Dysphagia in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus

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Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx

Dysphagia in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus Antonio Schindler a , Nerina Denaro b , Elvio G. Russi c,∗ , Nicole Pizzorni a , Paolo Bossi d , Anna Merlotti e , Massimo Spadola Bissetti f , Gianmauro Numico g , Alessandro Gava h , Ester Orlandi i , Orietta Caspiani j , Michela Buglione k , Daniela Alterio l , Almalina Bacigalupo m , Vitaliana De Sanctis n , Giovanni Pavanato o , Carla Ripamonti p , Marco C. Merlano b , Lisa Licitra e , Giuseppe Sanguineti q , Johannes A. Langendijk r , Barbara Murphy s a

r

Department of Biomedical and Clinical Sciences “L. Sacco”, University of Milan, Milan, Italy b Medical Oncology Department AO. S. Croce e Carle – Cuneo, Italy c Department of Radiation Oncology, A.O. S. Croce e Carle Cuneo, Italy d Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy e Radiation Oncology Department, Ospedale di Circolo di Busto Arsizio, Italy f Department of Audiology–Phoniatrics, Università degli Studi di Torino, Italy g Medical Oncology Unit, Ospedale U. Parini, Viale Ginevra 3, 11100 Aosta, Italy h Department of Radiation Oncology, Treviso Regional Hospital, Treviso, Italy i Radio-Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy j Radiation Oncology Department, Isola Tiberina Fatebenefratelli Hospital, Rome, Italy k Radiation Oncology Department, Spedali Civili Hospital, Brescia University, Italy l Advanced Radiotherapy Center, European Institute of Oncology, Milan, Italy m Radio-Oncology Department, IRCCS San Martino-IST, Largo R Benzi 10, 16132 Genoa, Italy n Department of Radiotherapy University “La Sapienza”, Rome, Italy o Department of Radiotherapy, Ospedale Santa Maria della Misericordia, Rovigo, Italy p Supportive Care in Cancer Unit, IRCCS Foundation National Cancer Institute, Milan, Italy q Department of Radiotherapy, National Cancer Institute Regina Elena, Rome, Italy Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands s Division of Hematology/Oncology, Department of Medicine, Vanderbilt University, Nashville, TN, USA Received 27 January 2015; received in revised form 13 May 2015; accepted 10 June 2015

Contents 1. 2. 3. 4.

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Comment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Assessment scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

∗

Corresponding author. Tel.: +39 3280971299. E-mail addresses: [email protected] (A. Schindler), [email protected] (N. Denaro), [email protected] (E.G. Russi), [email protected] (N. Pizzorni), [email protected] (P. Bossi), [email protected] (A. Merlotti), [email protected] (M. Spadola Bissetti), [email protected] (G. Numico), [email protected] (A. Gava), [email protected] (E. Orlandi), [email protected] (O. Caspiani), [email protected] (M. Buglione), [email protected] (D. Alterio), [email protected] (A. Bacigalupo), [email protected] (V. De Sanctis), [email protected] (G. Pavanato), [email protected] (C. Ripamonti), [email protected] (M.C. Merlano), [email protected] (L. Licitra), [email protected] (G. Sanguineti), [email protected] (J.A. Langendijk), [email protected] (B. Murphy). http://dx.doi.org/10.1016/j.critrevonc.2015.06.005 1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Schindler A, et al. Dysphagia in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.06.005

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4.2. Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.3. Preventive swallowing dysfunction evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.4. Deglutologist’s evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.5. Radiotherapic precautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.6. Preventative and therapeutic swallowing exercises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Abstract Background: Head and neck cancer (HNC) and its therapy are associated with acute and late swallowing dysfunction. Consensus guidelines regarding evaluation and management are lacking. To address this gap, a multidisciplinary team of experts (oncologists, practitioners, deglutologists, etc.) met in Milan 17–18 February 2013 with the aim of reaching a consensus on the management of swallowing difficulties in HNC patients treated with radiotherapy with or without systemic therapies (such as chemotherapy and targeted agents). The consensus was focused particularly on those statements with limited evidence. The results of the literature review and the statements that obtained a consensus are reported and discussed in this paper. Materials and methods: The Delphi Appropriateness Method was used for this consensus. External expert reviewers then evaluated the conclusions carefully according to their area of expertise. Results: This paper contains 6 clusters of statements about the management of swallowing problems in radio-treated HNC patients and a review of the recent literature on these topics. Conclusions: Dysphagia assessment and its management are difficult and require a multi-team cooperation (ENT specialists, radiation and medical oncologists, deglutologists, etc.). © 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Dysphagia; Swallowing dysfunction; Head and neck cancer; Deglutition; Radiotherapy; Chemotherapy; Radiation oncology

