Clinical and Instrumental Evaluation of Late Dysphagia in Patients With Oropharynx and Nasopharynx Cancer, Candidates to Combined Radiochemotherapy With Intensity Modulated Technique (IMRT)
Clinical and Instrumental Evaluation of Late Dysphagia in Patients With Oropharynx and Nasopharynx Cancer, Candidates to Combined Radiochemotherapy With Intensity Modulated Technique (IMRT)
Nowadays radio-chemotherapy is considered an alternative to surgical treatment in patients
 with locally advanced cancer of the cervico-cephalic district (LA-HNC), in order to guarantee
 organ preservation.

 Radio-induced dysphagia, as a multifactorial final effect, represents the real "Achilles
 Heel"; it occurs in more than 50% of patients and can lead to a serious state of
 malnutrition, with consequent long-term maintenance of a predominantly enteral nutrition with
 PEG or risk of aspiration pneumonia.

 A therapeutic strategy of organ preservation should guarantee the greater probability of
 tumor control and the minimum damage to the organ functions. Moreover, the reduction of
 symptoms, related to changes in swallowing function and possible complications, could lead to
 an improvement in the patient's quality of life and to a significant reduction in
 hospitalization costs. Intensity Modulated Radiotherapy (IMRT), have shown very promising
 results both in terms of increased tumor control and reduction of toxicity, due to a
 reduction in dose of radiation to the major salivary glands, pharyngeal mucosa and also to
 the structures responsible for swallowing. For a correct and complete evaluation of the
 deglutitory function should be useful the use of both clinical scales and instrumental
 methods. It is strongly recommended by the international scientific community to use, in
 association with the clinical evaluation, appropriate instrumental examinations for a correct
 evaluation of the swallowing function both before and after radiotherapy. The examens that
 are recognized as gold standards in the study of dysphagia are the Endoscopic Fibroscopy of
 Swallowing (FEES) and Videofluoroscopy (VFS). The protocol envisages the use of Swallowing
 Videoendoscopy (FEES) and Videofluoroscopy (VFS), that have to be performed in the baseline
 conditions to assess the presence or absence of dysphagia cancer related, and after 6 and 12
 months to evaluate the effect of the treatment. Patients should also complete a questionnaire
 for the assessment of quality of life in relation to dysphagia problems. The Primary aim is
 the Evaluation of changes of instrumental scores for swallowing function, the Secondary aims
 are the correlation between instrumental scores and clinical score and the dose received from
 each of the SWOARs with the deterioration of the instrumental and clinical scores. The
 evaluation of the swallowing functions effectuated by VFS and FEES have to be done in the 20
 days before the beginning of the treatment (Baseline Evaluation) and then at a distance of 6
 and 12 months from the end of the treatment. Clinical evaluation of the impact of dysphagia
 on quality of life by administering a specific MDADI (MD Anderson Dysphagia Inventory)
 questionnaire at baseline conditions and then at 6 and 12 months. Radiotherapy treatment have
 to be necessarily performed with IMRT technique (static or dynamic). For the optimization
 process of "Inverse Planning" the primary risk organs (P-OARs) and the secondary risk organs
 must be both identified as "Objective Structures" (S-OARs), which include the organs
 responsible for swallowing, indicated by the acronym SWOARs. In the treatment planning
 process, the highest priority must be given to respect the constraints on the P-OARs, the PTV
 coverage must have a higher priority than the constraints on the S-OARs.

 In the case of extensive overlapping between PTV and a secondary risk organ (eg for the upper
 constrictor muscle in patients with large nasopharyngeal tumor) it's a medical decision to
 set any dosimetric constraint and to limit the average dose received from the structure in
 analysis. At the end of radiotherapy planning, the average doses received from each of the
 SWOARs must be recorded and will be used in the final statistical analysis. The use of image
 fusion with MRI for the definition of both target volumes and OARs is strongly recommended.
 Finally, the radiation treatment must include the use of on-line verification and correction
 systems for the patient's Set-Up through three-dimensional imaging. The instrumental
 assessment of the swallowing function involves the execution, under basal conditions (in the
 20 days before the beginning of RT) and subsequently at a distance of 6 and 12 months from
 the end of RT, both of the FEES and of the VFS. The exams must be done by specialist doctors
 in Otorhinolaryngology (FEES) and Diagnostic Imaging (VFS), with consolidated experience in
 the field of deglutology. Both tests are important for the evaluation of the pharyngeal phase
 of the swallowing act.
Introduction Nowadays radio-chemotherapy is considered an alternative to surgical treatment
 in patients with locally advanced cancer of the cervico-cephalic district (LA-HNC), in order
 to guarantee organ preservation.

 Historically, radiotherapy performed using conventional techniques (two-dimensional or
 three-dimensional conformational) has always been burdened by high rates of severe toxicity,
 that often had influenced the final result of treatments.

