: CBC with diff. and platelets, 
Metabolic Panel to include- sodium, potassium, glucose, calcium, magnesium, BUN, serum 
creatinine, total protein, albumin, alkaline phosphatase, total bilirubin, AST, ALT, and a 
creatinine clearance) 
 
4.1.6 Completion of the following radiologic studies: CT of head and neck with < 3 mm 
 
contiguous slices in immobilization system (with contrast, unless contraindicated); whole 
 
body PET/CT (integration of both high resolution CT with contrast and dedicated PET 
 
acquisition through the head and neck are strongly suggested); MRI of head and neck with 
 
gadolinium including T1 and T2 weighted sequences in at least 2 different planes strongly 
 
suggested for primary tumors of the base of tongue (optional-see 5.1.2). 
4.1.7 Audiogram to be conducted before or within the first week of starting therapy (if inner 
ear is to be irradiated at mean dose ≥ 40 Gy).  
 
    
5 
RADIATION THERAPY  
5.1 
Treatment Planning, Imaging and Localization Requirements  
5.1.1 The immobilization device is a thermoplastic mask that covers both face and 
shoulders. A mouth piece is also indicated for all patients but those edentulous.  
5.1.2 Treatment planning CT scans will be performed with the patient in the treatment 
position. I.V. contrast at the time of simulation is also recommended. A planning MRI scan 
is optional.  
5.1.3 All tissues to be irradiated must be included in the CT scan. CT scan thickness should 
be 0.3 cm or less through the region that contains the primary target volumes. The regions 
above and below the target volume may be scanned with slice thickness up to 0.5 cm. MRI 
and PET/CT scans may be included to assist in definition of target volumes.   
5.1.4 The GTV, CTV and PTV and normal tissues will be outlined on all CT slices in which 
the structures exist. 
5.1.5 Image Guidance for IGRT: Daily image guidance of IMRT will be achieved using 
Linear-accelerator mounted MV cone beam CT images. 
The procedure to register treatment day imaging dataset with the reference dataset will 
comply with the following recommendations: 
 Region-of-Interest (ROI) or “clip box” for fusion is set to encompass the 
high dose PTV and adjacent spinal cord; if the supraclavicular region is a 
part of the target volume the ROI should extend to the C6 level; 

Version:  March 4, 2013 
 
20 
 
 Automatic (based on bony anatomy) registration will be used; the result 
of the fusion will be visually checked for the alignment of the bony 
anatomy, such as vertebral bodies and applicable soft tissue structures 
(e.g., optic nerves and/or optic chiasm). 
Following the registration, the translational corrections will be applied to the treatment 
couch. If all the variances are less than 2.0 mm, the treatment will proceed without 
correction (however, the physician/team may elect to perform adjustments even for a 
variance < 2.0 mm). If one or more corrections are 2.0-5 mm, adjustment is necessary 
prior to treatment; however, re-imaging 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. 
 
5.1.6 Management of Radiation Dose to the Patient from IGRT 
The estimates of patient doses per imaging study for various imaging systems vary 
considerably. The doses from helical MV CT scan on a tomotherapy unit were estimated 
to be in range from 1 to 3 cGy for head and neck studies, similar to doses reported for kV 
cone beam CT on Elekta Synergy machine. Thus, the doses for 3D imaging systems are 
in the range from 1 to 3 cGy for head and neck imaging and can contribute from 0.5 to 
1.5% to the daily dose of 2.0 Gy. These are small enough dose contributions that if there 
is only one or two imaging study done per treatment session, the dose does not need to be 
incorporated into treatment planning and is not expected to have any clinical relevance to 
the patient.  
 
5.2 
Volume and ICRU Reference Point Definitions 
The definition of volumes will be in accordance with the 1993 ICRU Report #50: Prescribing, 
Recording and Reporting Photon Beam Therapy.  
5.2.1 The Gross Tumor Volume (GTV) is defined as all known gross disease determined 
from CT, clinical information, endoscopic findings and MRI in the case of tumors treated 
after biopsy alone.  
 
5.2.2 The Clinical Target Volumes (CTV) is defined as the GTV plus areas considered to 
contain potential microscopic disease, delineated by the treating physician. The margin 
between the each GTV and its CTV will be typically 1-2 cm, with a minimum of 5 mm 
except in those areas where the GTV is immediately adjacent to structures known to be 
uninvolved. In postoperative cases, The CTV includes the operative bed and margins 
according to an assessment of the risk of subclinical disease.  
 
The Planning Target Volume (PTV) will provide a margin around each CTV (i.e. both the 
primary tumor and the lymph nodes containing clinical or radiographic evidence of 
metastases) to compensate for the uncertainties of treatment set up and tissue deformation. 
A minimum of 5 mm around the CTV will be required in all directions to define each 
respective PTV in the setting of IGRT. 
 

Version:  March 4, 2013 
 
21 
 
5.3 
Target Definition  
5.3.1 Targets are defined as follows: CTV1 or high dose volume that encompasses the 
GTV with a margin; in case there is no GTV available (i.e. after tonsillectomy) CTV1 
encompasses the tumor bed or where the tumor was before surgery; CTV2, that typically 
includes the tissue around the gross tumor volume and/or the neck nodal stations that 
have high (>15%) risk of cancer involvement and/or lymph nodes that look suspicious on 
imaging; CTV3 includes contralateral lymph nodal stations and lower neck lymph nodal 
stations which have relatively lower risk (5-15%) of cancer involvement and do not look 
suspicious at imaging.  
 
5.3.2 Positive lymph nodes are defined as those that meet any of the following criteria on 
CT: maximum axial diameter > 1cm (>5 mm if retropharyngeal); focal hypoattenuation 
within the node suggesting necrosis; irregular enhancement pattern; presence of 
extracapsular penetration as judged by 21peculated margins. Suspicious are those that 
measure between 7-9 mm in greatest axial dimension in neck levels III through IV; have 
a rounded appearance defined as a width to length ratio greater than 0.5; lack fatty hilum. 
 
5.3.3 Lymph node stations or levels in the neck follow the surgical nomenclature.   A 
station is considered positive if contains positive lymph nodes. However, in this case, 
only the positive lymph node(s) and not the whole station is (are) contoured as GTV. 
Moreover, expansion from GTV to CTV1 does not imply that the whole level will be part 
of CTV1.  
 
5.3.4 The following (entire) lymph nodal stations are considered at high (>15%) risk of 
containing microscopic disease when negative/normal on clinical exam and imaging: 
levels II and III ipsilateral to the site of a positive lymph node in the neck. The entire 
level is drawn as CTV2 42.   
 
5.3.5 For lymph node stations different from ipsilateral levels II and III (5.3.5) only the 
suspicious finding and not the whole level has to be contoured as CTV2; 
 
5.3.6 The following levels are routinely included in CTV3: level IB ipsilateral to neck 
disease; bilateral levels II, III, IV and V. Controlateral level IB is routinely excluded from 
any target volume. In the rare case that level IB has a positive or suspicious node, level 
IB becomes part of the appropriate target volume even in absence of positive level II 
nodes.   
 
5.3.7 The anterior extent of the contour of level IB when included in CTV3 will stop at 
the anterior extent of the submandibular gland and therefore exclude the triangular fat 
space lateral to the deep extrinsic muscles of the tongue as shown elsewhere 42.  
 
5.3.8 Retropharyngeal nodes on both sides are routinely included in CTV3 from C1 to the 
bottom of C2 
 

Version:  March 4, 2013 
 
22 
 
5.4 
Organ At Risk (OAR) Definitions 
Several organs at risk will be contoured on each patient planning CT as follows. In order to 
facilitate the spelling, a script will be run from Pinnacle to generate the regions of interest. 
OAR`s are: mandible, brain, brainstem, cord, submandibular glands, thyroid gland, parotid 
glands, upper gastrointestinal mucosa 47, larynx 45, masticatory spaces, upper, middle and inferior 
constrictor muscles, cricopharyngeous muscle, esophagus, brachial plexuses, temporomandibular 
joints (TMJ), inner ears, internal, external and common carotid arteries. Paired organs will be 
divided into those on the dominant side of disease (dominant) and those on the opposite side 
(contralateral). An atlas on how to contour each structure is available at the web site of the 
University of Texas Medical Branch, http://www.utmb.edu/radoncology/oar.htm 
For planning purposes, the cord is expanded by 4 mm. 
 
5.5 
PTV and subPTV generation 
Each CTV is expanded 5 mm isotropically to generate corresponding PTV`s, PTV1, 2 and 3. 
Each PTV is further adjusted to come off the skin, by excluding the part that is within 3 mm to 
skin surface (PTV= CTV + 5mm – (skin -3mm)).  
In order to achieve dose de-escalation on parts of the PTV (subPTV), each PTV is further 
divided into subPTV`s whose prescription dose is as follows in table 6. 
 