1. Background Dysphagia is defined as the difficulty in swallowing liquids, food, or medication and can occur during the oropharyngeal or the oesophageal phase of swallowing ([1]). Swallowing dysfunction has been reported in 30–50% of head and neck cancer patients (HNCPs) treated with intensive non-surgical regimens [1–3]. HNCPs with swallowing dysfunction are at risk of pneumonia and sepsis [4]. Although dysphagia improves over time in 32% of HNCPs, 48% of patients fail to report improvement in dysphagia-associated symptoms and in 20% of patients symptoms worsen over time [5]. Of note, dysphagia may develop or worsen years after therapy is completed [5,6]. There are several underlying causes for swallowing dysfunction in HNCPs. First and foremost, dysphagia may pre-exist therapy (14% [7] to 18% [8] of HNCPs) due to the obstruction by the tumour volume or infiltration of structures involved with swallowing. In the operative population, surgical extirpation of structures necessary for normal deglutition results in swallowing abnormalities. In the population treated with radiotherapy (RT), dysphagia is secondary to damage of neural and soft tissues [9]. RT-induced swallowing dysfunction may occur both acutely during treatment and as a late effect of therapy. Acute dysphagia is generally associated with soft tissue inflammation, oedema, pain, mucous

production, and xerostomia. After radiation has completed, soft tissues are able to heal. For some patients, the healing process results in soft tissue fibrosis, lymphedema, scar tissue formation, and neurological impairment. This may result in a decreased swallowing function. Predicting which HNCPs will develop swallowing dysfunction following non-surgical treatment is challenging [10]. There are, however, a number of factors that have been identified that may correlate with the development of acute or late dysphagia. Radiation dose delivery to dysphagia–aspiration-related structures (DARSs), those “anatomical” structures that are critical to the swallowing function [3], has been shown to predict swallow outcome in a number of studies [3,11–13]. Other important factors include the concomitant [14] use of chemotherapy (CT) and/or targeted therapy (TT) [3,13]. Patients receiving combined modality therapy experience higher-grade mucositis and pain with associated increase of percutaneousendoscopic-gastrostomy (PEG) use. Patients who receive radiation following surgery-involving DARSs may experience worse outcomes. Other factors that may worsen the swallowing function include: xerostomia [15–17], genetic factors [18,19], malnutrition [20], and tobacco smoking [21,22]. Efforts have been directed at developing predictive models that can be used in the clinical setting to identify patients

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at high risk for radio-induced dysphagia. Langendijk et al. [23] identified five independent prognostic factors predicting G2–G4 swallowing dysfunction (RTOG/EORTC) at 6 months after treatment (SWALL6 months): i.e. advanced T stage (T3–T4), oropharyngeal and nasopharyngeal tumour site, primary and bilateral neck irradiation, weight loss at baseline, and treatment modality (accelerated RT or concomitant CT–RT). Based on adverse swallowing outcomes, efforts have been made to ameliorate swallowing dysfunction in HNCPs. The use of intensity-modulated RT (IMRT) has been introduced in clinical practice in order to reduce the radiation doses to DARSs [15], masticatory structures [24,25], and salivary glands [26], and consequently reduce the incidence and severity of severe dysphagia [16,27,28]. In addition, more attention has been given to preventive and therapeutic physical exercises associated with treatments in order to maintain speech and swallowing functions [29–34]. A growing body of literature seems to indicate that swallowing therapy during and after treatment may improve long term swallowing outcomes. Data from randomized trials have been accumulated, but many of these are flawed. Of particular concern is the lack of consensus regarding critical issues such as optimal frequency, intensity, and content of swallowing therapy. Nonetheless, it is evident that the prolonged disuse of structures critical to normal swallowing results in increased rates of late dysphagia. It may be hypothesized that this is due to increased lymphedema and fibrosis as well as disuse atrophy. Considering the above, it is necessary to review carefully the available data and make recommendations for supportive measures as well as to establish directions for future research. Furthermore, radiation oncologists (ROs), medical oncologists (MOs), ENTs, nutritionists, deglutologists [35,36] (such as swallowing-expert physicians (SEPs) or speech language pathologists (SLPs)), infectious disease specialists, dentists, and nurses from Italy met with the aim of reaching a consensus on the management of HNCPs’ swallowing in order to provide standard recommendations for the centres that participate in common trials. It was felt that standards and consensus were most needed where there was limited evidence to guide clinicians. The results of the literature review and the statements that obtained consensus are reported and discussed in this paper.