 In fact radio-induced dysphagia, as a multifactorial final effect, represents the real
 "Achilles Heel"; it occurs in more than 50% of patients and can lead to a serious state of
 malnutrition, with consequent long-term maintenance of a predominantly enteral nutrition with
 PEG or risk of aspiration pneumonia; the percentage of dependence on PEG at 1 and 2 years is
 around 24% and 14%, the incidence of aspiration pneumonia is around 3%.

 A therapeutic strategy of organ preservation should guarantee the greater probability of
 tumor control (TCP) and the minimum damage to the organ functions.

 Moreover, the reduction of symptoms, related to changes in swallowing function and possible
 complications, could lead to an improvement in the patient's quality of life and to a
 significant reduction in hospitalization costs.

 In recent decades, technological improvements in the delivering of radiation treatment, for
 example Intensity Modulated Radiation Therapy (IMRT), have shown very promising results both
 in terms of increased tumor control and reduction of toxicity, due to a reduction in dose of
 radiation to the major salivary glands, pharyngeal mucosa and also to the structures
 responsible for swallowing, identified as SWOARs (SWOARs: Swallowing Organs At Risk).

 Numerous studies have tried to evaluate the role of IMRT in organ preservation but the most
 are retrospective studies, on heterogeneous case studies and in the absence of a baseline
 evaluation of the swallowing function, that would allow a real analisys of the impact of
 radiochemotherapy (RTCT).

 Furthermore, in most studies dysphagia was defined through the use of surrogate endpoints
 such as the time of use of PEG from the end of treatment, the events of aspiration pneumonia
 or the evidence of pharyngo-esophageal stenosis.

 For a correct and complete evaluation of the deglutitory function should be useful the use of
 both clinical scales and instrumental methods.

 The use of clinical assessment scales seems to significantly underestimate the dysphagic
 phenomenon, compared to the use of instrumental methods that seem to be more objective.

 Therefore, it is strongly recommended by the international scientific community to use, in
 association with the clinical evaluation, appropriate instrumental examinations for a correct
 evaluation of the swallowing function both before and after radiotherapy.

 The examns that are recognized as gold standards in the study of dysphagia are the Endoscopic
 Fibroscopy of Swallowing (FEES) and Videofluoroscopy (VFS).

 Aims The aim of the study is to prospectively investigate the impact of RTCT on the
 deglutitory function in patients affected by LA-HNC, with the final goal of an organ
 conservation therapy, that provides to preserved both anatomic and function of the
 deglutitory apparatus.

 To this aim the protocol envisages the use of Swallowing Videoendoscopy (FEES) and
 Videofluoroscopy (VFS), that have to be performed in the baseline conditions (before RTCT) to
 assess the presence or absence of dysphagia cancer related, and after 6 and 12 months to
 evaluate the effect of the treatment.

 Patients should also complete a questionnaire for the assessment of quality of life in
 relation to dysphagia problems (MDADI questionnaire).

 The Primary aim is the Evaluation of changes of instrumental scores for swallowing function,
 evaluated at 6 and 12 months from the end of the RTCT (variations between dichotomous
 variables or dichotomous yields); the Secondary aims are the correlation between instrumental
 scores and clinical score and the correlation of the dose received from each of the SWOARs
 with the deterioration of the instrumental and clinical scores Inclusion Criteria

 1. Histological diagnosis of squamous cell carcinoma or undifferentiated carcinoma of the
 otoiatric district

 2. Subsider of the primitive: (Nasopharynx Stage II and III); Oropharynx Stage III-IVA

 3. ECOG Status 0-2

 4. Chemiotherapy concomitant at radiotherapy (Cisplatin 100mg / m2 every 21 days or 40mg /
 m2 weekly)

 Exclusion criteria

 1. Histological diagnosis different from squamous or undifferentiated cell carcinoma

 2. Subsider of the primitive different from Nasopharynx, Oropharynx

 3. Nasopharynx Stage IV; Oropharynx Stage IVB and C

 4. ECOG ≥3

 5. Prior induction chemotherapy

 6. Prior oncological surgery on the ENT district

 7. Prior radiation treatment on the ENT district

 8. Concomitant diseases that could modify the swallowing function (ex Amyotrophic Lateral
 Sclerosis or Multiple Sclerosis)

 9. A history of excessive use of benzodiazepines or similar (ex patients in psychiatric
 therapy) or eastroesophageal reflux resistant at medical therapy Methods Evaluation of
 the swallowing functions effectuated by Videofluoroscopy (VFS) and Endoscopic Fibroscopy
 of the Swallowing (FEES) in the 20 days before the beginning of the treatment (Baseline
 Evaluation) and then at a distance of 6 and 12 months from the end of the treatment.

