Clinical and Instrumental Evaluation of Late Dysphagia in Patients With Oropharynx and Nasopharynx Cancer, Candidates to Combined Radiochemotherapy With Intensity Modulated Technique (IMRT)

Sponsor

Azienda Ospedaliero, Universitaria Pisana (Other)

Overall Status

Recruiting

CT.gov ID

NCT03448341

Collaborator

(none)

Enrollment

Location

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Cancer of Oropharynx Cancer of Nasopharynx

Detailed Description

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

Histological diagnosis of squamous cell carcinoma or undifferentiated carcinoma of the otoiatric district
Subsider of the primitive: (Nasopharynx Stage II and III); Oropharynx Stage III-IVA
ECOG Status 0-2
Chemiotherapy concomitant at radiotherapy (Cisplatin 100mg / m2 every 21 days or 40mg / m2 weekly)

Exclusion criteria

Histological diagnosis different from squamous or undifferentiated cell carcinoma
Subsider of the primitive different from Nasopharynx, Oropharynx
Nasopharynx Stage IV; Oropharynx Stage IVB and C
ECOG ≥3
Prior induction chemotherapy
Prior oncological surgery on the ENT district
Prior radiation treatment on the ENT district
Concomitant diseases that could modify the swallowing function (ex Amyotrophic Lateral Sclerosis or Multiple Sclerosis)
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.

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.

Study Design

Study Type:

Observational

Anticipated Enrollment :

85 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Valutazione Clinica e Strumentale Della Disfagia Tardiva in Pazienti Affetti da Neoplasia Del Rinofaringe e Orofaringe Candidati a Radiochemioterapia Con Modulazione di intensità di Dose

Actual Study Start Date :

Jul 16, 2016

Anticipated Primary Completion Date :

Jul 16, 2022

Anticipated Study Completion Date :

Jul 16, 2023

Outcome Measures

Primary Outcome Measures

Evaluation of changes of instrumental scores for swallowing function [before treatment, at 6 months and 12 months]
each patients will be analysed with the Swallowing Videoendoscopy (FEES) and Videofluoroscopy (VFS) to have an instrumental evaluation of the dysphagia.The two exames 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).

Secondary Outcome Measures

Correlation between dysphagia and dose receveid tot the SWOARs [before treatment, at 6 months and 12 months]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

Histological diagnosis of squamous cell carcinoma or undifferentiated carcinoma of the otoiatric district
Subsider of the primitive: (Nasopharynx Stage II and III); Oropharynx Stage III-IVA
ECOG Status 0-2
Chemiotherapy concomitant at radiotherapy (Cisplatin 100mg / m2 every 21 days or 40mg / m2 weekly)

Exclusion criteria

Histological diagnosis different from squamous or undifferentiated cell carcinoma
Subsider of the primitive different from Nasopharynx, Oropharynx
Nasopharynx Stage IV; Oropharynx Stage IVB and C
ECOG ≥3
Prior induction chemotherapy
Prior oncological surgery on the otoiatric district
Prior radiation treatment on the otoiatric district
Concomitant diseases that could modify the swallowing function (ex Amyotrophic Lateral Sclerosis or Multiple Sclerosis)
A history of excessive use of benzodiazepines or similar (ex patients in psychiatric therapy) or eostroesophageal reflux resistant at medical therapy