Table 6 
Main 
PTV 
SubPTV 
Note 
Px D 
(Gy) 
Nomenclature
PTV1 
overPTV1 
Part of PTV1 that overlaps with 
larynx for edema+8 mm, superior 
constrictor m+8 mm, mandible + 8 
mm, parotids, masticatory mm, 
esophagus, mid/low constrictor mm 
63 
PTV63 
 
truePTV1 
Rest of PTV1 
70 
PTV70 
PTV2 
None 
 
63 
PTV63 
PTV3 
overPTV3 
Part of PTV3 that overlaps with 
larynx for edema+8 mm, sup/mid/low 
constrictor mm+8 mm, parotids+8 
mm, masticatory mm+8 mm, 
esophagus+8 mm 
50.75 
PTV50.75 
 
lowPTV3 
Part of PTV3 that covers ipsilateral 
(to neck disease if present) level IV 
(and level III is negative) and/or 
contralateral (to neck disease or both 
heminecks if no neck disease is 
present) levels III and IV; if disease 
is present on both sides, each side is 
treated as ipsilateral one  
50.75 
PTV50.75 
 
truePTV3 
Rest of PTV3 (or without lowPTV3 
and overPTV3) 
58.1 
PTV58.1 

Version:  March 4, 2013 
 
23 
 
  
5.6 
Dose prescription 
The common practice of this institution for H&N cancer is to prescribe three dose levels, 70 Gy, 
63 Gy and 58.1 Gy to primary tumor and whole neck (PTV1-3) in 35 fractions. The Px to each 
PTV is reported in table 6. Now we have 4 dose levels, 70, 63, 58.1 and 50.75 Gy. In cases after 
primary tumor surgery where there is no residual macroscopic disease left, the total dose to 
PTV1 can be reduced from 70 Gy to 68.25 Gy. In this case PTV68.25 is treated as PTV70 
regarding overlap with the various OAR`s.   
 
5.7 
Planning 
5.6.1 A co-planar 9 beam whole field IMRT plan will be generated. The treatment plan used 
for each patient will be based on an analysis of the volumetric dose, including DVH 
analyses of the PTV and critical normal structures. An “inverse” planning using 
computerized optimization is used. The treatment aim will be the delivery of radiation to the 
PTVs and the exclusion of noninvolved tissue as feasible.  
 
 
5.6.2 Dose Specification  
5.6.2.1 The prescription dose is the isodose which encompasses at least 95% of the planning 
target volume (PTV). No more than 10% of any planning target volume (PTV) will receive 
>110% of its prescribed dose (V10%<110%). No more than 1% of any planning target 
volume (PTV) will receive <95% of its prescribed dose (V95%>99%). No more than 1% or 
1 cc of the tissue outside the PTVs and any OAR (`unspecified tissue) will receive >110% 
of the dose prescribed to PTV1.  
 
5.6.2.1 The prescription dose to the PTV`s and subPTV`s is reported in table 5. Breaks 
in treatment should be minimized. Break in treatment time of more than 5 days will be 
considered a major variation.  
 
5.6.2.2 The reported doses for each PTV shall include the prescription dose as well as 
the maximum point dose, % target volume receiving > 110% and >115% of its 
prescribed dose and the % target volume receiving < 95% of the prescribed dose, and 
the mean dose to the PTV.  
 
 
5.6.2.3 The dose prescription is to be based on a dose distribution corrected for 
heterogeneities 
 
 
5.6.3 Critical Normal Structures  
DVHs must be generated for all critical normal structures and the unspecified tissues. Dose 
constraints to normal tissues (and PTV`s) should be as per table 7. 
 

Version:  March 4, 2013 
 
24 
 
Table 7.  
Grou
p 
Region of interest 
 
 
1 
Cord+4 mm 
0.1 cc 
Max dose 45 Gy 
 
Brainstem 
0.1 cc 
Max dose 54 Gy 
 
Brain 
1 cc 
Max dose 60 Gy 
 
Larynx for edema+8 mm-
over2 
Portion overlapping with PTV2 
Max dose 63 Gy 
 
Larynx for edema+8 mm 
Portion 
not 
overlapping 
with 
PTV2 
Max dose 50.75 
Gy 
 
Mandible+8 mm 
 
Max dose 63 Gy 
 
Sup constrictor m+8 mm-
over2 
Portion overlapping with PTV2 
Max dose 63 Gy 
 
Sup constrictor m+8 mm 
Portion 
not 
overlapping 
with 
PTV2 
Max dose 50.75 
Gy 
 
Mid constrictor m – over2 
Portion overlapping with PTV2 
Max dose 63 Gy 
 
Mid constrict m+8 mm 
Portion 
not 
overlapping 
with 
PTV2 
Max dose 50.75 
Gy 
 
Low constrictor m – over2 Portion overlapping with PTV2 
Max dose 63 Gy 
 
Low constrict m+8 mm 
Portion 
not 
overlapping 
with 
PTV2 
Max dose 50.75 
Gy 
 
Parotids – over2 
Portion overlapping with PTV2 
Max dose 63 Gy 
 
Parotids+8 mm – over3 
Portion overlapping with PTV3 
Max dose 50.75 
Gy 
 
Masticatory mm – over2 
Portion overlapping with PTV2 
Max dose 63 Gy 
 
Masticatory mm+8 mm 
Portion 
not 
overlapping 
with 
PTV2 
Max dose 50.75 
Gy 
 
Esophagus – over2 
Portion overlapping with PTV2 
Max dose 63 Gy 
 
Esophagus+8 mm – over3 
Portion overlapping with PTV3 
Max dose 50.75 
Gy 
 
Mucosa -1 
 
V66.5 Gy<64.5 
cc 
 
Unspec. Tissue 
1 cc 
Max dose 77 Gy 
2 
overPTV1 
Portion overlapping with OAR`s 
(table 5) 
V60 Gy >99% 
 
truePTV1 
PTV1-overPTV1 
V66.5 Gy >99% 
 
PTV2 
 
V60 Gy >99% 
 
overPTV3 
Portion overlapping with OAR`s 
(table 5) 
V48.2 >99% 
 
lowPTV3 
Low/mid neck PTV3 (table 5) 
V48.2 >99% 
 
truePTV3 
PTV3-lowPTV3-overPTV3 
V55.2 >99% 
3 
Mucosa -2 
Portion not overlapping with any 
PTV 
Max dose 30 Gy 
 
Parotids 
At least one 
V30<50% 
(whole DVH) 

Version:  March 4, 2013 
 
25 
 
 
Brachial plexus 
 
Max dose 60 Gy 
 
Inner ears 
 
Mean D <40 Gy 
 
Esophagus-out 
Portion outside PTV3+8 mm 
Dmax 45 Gy 
 
 
5.6.4 Planning Priorities  
 
The priorities in addressing the protocol aims and constraints will be in the following order:  
 
 
1) Group 1 (table 6),  
 
 
2) Group 2 (table 6),  
 
 
3) Group 3 (table 6). 
  
5.8 
External Beam Equipment and Beam Delivery Methods  
Megavoltage equipment capable of delivering static or dynamic intensity modulation with a 
multileaf collimator is used. Whole field IMRT (without an anterior AP field) is used.  
 
5.9 
Treatment Verification and daily imaging  
 Pre-treatment radiation therapy planning CT scan; 
 Daily imaging with cone beam CT (5.1.5.1) 
 
5.10 
Quality Assurance of Target Volumes and Critical Structure Volumes  
The DVH`s of each target and Oar will be exported and converted to excel file format. 
 
5.10.1 Each treatment shall be scored with regard to the coverage of each PTV (i.e. 
PTV70, PTV63, PTV58.1, and PTV50.75) and with regard to the level of sparing of 
several OAR`s; the scores to be assigned are defined in table 8 below.  
 
Table 8.  
 