2. Materials and methods Due to the lack of evidence from randomized controlled trials on most aspects of best practice in the supportive care of HNCPs during RT, an alternative approach to provide guidance was adopted. A formal consensus methodology was employed according to the model proposed by the American Society of Clinical Oncology (ASCO) [37], through a modified Delphi strategy. Briefly, a consensus group of 40

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experts including ROs, MOs, ENTs, nutritionists, DEs, infectious disease specialists, dentists and nurses was set up in Milan 17–18 February 2013. A facilitator board of 8 expert members, from different clinical settings (3 ROs, 1 SEP, 1 SLP, 2 MOs, 1 ENT) was appointed. The facilitator board performed a systematic review of the literature on swallowing dysfunction in HNCPs treated with RT with or without systemic therapies. The MEDLINE database was searched for studies published from 1990 to March 2013 containing the terms dysphagia, aspiration, swallowing dysfunction, head and neck cancer, chemotherapy, Cetuximab, and RT. The literature search was limited to articles in Italian, English, and French regarding human cancers treated with RT. Potentially relevant abstracts presented at annual meetings of the ASCO, the American Society for Radiation Oncology (ASTRO) and the European Society of Medical Oncology (ESMO) were also examined. The study selection included the following: (a) Observational and prospective studies concerning assessment and treatment; (b) randomized, double blind, placebo-controlled, or uncontrolled studies; (c) retrospective and uncontrolled studies; (d) systematic reviews and meta-analyses; and (e) consensus guidelines. Furthermore, the electronic search results were supplemented by a manual examination of reference lists from selected articles and were periodically updated to April 2014 (before the second meeting). On the basis of this literature review, the facilitators identified a series of statements, which were differentiated according to the timing of intervention (pre-, during-, and post-treatment) and included an indication of the person in charge of the management of each behavioural physical social aspect (e.g. physician, nurse, patient, caregiver, etc.). Then, all experts rated these statements through a tworound process. A scale of 4 steps was used, where (1) was defined as “high consensus”, (2) “low consensus”, (3) “no consensus”, and (4) “unable to express an opinion”. A web meeting was held before the second rating where statements were discussed. The statements that received a weak or no approval (less than 75% of votes) were redefined according to the observations of panellists. The second ratings were analyzed to identify the statements that reached a consensus. Each expert (including facilitators) was equally weighted in scoring the statements. Then, two external ROs (JAL, GS), one MO (BM), and one SEP (SA) reviewed the statements. The statements were then finalized according to the suggestions of external reviewers. The process lasted from March 2013 to April 2014. The panellists had a second meeting in Milan on 5 May 2014 in order to approve the final version of the statements. Furthermore, the literature review had been updated to March 2014 before the second meeting.

Please cite this article in press as: Schindler A, et al. Dysphagia in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.06.005

Description

Whom is it in charge of?

1.