 Clinical evaluation of the impact of dysphagia on quality of life by administering a specific
 MDADI (MD Anderson Dysphagia Inventory) questionnaire at baseline conditions and then at 6
 and 12 months.

 Radiotherapy Radiotherapy treatment have to be necessarily performed with IMRT technique
 (static or dynamic), after TC acquisition of the anatomical volume of interest (from the
 skull base to the sternum-clavicular junction) with slices of 2.5 mm.

 For the optimization process of "Inverse Planning" the primary risk organs (P-OARs) and the
 secondary risk organs must be both identified as "Objective Structures" (S-OARs), which
 include the organs responsible for swallowing, indicated by the acronym SWOARs (8 in total).

 In the treatment planning process, the highest priority must be given to respect the
 constraints on the P-OARs, the PTV coverage must have a higher priority than the constraints
 on the S-OARs.

 In the case of extensive overlapping between PTV and a secondary risk organ (eg for the upper
 constrictor muscle in patients with large nasopharyngeal tumor) it's a medical decision to
 set any dosimetric constraint and to limit the average dose received from the structure in
 analysis.

 At the end of radiotherapy planning, the average doses (DM) received from each of the 8
 SWOARs must be recorded and will be used in the final statistical analysis.

 The use of image fusion with MRI for the definition of both target volumes and OARs is
 strongly recommended.

 Finally, the radiation treatment must include the use of on-line verification and correction
 systems for the patient's Set-Up through three-dimensional imaging (IGRT-3D).

 Instrumental evaluation of the deglutitory function (Endpoints) The instrumental assessment
 of the swallowing function involves the execution, under basal conditions (in the 20 days
 before the beginning of radiotherapy) and subsequently at a distance of 6 and 12 months from
 the end of radiotherapy, both of the FEES and of the VFS.

 The exams must be done by specialist doctors in Otorhinolaryngology (FEES) and Diagnostic
 Imaging (VFS), with consolidated experience in the field of deglutology.

 Both tests are important for the evaluation of the pharyngeal phase of the swallowing act.

 The instrumental parameters to be studied are the following:

 -  Pre-deglutitory Fall: Deficit in the oral phase; delay in triggering the swallowing act;
 nasal regurgitation (Velopalatin insufficiency)

 -  TTF (Faringeal Transit Time): expression of the transit time of the bolus through the
 pharynx

 -  IRF (Pharyngeal Retention Index): expression of the bolus residue percentage in pharynx
 (glosso-epiglottic vallecule and / or piriform sinuses and / or posterior laryngeal
 commissure, pharyngeal lateral wall) following the deglutitory act

 -  Penetration / Aspiration: expression of the bolus entry into the airways above the
 glottal plane (Penetration) or beyond the glottal plane (Aspiration) and the
 effectiveness of the tussigen reflex mechanisms.

 The exams must be performed following the intake of boluses of different consistencies.

 For FEES it's important to use liquid bolus (L), semi-solid bolus (SS) and solid bolus (S),
 while for VFS a liquid (L) and semi-solid (SS) bolus; each instrument parameter must be
 tested for the different consistencies of boluses.

 Therefore, being assessed for FEES 3 parameters for 3 different bolus consistencies and for
 VFS 4 parameters for 2 different bolus consistencies, 9 instrumental scores for FEES and 8
 instrumental scores for VFS will be reported by the operators.

 In case of penetration or aspiration, a score (from 1 to 8) must be assigned according to the
 PAS scale.

 Clinical evaluation of swallowing function (Endpoints) Before the start of the RTCT treatment
 and at 6 and 12 month from the end of treatment, the MDADI questionnaire will be administered
 in order to evaluate the impact of treatment related dysphagia on the patient's quality of
 life .

 Statistical Methodology Primary objective n. 1 The Mc Nemar Test will be used to evaluate the
 significant changes in instrumental scores related to the different parameters of dysphagia
 between the baseline and 6 and 12 months.

 The p-value and the power of the study are fixed at 0.05 and 0.80 respectively. To make the
 deterioration of one or more (variable) parameters of dysphagia (eg, predegulatory and
 aspiration fall) significant after radiochemotherapy, which involves a variation from 5%
 (baseline) to 25% (6 or 12 months post-treatment), 35 patients are needed.

 Primary objective n. 2 To evaluate the correlation between instrumental scores and the
 clinical score of dysphagia (quantitative variables), Pearson correlation analysis will be
 used.

 The p-value and the power of the study are fixed at 0.05 and 0.80 respectively. To make a
 coefficient of correlation between instrumental and clinical scores equal to 0.3, 85 patients
 are needed.

 Secondary objective For the analysis of the correlations between the dose received from each
 of the 8 structures responsible for swallowing (SWOARs) and the worsening of instrumental
 scores, Pearson correlation analysis will be used (after which multivariate analyzes will be
 carried out).