Per protocol 
Minor variation 
Major variation 
Overall treatment time 
47 days 
48-51 days 
>51 days 
PTV coverage 
V95%>99% 
95%<V95%<99% 
V95%<95% 
Cord + 4 mm 
Max Dose 45Gy 
Max Dose 47.5Gy 
Max Dose 49.5Gy 
Brainstem 
Max Dose 54Gy 
Max Dose 56.7Gy 
Max Dose ≤ 59.4Gy 
Brain 
Max Dose 60Gy 
Max Dose 63Gy 
Max Dose 66Gy 
Larynx for edema  
V50 < 30%  
30% < V50 < 31.5% 31.5% < V50 < 33%
Mandible 
Max Dose 70Gy 
Max Dose 73.5Gy 
Max Dose 75Gy 
Superior constrictor 
V40 < 95% 
95% < V40 < 100% 
 
Superior constrictor 
V50 < 90% 
90% < V50 < 94.5% 
94.5% V50 < 99% 
Superior constrictor 
V60 < 80% 
80% < V60 < 84% 
84% < V60 < 88% 
Superior constrictor 
V65 < 70% 
70% < V65 < 73.5% 73.5% < V65 < 77%
Parotids 
V30 < 50% 
50% < V30 < 52.5% 52.5% < V30 < 55%
Esophagus 
Max Dose 45Gy 
Max Dose 47.3Gy 
Max Dose 49.5Gy 
Brachial plexus 
Max Dose 60Gy 
Max Dose 63Gy 
Max Dose 66Gy 
Inner Ears 
Mean Dose 40Gy 
Mean Dose 42.5Gy 
Mean Dose 45Gy 

Version:  March 4, 2013 
 
26 
 
 
 
5.11 
Radiation Therapy Toxicity Adjustments  
 
5.11.1 Treatment Interruptions  
Interruptions in radiotherapy are strongly discouraged based on the well known correlation 
between overall treatment time and outcome especially in the context of IMRT alone. 
 
5.12 
Toxicity Reporting Guidelines  
5.12.1 For both acute and late effect, the NCI CTCAE Version 4.0 will be used (Appendix 
1). All events will be recorded and loaded into software that is routinely used for clinical 
purposes in our Department called Mosaiq (v1.6 IMPAC, Sunnyvale, California).   
 
5.12.2 The Head and Neck Cancer specific module of the MD Anderson Symptom Index 
(MDASI-HN)(Appendix 2) and the Xerostomia questionnaire (Appendix 3) will be used as 
patient-reported outcome instruments48,49 
 
5.12.3 The swallowing related instruments (see 1.6) are: Penetration/Aspiration scale 
(Appendix 4); Montreal Cognitive Assessment (Appendix 5); MD Anderson Dysphagia 
Inventory (MDADI)(Appendix 6).  
5.12.4 All life-threatening (grade 4) toxicities from protocol treatment will be reported to 
the PI within 24 hours of discovery. Institutional guidelines will be followed in reporting 
serious adverse events to the IRB. 
 
6 
DRUG THERAPY  
 
Chemotherapy will be reserved for patients with T3 lesions (3.1.1) and/or clinically staged nodal 
disease greater than N1 and/or evidence of microscopic extracapsular extension after neck 
surgery (T3 and/or N2a > 5cm, N2b, N2c, N3 stage cancer or Nx with ECE). Chemotherapy 
consists of single agent cisplatin or carboplatin. 
 
6.1 
Cisplatin 
 
6.1.1 The first dose of cisplatin, 40mg/m2 IV, will be administered within the first 3 days of 
the start of RT and repeated weekly for the first 3 weeks and last 3 weeks of RT. Patients will 
not receive chemotherapy during week 4 of treatment. The last dose of chemotherapy may be 
given up to one week following completion of RT. If RT is held, cisplatin will also be held.   
 
 
 
6.1.2 Hydration: Patients should be adequately hydrated with 1-2 liters of fluid PO in the 24 
hours prior to and post cisplatin administration. 
 
 
 
6.1.3 Immediately prior to the cisplatin administration, patients should receive 1 Liter of 
Normal Saline over 1-2 hours. 

Version:  March 4, 2013 
 
27 
 
 
 
 
6.1.4 Cisplatin 40 mg/m2 should be mixed in 1 liter normal saline and infused over 2-3 hours. 
Cisplatin is a commercially available agent. 
 
 
 
6.1.5 Antiemetics: Antiemetics must be given in conjunction with cisplatin. Antiemetic 
selection will be at the discretion of the treating physician and is recommended with each 
chemotherapy infusion. These include dolasetron, ondansetron, dexamethasone, lorazepam, 
or procholperazine. Therapy for prevention of delayed emesis may be considered. 
 
6.2 
Cisplatin Dose Modification for toxicity 
 
6.2.1 Hematologic: Patients must have an ANC ≥ 1000 /mm3 and platelets >100,000/ mm3 
prior to receiving cisplatin.  If the patient’s counts are below these levels, cisplatin will not be 
given and weekly dosing reinstituted the following week as long as counts are within 
acceptable treatment parameters. Held doses will not be made up. Grade 4 neutropenia (ANC 
<500/mm3) or febrile neutropenia requiring hospitalization for antibiotics or grade 4 
thrombocytopenia (platelets <25,000/ mm3) require a dose reduction of cisplatin of 25%.   
 
 
 
6.2.2 Neurotoxicity: Patients developing grade 2 sensory or motor neuropathy or > grade 2 
hearing loss will have cisplatin discontinued and carboplatin substituted (see 6.3.4).  
 
6.2.3 Nephrotoxicity: Measurement of serum creatinine is required before each treatment 
with cisplatin and must be within normal limits.  Serum creatinine above the upper limit of 
normal necessitates creatinine clearance assessment using the modified Cockgroft-Gault 
formula. If the patient’s calculated creatinine clearance is less than 60 ml/min, cisplatin will 
be held and additional hydration will be given.  Serum creatinine and creatinine clearance 
should be repeated weekly and/or as needed after additional hydration is given.  Cisplatin 
may be reinstituted, under the discretion of the treating physician, if the CCl improves to 
greater than or equal to 60 ml/min.  If the creatinine clearance does not improve despite 
additional hydration, cisplatin will be substituted with carboplatin (see section 6.3.4).  Held 
doses will not be made up. 
 
6.2.4 Switch to Carboplatin: In case of any of the followings, cisplatin will be substituted to 
carboplatin: creatinine clearance < 60 ml/min; ototoxicity; peripheral sensory or motor 
neuropathy grade 2. Weekly carboplatin dosing would be at AUC=2. Dose modifications of 
cisplatin and carboplatin will be under the discretion of the treating medical oncologist. If the 
patient has peripheral neuropathy > grade 1, and/or frequency hearing loss that interferes 
with activities of daily living, cisplatin can be dose reduced or substituted with carboplatin.    
 
6.3 
Carboplatin 
 
6.3.1 Carboplatin may be administered as a substitution for cisplatin when cisplatin-related 
toxicities occur as described in 6.3 Cisplatin Dose Modification for Toxicity or when patients 
present with >grade 2 sensory or motor neuropathy, >grade 2 hearing loss, or <60 ml/min 
calculated creatinine clearance at baseline.   
 

Version:  March 4, 2013 
 
28 
 
 
6.3.2 The first dose of carboplatin, AUC=2 IV, will be administered within the first 3 days 
of the start of RT and repeated weekly during the 7 weeks of RT. The last dose of 
chemotherapy may be given up to one week following completion of RT. If RT is held, 
carboplatin will also be held.   
 
6.4 
Carboplatin Dose Modification for Toxicity  
 
6.4.1 Hematologic: Patients must have an ANC ≥ 1000 /mm3 and platelets >100,000/ mm3 
prior to receiving carboplatin. If the patient’s counts are below these levels, carboplatin will 
not be given and weekly dosing reinstituted the following week as long as counts are within 
acceptable treatment parameters. Held doses will not be made up. Grade 4 neutropenia (ANC 
<500/mm3) or febrile neutropenia requiring hospitalization for antibiotics or grade 4 
thrombocytopenia (platelets <25,000/ mm3) require a dose reduction of carboplatin of 25%.   
 
 
 
6.4.2 Nephrotoxicity: Serum creatinine and creatinine clearance should be checked weekly 
before each treatment with carboplatin and/or as needed to calculate appropriate carboplatin 
dose and assess hydration status.   
 
7 
SURGERY  
7.1 Upfront neck surgery (excisional biopsy or neck dissection) is at the discretion of the 
surgeon.  
 
7.2 Surgery at the primary tumor is expected to consist of an incisional biopsy for diagnostic 
purposes only. An excisional surgery (i.e. tonsillectomy) is allowed if other gross disease is 
present e.g. neck lymph nodes. Patient will be also staged according to the clinical stage before 
any surgical procedure.   
 
7.3 Surgery should be performed for persistent tumor following RT as documented by PET/CT 
(CT with thin slices and i.v. contrast for the HN part) at 8-12 weeks after the end of the 
treatment, or at the discretion of the surgeon. Suspected residual disease is defined as persistent 
FDG uptake at the site of the primary tumor qualitatively assessed by comparing to background 
and corresponding abnormal tissue on CT. Surgery is recommended for PET/CT positive 
residual disease, as described. A selective neck dissection is appropriate for patients with 
positive residual disease in levels II-IV and levels IB and V were initially negative. A 
comprehensive neck dissection is recommended in the other cases. 
 