Pre-therapy/therapy/followup

Assessment scales 1.1 Patient-reported outcome (PRO)-scales: It is suggested that a PRO scale evaluating subjective dysphagia and its impact on Health-related quality of life (HRQoL) be administered to all patients, before treatment starts, again at the time treatment ends and regularly during follow up. Among the multiple self-administered questionnaire available at the present time, the M.D. Anderson Dysphagia inventory (MDADI) was considered a practical option for a dysphagia screening tool because it is disease-specific, short, and specifically designed to evaluate dysphagia in patients with HNC 1.2 Operator-reported outcome (ORO)-scales: An ORO scale, such as NCI-CTCAE grading scale, can be associated Risk factors 2.1 All patients need to be clinically evaluated in order to search for signs and symptoms that herald dysphagia and/or inhalation and/or aspiration (e.g. “Murphy’s trigger symptoms”, 3-ounce water swallow test, recent history of recurrent pneumonia, etc.) at baseline, during and after treatment Preventive swallowing dysfunction evaluation 3.1 It is recommended that nutritionists and deglutologist evaluate patients before starting treatment and at any time there is a clinical indication of swallowing impairment Deglutologist’s evaluation 4.1. The detailed swallowing evaluation by a deglutologist aims to: (1) identify swallowing abnormalities, (2) prescribe additional testing (clinical/radiological tests) in order to assess inhalation/aspiration risks, and (3) develop an appropriate treatment plan (correction of swallowing mechanisms through patient education and exercises) 4.2. Instrumental evaluation: In order to identify swallowing abnormalities, instrumental testing such as FEES (Fibreoptic Endoscopic Evaluation of Swallowing) and/or SVF (Swallowing Video-fluoroscopy) can be recommended on the basis of the deglutologist’s prescription and of test availability/accessibility Radio-therapeutic precautions 5.1. Simulation Computerized Tomography (S-CT)-based delineation of DARS and the collection of dosimetric parameters are suggested and encouraged, although available data from literature are not yet consolidated for routine use in clinical practice 5.2. A multimetric model (more than one parameter: e.g. Dmean, different DVHs) should be considered in order to evaluate DARS dose constraints. Christianen’s predictive model for swallowing dysfunction can help ROs to predict the risk in non-operated patients without pre-treatment dysphagia 5.3. It is recommended that the dose to the main DARS (i.e. swallowing muscles, Parotid glands, and oral mucosa outside PTV) be minimized as far as possible 5.4. Acute mucositis can worsen dysphagia; therefore dose distribution through oral mucosa (outside PTV) needs to be kept as low as possible (≤30 Gy in 6/7 weeks) Preventative and therapeutic swallowing exercises 6.1. Patients may benefit from strategies aimed at the prevention of swallowing dysfunction after curative RT ± CT/TT such as preventative swallowing exercises during treatment. Swallowing exercises should be prescribed and supervised by a SLP 6.2. Two types of exercises can be suggested for patients with dysphagia, both of which are to be performed at the beginning, during and after treatment: indirect (exercises to strengthen swallowing muscles) and direct (postural exercises to be performed while swallowing) 6.3. If enteral nutrition is adopted, patients should be encouraged to continue to swallow and to wean from artificial nutrition as quickly and safely as is feasible, regardless of the method (e.g. nasogastric tube, PEG, and parenteral nutrition)

Oncology Physician – Nurse

2.

Pre-treatment

3.

Pre-treatment

4.

Pre-treatment

5.

6.

Pre-treatment

Pre-treatment/during therapy

The degree of consensus 83%

76% Oncology Physician – Nurse

77%

Oncologist – Nurse – Nutritionists and Deglutologists Oncology Physician – Nurse – Deglutologist

85%

90%

88%

Radiation Oncologist

78%

85%

95% 85% Oncology Physician – Nurse – Deglutologist

95%

88%

95%

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Table 1 Consensus-reached statements.

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Before RT Timeline Baseline PRO-SCALE ORO-SCALE Searching for Sign and Symptoms Nutrionist evaluaon Deglutologist evaluaon Instrumental evaluaon Radiotherapeuc precauons Swallowing exercises Pain assessment and control

Yes Yes Yes Yes Yes On demand Yes Yes Yes

During RT Other w

1st w

2ndw

Yes Yes Yes On demand On demand No -Yes Yes

Yes Yes Yes On demand On demand No -Yes Yes

Yes Yes Yes On demand On demand No -Yes Yes

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Follow up period Last week Yes Yes Yes On demand On demand No -Yes

Yes at each visit Yes at each visit Yes at each visit Yes at 1st visit, then on demand Yes at 1st visit, then on demand On demand -Yes Yes

Fig. 1. The recommendations along the timeline.