 The p-value and the power of the study are fixed at 0.05 and 0.80 respectively. To make a
 correlation coefficient of 0.3 between the doses received by each individual SWOAR and the
 worsening of the instrumental scores of one or more parameters of dysphagia significant,
 about 85 patients are needed.

 The SPSS Sample Power program was used to calculate the sample size.

 Operating Mode The referring physician of each participating, will have the database in
 Access format for the compilation and electronic registration of the data, which must be
 personalized by inserting the center of origin in the appropriate box.

 At the time of recruitment the patient will be registered on the database in addition to
 personal data (initial surname and name and date of birth), general oncological data (staging
 and risk factors).

 Before the start of radiotherapy, the scores of the instrumental examinations relative to the
 baseline evaluation and the average doses (Dm) that will receive the single SWOARs will have
 to be recorded.

 At the end of the radiotherapy, the clinical data of the treatment will be recorded (date of
 start and end of radiotherapy, scheduling of the chemotherapy and total number of cycles).

 The results of the revaluation instrumental tests will instead be updated respectively at 6
 and 12 months from the end of the therapy.

 The follow-up will finally be systematically updated at each control visit, based on the
 timing provided by the single center, according to the specifications reported in the
 database.

 The patient will be excluded form study in case of persistence / relapse of histological
 documented local or regional disease, that includes rescue surgery on T or chemotherapy in
 the period of study enrollment.

 On the other hand, rescue surgery on N is not a criterion for leaving the study.

 Also the appearance of distant metastases documented with radiological and nuclear imaging in
 the study enrollment period is an exit criteria.

 In order to verify the correctness in the performance of the instrumental evaluation, the
 Coordinating Center will be able to request, in a "random" way, the sending of the videos of
 the examinations carried out.

 indicating the progressive identification number, the patient's initials and the enrollment
 center

 Clinical Benefits and Economic / Organizational Relapses The clinical management of patients
 with locally advanced neoplasm of the head-neck district has always been extremely complex
 due to the serious "treatment-related" toxicities, that have as main factor the difficulty in
 feeding and consequently maintain an adequate nutritional intake, essential for cope with
 curative treatments such as radiochemotherapy.

 It is therefore frequent the placement of devices for enteral feeding, such as nasogastric
 tubes or percutaneous gastrostomy (PEG), or to the use of parenteral nutrition pockets, which
 inevitably require long periods of hospitalization for the patient, during treatment and
 often for weeks after the end of RTCT. The consequences are doubly negative, for the
 worsening of the patient's quality of life and psychological conditions, and also for the
 considerable increase in healthcare costs.

 A clinical management of this type also requires a period of suspension of the radiant
 treatment, with negative repercussions in terms of the patient's chance of recovery.

 A view to a multidisciplinary sharing of therapeutic choices, that involve not only the
 surgeon, the oncologist, radiotherapist and the medical oncologist as usually in done, but
 also involving other professionals figures (deglutologist, nutritionist, speech therapist)
 that can improve the clinical management of the radiochemotherapy patient, and consequently
 reduce the number of admissions for toxicity during and after the end of treatment.

 In this regard, we believe that a study of swallowing capacity and nutritional set-up may
 help in establishing early, before treatment and shortly distance from the end of the same,
 all possible aids, for example by means of postural compensation exercises, swallowing
 maneuvers and advice on the type of food to be preferred in relation to the risks of
 inhalation and nutrition, through careful monitoring and personalized nutritional support .

 In this way the patient is n the best conditions to face the radiochemotherapy treatment and
 to recover from the side effects.
Inclusion Criteria

 1. Histological diagnosis of squamous cell carcinoma or undifferentiated carcinoma of the
 otoiatric district

 2. Subsider of the primitive: (Nasopharynx Stage II and III); Oropharynx Stage III-IVA

 3. ECOG Status 0-2

 4. Chemiotherapy concomitant at radiotherapy (Cisplatin 100mg / m2 every 21 days or 40mg
 / m2 weekly)

 Exclusion criteria

 1. Histological diagnosis different from squamous or undifferentiated cell carcinoma

 2. Subsider of the primitive different from Nasopharynx, Oropharynx

 3. Nasopharynx Stage IV; Oropharynx Stage IVB and C

 4. ECOG ≥3

 5. Prior induction chemotherapy

 6. Prior oncological surgery on the otoiatric district

 7. Prior radiation treatment on the otoiatric district

 8. Concomitant diseases that could modify the swallowing function (ex Amyotrophic Lateral
 Sclerosis or Multiple Sclerosis)

 9. A history of excessive use of benzodiazepines or similar (ex patients in psychiatric
 therapy) or eostroesophageal reflux resistant at medical therapy