8 
PATHOLOGY  
Tumors will be evaluated for the presence of HPV16 DNA by use of the in situ hybridization – 
catalyzed signal amplification method for biotinylated probes (GenPoint; Dako, Carpinteria, 
CA)50. The expression status of p16 is strongly correlated with tumor HPV status and therefore it 
will be evaluated by immunohistochemistry, as previously described51. For tumors positive at 
P16 but negative for HPV16, a wide spectrum in-situ hybridization test will be run to exclude 
infection by less frequent subtypes of HPV (30, 31…). In the latter case, specimens will still be 
considered HPV positive and therefore eligible for the study.

Version:  March 4, 2013 
 
29 
 
9 
 PATIENT ASSESSMENTS 
9.1 
Patient Assessments 
Table 9. 
 
Pretreatment
During treatment1  Follow up2
Weight & PS  
X 
X 
X 
History & Physical  
X 
 
 
Dental Evaluation 
X 
 
 
Nutritional evaluation 
X3 
X3 
 
CBC with diff. and platelet count  
X 
X15  
 
CMP18 
X 
X 15 
 
Creatinine Clearance 
X 
X17 
 
Pregnancy Test  
X16 
 
 
Thyroid Function Test (TSH)  
X 
 
X 
PET/CT (CT w contrast) 
X 
 
X5 
MRI of head and neck 
X6 
 
X5 
Toxicity Evaluation7 
X 
X 
X 
Flexible fibroscope10 
X 
 
X 
Audiogram14 
X 
X 
X 
Speech therapy evaluation12 
X 
X8 
X9  
MBSS  
 
 
X11  
Biopsy 
X13 
 
X13 
Appendix 2 & 3 
X 
X 
X 
 
1. Weekly during radiotherapy  
2. Follow-up will be performed 6-8 weeks after the end of RT (+ or – 7 days), at 3 months (+ or - 14 days) after the 
end of radiotherapy and every 3 months thereafter for the first two years; then every 6 months (+ or – 30 days) 
during years 3 to 5  
3. Initial evaluation must be done within a week of starting therapy and then as clinically indicated. On treatment 
nutrition evaluations will be performed as clinically indicated.  
4. Every 6 months for 5 years 
5. PET/CT is required at 10-12 weeks after the end of treatment to evaluate response. Afterwards a PET/CT should 
be obtained at the discretion of treating physician.  Alternatively a CT or MRI can be obtained if a PET/CT is not 
approved.  
6.  A pre-study MRI is at the discretion of the treating physician 
7. See 5.12 
8. At approximately the 4th week of treatment 
9. To be performed 6-8 weeks, 6 months, and 12 months after the end of RT 
10. Primary tumor assessment may require the use of a flexible fibroscope as deemed by the treating physician. 
11. To be performed at 6-8 weeks and 12 months even in absence of specific symptoms 
12. The MD Anderson Dysphagia Inventory (MDADI) will be given at each visit; the Montreal Cognitive 
Assessment (MCA) will only be given at baseline and 6-8 weeks after completion 
13. Pretreatment Biopsy can be done outside JH provided that pathology blocks are submitted at JH for review and 
HPV testing; During follow up, any suspicious mucosal lesion in the upper aerodigestive tract should trigger a 
search for recurrent disease that may or may not include a biopsy; in the latter case, the biopsy can be done at JH or 
outside, but, again, the pathology specimen must be reviewed at JH. No further HPV testing is necessary on the 
repeat biopsy. 
14. Pre-study audiogram is required if the inner ear is to be irradiated at a dose ≥  40 GY (the audiogram should be 
done before or within 1 week after starting treatment); subsequent audiograms are under the discretion of the 
treating physician as indicated by symptoms. 

Version:  March 4, 2013 
 
30 
 
15. Only if concomitant chemotherapy is part of the treatment 
16. Only for women of child bearing potential 
17. Creatinine clearance (CCL) required weekly for patient receiving chemotherapy. 
18. CMP to include: sodium, potassium, glucose, calcium, magnesium, BUN, serum creatinine, total protein, 
albumin, alkaline phosphatase, total bilirubin, AST and ALT 
 
 
9.2 
Evaluations  
9.2.1 Every Follow-up Visit 
 All patients will enter a common follow-up program following completion of 
radiotherapy. Routine follow-up care: complete head and neck examination, including 
mirror and/or endoscopic examination (flexible fibroscope if deemed clinically 
necessary by the treating physician), 
 Performance Status, Weight, and Toxicity Notation  
 Follow up speech-language pathology evaluation will include clinical swallow 
assessment and inter incisors distance measurement. Prophylactic exercises will be 
reviewed as well as the importance of oral hygiene and strategies to ameliorate 
xerostomia.  Patients’ ability to follow through with recommended exercises and 
strategies will be recorded. Documentation of the presence of a gastrostomy feeding 
tube, estimated percent of oral alimentation/hydration via the feeding tube; estimated 
percentage of PO intake at baseline. In addition, at the first post-treatment follow up 
examination (6-8 wks), a MBSS will be obtained, even in absence of specific 
symptoms as well as a Montreal Cognitive Assessment (MCA).    
 
9.2.2 Studies  
 Biopsy: Any suspicious mucosal lesion in the upper aerodigestive tract; pharyngeal 
pain referred to the ear should trigger a search for recurrent disease; any firm node 
that persists longer than four weeks; epistaxis; chronic nasal congestion though not to 
be due to radiation mucosal changes. 
 PET/CT as per 9.1 
 Modified barium swallow test will be obtained 6-8 weeks after completion of 
treatment. Subsequently, a MBSS will be obtained only if clinically indicated. 
 Audiogram: Pre-RT if the inner ear receives a mean dose ≥40 Gy, or if any hearing 
loss, vertigo or tinnitus occur. Subsequent audiograms will be conducted at the 
discretion of treating physician as indicated by patient reported symptoms  
 
9.3 
Response Criteria  
9.3.1 Tumor Response Measurements (RECIST Criteria) 
The use of the flexible fibroscope may be used for tumor measurement. This will   be 
determined by the treating physician. 
 
All tumor measurements must be recorded in centimeters and should consist of the 
longest perpendicular diameters. In no case will complete response be reported unless all 
clinically demonstrable disease has disappeared.  
 

Version:  March 4, 2013 
 
31 
 
9.3.1.1 Complete Response (CR)  
No measurable tumor is present on clinical and radiological examination.  
 
9.3.1.2 Partial Response (PR)  
A greater than 50% decrease in the product of the longest diameter multiplied by 
its perpendicular diameter when compared to the initial ‘on-study product, 
providing there is no increase greater than 25% of any area of known disease or 
the appearance of any new lesions.  
 
9.3.1.3 Minor Response (MR)  
The difference between products is less than 50 percent of the initial product. No 
new lesions have appeared.  
 
9.3.1.4 Stable Disease (SD)  
Tumor size has not changed; no progression, no new lesions.  
 
9.3.1.5 Progression (PD)  
The second product shows a greater than 25 percent increase over the initial 
product, or appearance of new lesions.  
 
9.4 
Definition of locoregional control 
9.4.1 A patient is defined as locoregionally controlled if he achieves a CR at both the 
primary site and the neck within 10-12 weeks from treatment end as previously defined 
(7.2, 9.3.1.1).  
 
9.4.2 Patients who shows a CR at the primary site and a <CR (residual disease) in the 
neck at re-evaluation imaging 8-10 weeks, are evaluated for neck surgery (7.2). Patients 
who are cleared for residual disease in the neck by surgery are still considered having 
achieved a CR after treatment provided there is no residual disease left after surgery 
 
9.4.3 Patients who fail to achieve a CR with or without neck surgery are scored as 
failures at day 1 of radiotherapy. 
 
9.4.4 In order to remain controlled, patients who achieve a CR with or without neck 
surgery must remain cancer free at both T and N during each subsequent follow up 
examination (9.2.1).Treatment failure is defined as the documented (biopsy-proven) 
reappearance of disease at the primary site and/or the neck.  
 
9.4.5 Distant disease is defined as the clinical or radiological appearance of metastases 
below the clavicles. 
   
9.5 
Scoring of toxicity (see also 5.11) 
9.5.1 `Severe` toxicity is considered the one grade 3 or more in the CTCAE 4.0 
(Appendix 1). Therefore, event is considered the presence of grade 3+ toxicity.  

Version:  March 4, 2013 
 
32 
 
 
9.5.2 Similarly, in a 0-10 scale, 7 or more is considered `severe` (Appendix 2 and 3) 48.   
 
9.6 
Criteria for Removal from Treatment  
9.6.1 Progression of disease while on treatment.  
 
9.6.2 Sustained severe radiation mucositis resulting in dehydration and poor nutrition 
unresponsive to tube feeding and break from radiation for up to 2 weeks. Every effort 
should be made to sustain the patient so as to avoid such complications. Should the 
patient be removed from study, surgical removal followed by radiation post-operatively 
may be attempted.  
 
9.6.3 Patients’ wishes to stop participation on the trial.  
 
10 
STATISTICAL CONSIDERATIONS  
10.1 
Sample Size 
The accrual rate for this study is expected to be approximately 10 patients per year, over a 6-year 
accrual period. This would yield an expected sample size of 60 patients.  The primary objective 
of this study is to estimate the prevalence of toxicity and efficacy two years following treatment 
administration. We expect approximately 15% of patients to die before reaching two years post-
treatment, so our sample size for evaluation of our primary objective has been adjusted to 50 
patients. The goal of this study is to demonstrate a maximum grade 3+ toxicity rate of 15% 
between six months and two years after treatment administration and a minimum locoregional 
tumor control rate (efficacy) of 85%.  The table below shows the precision we have to estimate 
these endpoints with a sample size of 50 patients. 
 
Endpoint 
Prevalence 
Exact 95% Confidence 
Interval 
Precision (Half the width of the 
confidence interval) 
Toxicity 
2% 
6% 
10% 
14% 
0.05 – 11% 
1 – 17% 
3 – 22% 
6 – 27% 
5.5% 
8% 
9.5% 
10.5% 
Efficacy 
84% 
90% 
94% 
71 – 93% 
78 – 97% 
83 – 99% 
11% 
9.5% 
8% 
 
The locoregional tumor control rate in this patient population is expected to be at least 85%.  We 
will ensure that this treatment does not reduce toxicity at the expense of efficacy.  At the same 
time, we will monitor for excess toxicity.  If convincing evidence develops that: 
 Locoregional control failure rate exceeds 25%; or 
 Prevalence of new grade 3+ toxicities six months post-treatment exceeds 25%, the study 
will stop pending a data safety monitoring committee review.  The complete stopping 

Version:  March 4, 2013 
 
33 
 
guideline scenarios are shown in the table below, with the proportion of toxicities and 
failures being considered for the first 10, 20, 30 and 40 patients enrolled. For example, if 
9 of the first 20 patients have a grade 3+ toxicity six months after treatment, the study 
will stop.  If 9 patients have either a grade 3+ toxicity or fail, e.g., 4 have toxicity and 5 
fail, the trial will not stop.  Once the 40th patient reaches six months of follow-up, we 
expect to have enrolled 48 out of the total 60 patients on the study.  At this point, 
monitoring for excess toxicity or failures will stop, as the trial’s accrual phase will nearly 
be completed.  The upper bound for the confidence intervals is 100%.   
 
 
Toxicity 
[Locoregional 
Control Failure 
Rate] 
Number of patients who 
develop a toxicity [fail] 
Number 
of 
patients 
enrolled 
Lower bound of exact one-
sided 
90% 
confidence 
interval 
25% 
5 
9 
12 
15 
10 
20 
30 
40 
26.7% 
29.3% 
27.7% 
27.1% 
 
10.2 
Monitoring for Efficacy and Toxicity  
(Data Safety Monitoring Committee [DSMC]) 
 
The principal investigators (Drs. Quon and Forastiere), the Lead research nurse (Kelly Szajna), 
and the statistician (Amanda Blackford) will make up the Data Safety and Monitoring 
Committee for this trial. This is a Level 1 trial and will be monitored by The Johns Hopkins 
Clinical Research Office. The function and role of the Data Safety Monitoring Committee will 
review the protocol per their institutional standards to help ensure that the trial is running safely. 
 
10.3 
Analysis of Endpoints 
10.3.1. To achieve a prevalence of grade 3+ toxicities between six months and two years 
post-treatment <15% while maintaining a locoregional tumor control of at least 85% 
during the same time interval.   
 
The primary endpoints, prevalence of toxicity and locoregional control rate, will be 
reported for all patients with an exact 95% confidence interval. 
 
10.3.2. To determine the nature and prevalence of side effects at different time intervals 
and describe their relationship to pre-treatment function (toxicity) and local dose and 
treated volume. 
 
Patients will be grouped by whether they had none or a grade 0-2 toxicity versus a grade 
3+ toxicity.  We will tabulate the frequency of patients in each group by a dichotomous 
measure of dose and tests for differences with a Chi-square or Fisher’s exact test.  
Patients will also be grouped dichotomously by the number of side effects experienced 

Version:  March 4, 2013 
 
34 
 
and frequencies will be compared to dose category and toxicity category using Chi-
square or Fisher’s exact tests. 
 
10.3.3. To determine the quality of life of surviving patients. 
 
The results of the Head and Neck MD Anderson Symptom Inventory (MDASI-HN) will 
be calculated for each patient.  The mean score will be reported with a 95% confidence 
interval.  The range and quartiles of the distribution of scores will also be reported. 

Version:  March 4, 2013 
 
35 
 
11 
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Hermans R, Van den Bogaert W, Rijnders A, et al. Value of computed tomography as 
outcome predictor of supraglottic squamous cell carcinoma treated by definitive radiation 
therapy. Int J Radiat Oncol Biol Phys 1999;44:755-765. 
19. 
Studer G, Lutolf UM, El-Bassiouni M, et al. Volumetric staging (VS) is superior to TNM 
and AJCC staging in predicting outcome of head and neck cancer treated with IMRT. 
Acta Oncol 2007;46:386-394. 
20. 
Fletcher GH. Textbook of Radiotherapy. 3rd edition (PA). Lea & Febiger Publishers. 
1980. 
21. 
Silva P, Slevin NJ, Sloan P, et al. Prognostic significance of tumor hypoxia inducible 
factor-1alpha expression for outcome after radiotherapy in oropharyngeal cancer. Int J 
Radiat Oncol Biol Phys 2008;72:1551-1559. 
22. 
Aebersold DM, Burri P, Beer KT, et al. Expression of hypoxia-inducible factor-1alpha: a 
novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. 
Cancer Res 2001;61:2911-2916. 
23. 
Worden FP, Kumar B, Lee JS, et al. Chemoselection as a strategy for organ preservation 
in advanced oropharynx cancer: response and survival positively associated with HPV16 
copy number. J Clin Oncol 2008;26:3138-3146. 
24. 
Pignon JP, le Maitre A, Bourhis J. Meta-Analyses of Chemotherapy in Head and Neck 
Cancer (MACH-NC): an update. Int J Radiat Oncol Biol Phys 2007;69:S112-114. 
25. 
Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and 
neck cancers: a comparative analysis of concurrent postoperative radiation plus 
chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 
2005;27:843-850. 
26. 
Harari PM, Wheeler DL, Grandis JR. Molecular target approaches in head and neck 
cancer: epidermal growth factor receptor and beyond. Semin Radiat Oncol 2009;19:63-
68. 
27. 
Eisbruch A, Schwartz M, Rasch C, et al. Dysphagia and aspiration after 
chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and 
can they be spared by IMRT? Int J Radiat Oncol Biol Phys 2004;60:1425-1439. 
28. 
Rosenthal DI, Lewin JS, Eisbruch A. Prevention and treatment of dysphagia and 
aspiration after chemoradiation for head and neck cancer. J Clin Oncol 2006 ;24 :2636-
2643. 
29. 
Nguyen NP, Frank C, Moltz CC, et al. Aspiration rate following chemoradiation for head 
and neck cancer: an underreported occurrence. Radiother Oncol 2006;80:302-306. 
30. 
Goguen LA, Posner MR, Norris CM, et al. Dysphagia after sequential chemoradiation 
therapy for advanced head and neck cancer. Otolaryngol Head Neck Surg 2006;134:916-
922. 
31. 
de Arruda FF, Puri DR, Zhung J, et al. Intensity-modulated radiation therapy for the 
treatment of oropharyngeal carcinoma: the Memorial Sloan-Kettering Cancer Center 
experience. Int J Radiat Oncol Biol Phys 2006;64:363-373. 

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32. 
Machtay M, Moughan J, Trotti A, 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;26:3582-3589. 
33. 
Gunn GB, Endres E, Sormani MP, et al. A Phase I-II Study of Accelerated 
Hyperfractionated IMRT Alone for Intermediate T-Stage Oropharyngeal Carcinoma. Int 
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34. 
Eisbruch A. Reducing xerostomia by IMRT: what may, and may not, be achieved. J Clin 
Oncol 2007;25:4863-4864. 
35. 
Rosenthal DI, Chambers MS, Fuller CD, et al. Beam Path Toxicities to Non-Target 
Structures During Intensity-Modulated Radiation Therapy for Head And Neck Cancer. 
Int J Radiat Oncol Biol Phys 2008. 
36. 
Withers HR, Peters LJ, Taylor JM, et al. Late normal tissue sequelae from radiation 
therapy for carcinoma of the tonsil: patterns of fractionation study of radiobiology. Int J 
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Shen Z, Popovtzer A, Cao Y, et al. MRI based Dose-response Relationships for the 
Pharyngeal Constrictor (PC) Muscles after Chemo-RT of Head and Neck (HN) Cancer. 
Int J Radiat Oncol Biol Phys 2008;72:S383. 
38. 
Le YS, G; McNutt, T. A Dosimetric Study Comparing Different Strategies to de-Escalate 
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worth in advanced head and neck cancer? Int J Radiat Oncol Biol Phys 2007;68:1491-
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Forastiere AA, Ang KK, Brizel D, et al. Head and neck cancers. J Natl Compr Canc 
Netw 2008;6:646-695. 
41. 
Merlano M, Vitale V, Rosso R, et al. Treatment of advanced squamous-cell carcinoma of 
the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 
1992;327:1115-1121. 
42. 
Sanguineti G, Califano J, Stafford E, et al. Defining the Risk of Involvement for Each 
Neck Nodal Level in Patients With Early T-Stage Node-Positive Oropharyngeal 
Carcinoma. Int J Radiat Oncol Biol Phys 2009. 
43. 
van Asselen B, Dehnad H, Raaijmakers CP, et al. The dose to the parotid glands with 
IMRT for oropharyngeal tumors: the effect of reduction of positioning margins. 
Radiother Oncol 2002;64:197-204. 
44. 
Feng FY, Kim HM, Lyden TH, et al. Intensity-modulated radiotherapy of head and neck 
cancer aiming to reduce dysphagia: early dose-effect relationships for the swallowing 
structures. Int J Radiat Oncol Biol Phys 2007 ;68 :1289-1298. 
45. 
Sanguineti G, Adapala P, Endres EJ, et al. Dosimetric predictors of laryngeal edema. Int 
J Radiat Oncol Biol Phys 2007;68:741-749. 
46. 
Kulbersh BD, Rosenthal EL, McGrew BM, et al. Pretreatment, preoperative swallowing 
exercises may improve dysphagia quality of life. Laryngoscope 2006;116:883-886. 
47. 
Sanguineti G, Sosa M, Culp L, et al. Is it feasible to spare part of the mucosa with IMRT 
and does it matter. Int J Radiat Oncol Biol Phys 2004;60:S517-518. 
48. 
Rosenthal DI, Mendoza TR, Chambers MS, et al. The M. D. Anderson symptom 
inventory-head and neck module, a patient-reported outcome instrument, accurately 
predicts the severity of radiation-induced mucositis. Int J Radiat Oncol Biol Phys 
2008;72:1355-1361. 

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49. 
Meirovitz A, Murdoch-Kinch CA, Schipper M, et al. Grading xerostomia by physicians 
or by patients after intensity-modulated radiotherapy of head-and-neck cancer. Int J 
Radiat Oncol Biol Phys 2006;66:445-453. 
50. 
Huang CC, Qiu JT, Kashima ML, et al. Generation of type-specific probes for the 
detection of single-copy human papillomavirus by a novel in situ hybridization method. 
Mod Pathol 1998;11:971-977. 
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Begum S, Cao D, Gillison M, et al. Tissue distribution of human papillomavirus 16 DNA 
integration in patients with tonsillar carcinoma. Clin Cancer Res 2005;11:5694-5699. 
 
 

Version:  March 4, 2013 
 
39 
 
APPENDIX 1 CTCAE V4.0 TOXICITY 
 
Grade 
1 
2 
3 
4 
5 
Gastrointestinal 
disorders: 
Mucositis oral  
 
Definition: A disorder 
characterized by 
inflammation of the oral 
mucosal. 
Asymptomatic 
or mild 
symptoms; 
intervention not 
indicated 
Moderate pain; 
not interfering 
with oral intake; 
modified diet 
indicated 
Severe pain; 
interfering with 
oral 
intake 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
Injury, poisoning, & 
procedural 
complications: 
Skin Radiation recall 
reaction 
(dermatologic) 
 
Definition: A finding of 
acute skin inflammatory 
reaction caused by 
drugs, especially 
chemotherapeutic 
agents, for weeks or 
months following 
radiotherapy. The 
inflammatory reaction 
is confined to the 
previously irradiated 
skin and the symptoms 
disappear after the 
removal of the 
pharmaceutical agent. 
 
OR 
Injury, poisoning, & 
procedural 
complications: 
Dermatitis radiation 
(Definition: A finding of 
cutaneous inflammatory 
reaction occurring as a 
result of exposure to 
biologically effective 
levels of ionizing 
radiation). 
Faint erythema 
or dry 
desquamation 
Moderate to 
brisk erythema; 
patchy moist 
desquamation, 
mostly confined 
to skin folds 
and creases; 
moderate edema 
Moist 
desquamation in 
areas other than 
skin folds and 
creases; 
bleeding 
induced by 
minor trauma or 
abrasion 
Life-threatening 
consequences; 
skin necrosis or 
ulceration of full 
thickness 
dermis; 
spontaneous 
bleeding from 
involved site; 
skin 
graft indicated 
Death 

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40 
 
Grade 
1 
2 
3 
4 
5 
Musculoskeletal & 
connective tissue 
disorders: 
Superficial soft tissue 
fibrosis 
 
Definition: A disorder 
characterized by fibrotic 
degeneration of the 
superficial soft tissues. 
Mild induration, 
able to move 
skin parallel to 
plane (sliding) 
and 
perpendicular to 
skin (pinching 
up) 
Moderate 
induration, able 
to 
slide skin, 
unable to pinch 
skin; 
limiting 
instrumental 
ADL 
Severe 
induration; 
unable to slide 
or pinch skin; 
limiting joint or 
orifice 
movement (e.g. 
mouth, anus); 
limiting self care 
ADL 
Generalized; 
associated with 
signs or 
symptoms of 
impaired 
breathing or 
feeding 
Death 
Gastrointestinal 
disorders: 
Dry mouth 
 
Definition: A disorder 
characterized by reduced 
salivary flow in the oral 
cavity. 
Symptomatic 
(e.g., dry or 
thick (saliva) 
without 
significant 
dietary 
alteration; 
unstimulated 
saliva 
flow >0.2 
ml/min  
Moderate 
symptoms; oral 
intake 
alterations (e.g., 
copious water, 
other lubricants, 
diet limited to 
purees and/or 
soft, moist 
foods); 
unstimulated 
saliva 0.1 to 0.2 
ml/min 
Inability to 
adequately 
aliment orally; 
tube feeding or 
TPN 
indicated; 
unstimulated 
saliva 
<0.1 ml/min  
 
 
 Nervous system 
disorders: 
Dysgeusia 
 
Definition: A disorder 
characterized by 
abnormal sensual 
experience with the taste 
of foodstuffs; it can be 
related to a decrease in 
the sense of smell. 
Altered taste but 
no change in 
diet 
 
Altered taste 
with change in 
diet (e.g., oral 
supplements); 
noxious or 
unpleasant taste; 
loss of taste 
 
 
 
Gastrointestinal 
disorders: 
Nausea 
 
Definition: A disorder 
characterized by a 
queasy sensation and/or 
the urge to vomit. 
Loss of appetite 
without 
alteration in 
eating habits 
 
Oral intake 
decreased 
without 
significant 
weight loss, 
dehydration or 
malnutrition 
Inadequate oral 
caloric or fluid 
intake; tube 
feeding, TPN, or 
hospitalization 
indicated  
 
Death 
 
Gastrointestinal 
disorders: 
Vomiting 
 
Definition: A disorder 
characterized by the 
1 – 2 episodes 
(separated by 5 
minutes) in 24 
hrs 
3 – 5 episodes 
(separated by 5 
minutes) in 24 
hrs 
>=6 episodes 
(separated by 5 
minutes) in 24 
hrs; tube 
feeding, 
TPN or 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 

Version:  March 4, 2013 
 
41 
 
reflexive act of ejecting 
the contents of the 
stomach through the 
mouth. 
hospitalization 
indicated 
Metabolism & 
nutrition disorders: 
Dehydration 
 
Definition: A disorder 
characterized by 
excessive loss of water 
from the body. It is 
usually caused by severe 
diarrhea, vomiting or 
diaphoresis. 
Increased oral 
fluids indicated; 
dry mucous 
membranes; 
diminished skin 
turgor 
IV fluids 
indicated <24 
hrs 
IV fluids or 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Gastrointestinal 
disorders: 
Dysphagia 
 
Definition: A disorder 
characterized by 
difficulty in swallowing. 
symptomatic, 
able to eat 
regular diet 
Symptomatic 
and altered 
eating/swallowi
ng 
Severely altered 
eating/swallowi
ng; tube feeding 
or TPN or 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Respiratory, thoracic, 
& mediastinal 
disorders: 
Aspiration 
 
Definition: A disorder 
characterized by 
inhalation of solids or 
liquids into the lungs. 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Altered eating 
habits; coughing 
or choking 
episodes after 
eating or 
swallowing; 
medical 
intervention 
indicated (e.g., 
suction or 
oxygen)) 
Dyspnea and 
pneumonia 
symptoms (e.g., 
aspiration 
pneumonia); 
hospitalization 
indicated; 
unable to 
aliment 
orally 
Life-threatening 
respiratory or 
hemodynamic 
compromise; 
intubation or 
urgent 
intervention 
indicated 
Death 
Respiratory, thoracic, 
& mediastinal 
disorders: 
Cough 
 
Definition: A disorder 
characterized by sudden, 
often repetitive, 
spasmodic contraction of 
the thoracic cavity, 
resulting in violent 
release of air from the 
lungs and usually 
accompanied 
by a distinctive sound. 
Mild symptoms; 
nonprescription 
intervention 
indicated 
Moderate 
symptoms, 
medical 
intervention 
indicated; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self 
care ADL 
 
 

Version:  March 4, 2013 
 
42 
 
Gastrointestinal 
disorders: 
Esophageal stenosis 
 
Definition: A disorder 
characterized by a 
narrowing of the lumen 
of the esophagus. 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Symptomatic; 
altered GI 
function 
Severely altered 
GI function; 
tube feeding; 
hospitalization 
indicated; 
elective 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
urgent operative 
intervention 
indicated 
Death 
Investigations: 
Weight loss 
 
Definition: A finding 
characterized by a 
decrease in overall body 
weight; for pediatrics, 
less than the baseline 
growth curve. 
5 to <10% from 
baseline; 
intervention not 
indicated 
10 - <20% from 
baseline; 
nutritional 
support 
indicated 
>=20% from 
baseline; tube 
feeding or TPN 
indicated 
 
 
Infections & 
infestations: 
Wound infection 
 
Definition: A disorder 
characterized by an 
infectious process 
involving the wound. 
 
Localized; local 
intervention 
indicated (e.g., 
topical 
antibiotic, 
antifungal, or 
antiviral) 
IV antibiotic, 
antifungal, or 
antiviral 
intervention 
indicated; 
radiologic or 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Blood & lymphatic 
system disorders: 
Febrile neutropenia 
 
Definition: A disorder 
characterized by a 
decrease in neutrophils 
associated with fever. 
 
 
present 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Blood & lymphatic 
system disorders: 
Anemia 
 
Definition: A disorder 
characterized by an 
reduction in the amount 
of hemoglobin in 100 ml 
of blood. Signs and 
symptoms of anemia 
may include pallor of the 
skin and mucous 
membranes, shortness of 
breath, palpitations of 
the heart, soft systolic 
Hemoglobin 
(Hgb) <LLN – 
10.0 g/dL; 
<LLN – 6.2 
mmol/L; <LLN 
–100 g/L 
Hgb <10.0 – 8.0 
g/dL; <6.2 – 4.9 
mmol/L; <100 – 
80g/L 
Hgb <8.0 – 6.5 
g/dL; <4.9 – 4.0 
mmol/L; <80 – 
65 g/L; 
transfusion 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 

Version:  March 4, 2013 
 
43 
 
murmurs, lethargy, and 
fatigability. 

Version:  March 4, 2013 
 
44 
 
 
Investigations: 
White blood cell 
decreased  
 
Definition: A finding 
based on laboratory test 
results that indicate an 
decrease in number of 
white blood cells in a 
blood specimen. 
<LLN – 
3000/mm3; 
<LLN – 3.0 x 
10e9 /L 
<3000 – 
2000/mm3; <3.0 
– 2.0 x 10e9 /L 
<2000 – 
1000/mm3; <2.0 
– 1.0 x 10e9 /L 
<1000/mm3; 
<1.0 x 10e9 /L 
Death 
Investigations: 
Neutrophil count 
decreased  
 
Definition: A finding 
based on laboratory test 
results that indicate a 
decrease in number of 
neutrophils in a blood 
specimen. 
<LLN – 
1500/mm3; 
<LLN – 1.5 x 
10e9 /L 
<1500 – 
1000/mm3; <1.5 
– 1.0 x 10e9 /L 
<1000 – 
500/mm3; <1.0 
– 0.5 x 10e9 /L 
<500/mm3; <0.5 
x 10e9 /L 
Death 
Investigations: 
Platelet count 
decreased  
 
Definition: A finding 
based on laboratory test 
results that indicate a 
decrease in number of 
platelets in a blood 
specimen. 
<LLN - 
75,000/mm3; 
<LLN - 75.0 x 
10e9 /L 
<75,000 - 
50,000/mm3; 
<75.0 - 50.0 x 
10e9 /L 
<50,000 - 
25,000/mm3; 
<50.0 - 25.0 x 
10e9 /L 
<25,000/mm3; 
<25.0 x 10e9 /L 
Death 
Respiratory, thoracic, 
& mediastinal 
disorders: 
Voice alteration 
 
Definition: A disorder 
characterized by a 
change in the sound 
and/or speed of the 
voice. 
Mild or 
intermittent 
change from 
normal voice 
Moderate or 
persistent 
change from 
normal voice; 
still 
understandable 
Severe voice 
changes 
including 
redominantly 
whispered 
speech; may 
require frequent 
repetition or 
face-to-face 
contact for 
understandabilit
y; may require 
assistive 
technology 
 
Death 
Respiratory, thoracic, 
& mediastinal 
disorders: 
Laryngeal edema 
 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
Symptomatic; 
medical 
intervention 
indicated (e.g., 
dexamethasone, 
Stridor; 
respiratory 
distress; 
hospitalization 
indicated 
Life-threatening 
airway 
compromise; 
urgent 
intervention 
Death 

Version:  March 4, 2013 
 
45 
 
Definition: A disorder 
characterized by 
swelling due to an 
excessive accumulation 
of fluid in the larynx. 
intervention not 
indicated 
epinephrine, 
antihistamines) 
indicated (e.g., 
tracheotomy or 
intubation) 
Musculoskeletal & 
connective tissue 
disorders: 
Osteonecrosis of jaw 
 
Definition: A disorder 
characterized by a 
necrotic process 
occurring in the bone of 
the mandible. 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Symptomatic; 
medical 
intervention 
indicated (e.g., 
topical agents); 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self 
care ADL; 
elective 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Gastrointestinal 
disorders: 
Dental caries 
One or more 
dental caries, 
not 
involving the 
root 
Dental caries 
involving the 
root 
Dental caries 
resulting in 
pulpitis 
or periapical 
abscess or 
resulting in 
tooth loss 
 
 
Musculoskeletal & 
connective tissue 
disorders: 
Trismus 
 
Definition: A disorder 
characterized by lack of 
ability to open the mouth 
fully due to a decrease in 
the range of motion of 
the muscles of 
mastication. 
Decreased ROM 
(range of 
motion) without 
impaired 
eating 
Decreased ROM 
requiring 
small bites, soft 
foods or 
purees 
Decreased ROM 
with inability 
to adequately 
aliment or 
hydrate orally 
 
 
Nervous system 
disorders:  
Myelitis 
 
Definition: A disorder 
characterized by 
inflammation involving 
the spinal cord. 
Symptoms include 
weakness, paresthesia, 
sensory loss, marked 
discomfort and 
incontinence. 
Asymptomatic; 
mild signs (e.g., 
Babinski’s 
reflex or 
Lhermitte’s 
sign) 
Moderate 
weakness or 
sensory loss; 
limiting 
instrumental 
ADL 
Severe 
weakness or 
sensory loss; 
limiting self care 
ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Nervous system 
disorders: 
Neuralgia 
Mild pain 
Moderate pain; 
limiting 
instrumental 
Severe pain; 
limiting self care 
ADL 
 
 

Version:  March 4, 2013 
 
46 
 
 
Definition: A disorder 
characterized by intense 
painful sensation along a 
nerve or group of nerves. 
ADL 
General disorders & 
administration site 
conditions: 
Fatigue 
 
Definition: A disorder 
characterized by a state 
of generalized weakness 
with a pronounced 
inability to summon 
sufficient energy to 
accomplish daily 
activities. 
Fatigue relieved 
by rest 
Fatigue not 
relieved by rest; 
limiting 
instrumental 
ADL 
Fatigue not 
relieved by rest, 
limiting self care 
ADL 
 
 
Ear & labyrinth 
disorders: 
Hearing impaired 
 
Definition: A disorder 
characterized by partial 
or complete loss of the 
ability to detect or 
understand sounds 
resulting from damage to 
ear structures. 
Adults enrolled 
on a 
monitoring 
program (a 1, 2, 
3, 4, 6 and 8 
kHz 
audiogram): 
threshold shift 
of 15 – 25 dB 
averaged at 2 
contiguous test 
frequencies in at 
least one ear or 
subjective 
change in the 
absence of a 
Grade 1 
threshold shift 
Adults enrolled 
in monitoring 
program (a 1, 2, 
3, 4, 6 and 8 
kHz 
audiogram): 
threshold 
shift of >25 dB 
averaged at 2 
contiguous test 
frequencies in at 
least one ear. 
 Adult not 
enrolled in 
monitoring 
program: 
hearing 
loss but hearing 
aid or 
intervention not 
indicated; 
limiting 
instrumental 
ADL 
Adults enrolled 
in monitoring 
program (a 1, 2, 
3, 4, 6 and 8 
kHz 
audiogram): 
threshold 
shift of >25 dB 
averaged at 3 
contiguous test 
frequencies in 
at least one ear; 
therapeutic 
intervention 
indicated.  
Adults not 
enrolled in 
monitoring 
program: 
hearing loss 
with hearing aid 
or intervention 
indicated; 
Adults: 
profound 
bilateral hearing 
loss (>80 dB at 
2 kHz and 
above); non-
serviceable 
hearing 
 
Ear & labyrinth 
disorders: 
Tinnitus  
 
Definition: A disorder 
characterized by noise in 
the ears, such as ringing, 
buzzing, roaring or 
clicking. 
Mild symptoms; 
intervention 
not indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care 
ADL 
 
 

Version:  March 4, 2013 
 
47 
 
 
 
Neoplasms 
benign,malignant, & 
unspecified: 
Treatment related 
secondary 
Malignancy 
 
Definition: A disorder 
characterized by 
development of a 
malignancy most 
probably as a result of 
treatment for a 
previously existing 
malignancy. 
 
 
Non life-
threatening 
secondary 
malignancy 
Acute life-
threatening 
secondary 
malignancy; 
blast 
crisis in 
leukemia 
Death 
 
Ear & labyrinth 
disorders: 
Vertigo 
 
Definition: A disorder 
characterized by a 
sensation as if the 
external world were 
revolving around the 
patient (objective 
vertigo) or as if he 
himself were revolving 
in space (subjective 
vertigo). 
Mild symptoms 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self 
care ADL 
 
 
Performance status 
(ECOG) 
1 
2 
3 
4 
5 
PEG tube 
No 
Yes 
 
 
 
PO 
No 
Yes 
 
 
 
Admission(s) 
No 
Yes 
# days_______ 
 
 
Weight (kg) 
 
 
 
 
 
Items in grey denote modifications and additions to the original scale 
 

Version:  March 4, 2013 
 
48 
 
APPENDIX 2 – HEAD AND NECK MD ANDERSON SYMPTOM INVENTORY 
(MDASI-HN) 
 

Version:  March 4, 2013 
 
49 
 

Version:  March 4, 2013 
 
50 
 
APPENDIX 3 – XEROSTOMIA QUESTIONNAIRE 
Please circle the one that best applies to you: 
 
1. Rate your difficulty in talking due to dryness 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
BETTER 
 
 
 
 
 
 
 
 
        WORSE 
 
2. Rate your difficulty in chewing due to dryness 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
BETTER 
 
 
 
 
 
 
 
 
        WORSE 
 
3. Rate your difficulty in swallowing solid food due to dryness 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
BETTER 
 
 
 
 
 
 
 
 
        WORSE 
 
4. Rate the frequency of your sleeping problems due to dryness 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
BETTER 
 
 
 
 
 
 
 
 
        WORSE 
 
5. Rate your mouth or throat dryness when eating food 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
BETTER 
 
 
 
 
 
 
 
 
        WORSE 
 
6. Rate your mouth or throat dryness while not eating 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
BETTER 
 
 
 
 
 
 
 
 
        WORSE 
 
7. Rate the frequency of sipping liquids to aid swallowing food 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
BETTER 
 
 
 
 
 
 
 
 
        WORSE 
 
8. Rate the frequency of sipping liquids for oral comfort when not eating  

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0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
BETTER 
 
 
 
 
 
 
 
 
        WORSE 

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APPENDIX 4 – PENETRATION/ASPIRATION SCALE 
 
 
 
Score                                Description of Events  
 
 
 
1.        Material does not enter airway  
 
2.        Material enters the airway, remains above the vocal folds,  
           and is ejected from the airway.  
 
3.        Material enters the airway, remains above the vocal folds,  
           and is not ejected from the airway.  
 
4         Material enters the airway, contacts the vocal folds,  
           and is ejected from the airway.  
 
5.        Material enters the airway, contacts the vocal folds,  
           and is not ejected from the airway.  
 
6.        Material enters the airway, passes below the vocal folds,  
           and is ejected into the larynx or out of the airway.  
 
7.        Material enters the airway, passes below the vocal folds,  
           and is not ejected from the trachea despite effort.  
 
8.        Material enters the airway, passes below the vocal folds,  
           and no effort is made to eject. 
 
 

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APPENDIX 5 – MONTREAL COGNITIVE ASSESSMENT 

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APPENDIX 6 – MD ANDERSON DYSPHAGIA INVENTORY (MDADI) 
 
MDADI 
 

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Index of Abbreviations 
 
3D 
Three Dimensional 
ADLADL 
Activities of Daily Living 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase) 
AUC 
Area Under the Curve 
BED 
Biologically Effective Dose 
Brach Pl 
Brachial Plexus 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Cell Count 
CCL 
Calculated Creatinine Clearance 
CDDP 
Cisplatin 
CHT 
Chemotherapy 
CI 
Confidence Interval 
CONT 
Continued 
CONTR 
Contralateral 
CR 
Complete Response 
CRICOPHAR 
Cricopharyngeous 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical Target Volume 
DB 
Decibel 
Diff 
Differential 
DNA 
Deoxyribonucleic Acid 
DOM 
Dominant 
DSMC 
Data Safety and Monitoring Committee 
DVH 
Dose-Volume Histogram 
e.g. 
Ergo 
ECE 
Extracapsular Extension 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
FEES 
Flexible Endoscopic Evaluation of Swallowing 
GI 
Gastrointestinal 
GLS 
Mitochondrial Glutaminase 
GTV 
Gross Tumor Volume 
Gy 
Gray 
HGB 
Hemoglobin 
HIF-1a 
Hypoxia-Inducible Factor-1a 
HN 
Head and Neck 
HPV 
Human Papillomavirus 
HR 
Hazard Ratio 
HRS 
Hours 

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ICRU 
International Commission on Radiation Units and 
Measurements 
IGRT 
Image Guided Radiotherapy 
IMRT 
Intensity Modulated Radiation Therapy 
INF 
Inferior 
IV 
Intravenous 
JH 
Johns Hopkins 
KG 
Kilogram 
KHZ 
Kilohertz 
LC 
Local Control 
LLN  
Less than the Lower Limits of Normal 
LQED 
Linear Quadratic Equivalent Dose 
LRC 
Locoregional Control 
M 
Muscle 
M 
Metastases 
MASTICAT 
Masticatory Muscles 
MAX 
Maximum  
MBSS 
Modified Barium Swallowing Study 
MCA 
Montreal Cognitive Assessment 
MDACC 
MD Anderson Cancer Center 
MDADI 
MD Anderson Dysphagia Inventory 
MDASI-HN 
MD Anderson Specific Head and Neck Symptom Index 
MID 
Middle 
MOCA 
Montreal Cognitive Assessment 
MR 
Minor Response 
MRI 
Magnetic Resonance Imaging 
MSKCC 
Memorial Sloan Kettering Cancer Center 
N 
Node 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
OAR 
Organs at Risk 
ORO-SCC 
Oropharynx Squamous Cell Carcinoma 
OTT 
Overall Treatment Time 
PD 
Progression 
PEG 
Percutaneous Endoscopic Gastrostomy 
PET 
Positron Emission Tomography 
PI  
Principal Investigator 
PO 
By Mouth 
POST 
After 
PR 
Partial Response 
PS 
Performance Status 
PSA 
Prostate-Specific Antigen 
PTV 
Planning Target Volume 
PT 
Patient 
Q 
Every 

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RC 
Regional Control 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROI 
Region of Interest 
ROM 
Range of Motion 
RT 
Radiation Therapy 
RTOG 
Radiation Therapy Oncology Group 
SD 
Stable Disease 
SEER 
Surveillance Epidemiology and End Results 
SUB 
Under 
SUBM GI 
Submandibular Glands 
SUP 
Superior 
T 
Tumor 
TMJ 
Temporomandibular Joints 
TPN 
Total Parenteral Nutrition 
TSH 
Thyroid Function Test 
ULN 
Upper Limits of Normal 
Univ IOWA 
University Of Iowa 
UTMB 
University of Texas Medical Branch 
V 
Volume 
v. 
Version 
Wash U 
Washington University 
WK 
Week 
WNL 
Within Normal Limits