3. Results Consensus-reached statements are listed in Table 1 and summarized along a timeline in Fig. 1. Seventeen statements were presented at the first round of rating, after which 8 statements reached a high level of consensus. Nine were deleted, changed, revised, or modified according to the experts’ comments. After the second round of rating, 15 statements were proposed, of which 13 received a high consensus. These were proposed to external experts’ revision following which statements 11 and 12 were merged. Then, they were clustered together into 6 groups (clusters).

4. Comment 4.1. Assessment scales 4.1.1 Patient-reported outcome (PRO)-scales: It is suggested that a PRO scale evaluating subjective dysphagia and its impact on health-related quality of life (HRQoL) be administered to all patients, before treatment starts, again at the time treatment ends and regularly during follow up. Among the multiple self-administered questionnaires available at the present time, the M.D. Anderson Dysphagia Inventory (MDADI) was considered a practical option as a dysphagia-screening tool because it is disease-specific, short, and specifically designed to evaluate dysphagia in patients with HNC. 4.1.2 Operator-reported outcome (ORO)-scales: An ORO scale, such as NCI-CTCAE grading scale, can be associated. Accurate and detailed information about acute and late swallowing dysfunction assessment is limited. Objective measures of the swallowing function, such as the MBS and FEES, provide detailed and rich information, but are costly, time-consuming, and operator-dependent. Clinical trials often report blunt surrogated endpoints such as feeding tube dependence (e.g. NCI-CTCAE grading system [38]) to

report swallowing abnormalities [3]. However, this grossly underrepresents swallowing dysfunction. As an alternative, investigators are interested in using patient-reported outcomes (PROs) to assess the swallowing function. PROs are subjective reports garnered directly from the patient. PROs have the benefit of being brief, inexpensive, and amenable to repeated measures. Yet, inadequate sensitivity, specificity, and predictive values of these PRO scales have been identified in comparisons to the objective findings of aspiration or penetration in patients undergoing FEES evaluation of swallowing [39]. Available PRO tools include: swallowing-related questions in cancer specific HRQOL tools, such as the EORTC QLQ 30 H&N 35 [40], FACT-HN [41], EAT-10 [42], SWALQOL [43,44] and the M.D. Anderson Dysphagia Inventory (MDADI) [45]. The MDADI has the advantage of brevity [46–49]. Unfortunately, these measures were developed as research tools, not as screening tools. A screening tool must be: brief, clinically directed, able to identify actionable items and proven to enhance clinical outcomes. In order for screening to impact on outcomes, there should be a clearly defined and effective treatment for the condition for which screening is attempted. In addition, screening tools must be easily incorporated into the provider’s routine clinical flow and procedures. Unfortunately, none of the existing tools has been tested to determine whether they screen effectively for dysphagia. Further perspective longitudinal studies are needed to develop and test screening tools. While awaiting such results it is reasonable to choose a brief questionnaire with items directed at identifying swallowing dysfunction in order to refer for swallowing evaluation. 4.2. Risk factors 4.2.1 All patients need to be clinically evaluated in order to search for signs and symptoms that herald dysphagia and/or inhalation and/or aspiration (e.g. “Murphy’s trigger symptoms” or a recent history of recurrent pneumonia, etc.) at baseline, during and after treatment. Patients should be educated about the signs and symptoms of aspiration and told to report them immediately to their

Please cite this article in press as: Schindler A, et al. Dysphagia in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.06.005

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Table 2 Murphy’s trigger symptoms. Inability to control food, liquids, or saliva in the oral cavity Pocketing of food in cheek Excessive chewing Drooling Coughing, choking, or throat clearing before, during, or after swallowing Abnormal vocal quality after swallowing; “wet” or “gurgle” voice Build-up or congestion after a meal Complaint of difficulty swallowing Complaint of food “sticking” in throat Nasal regurgitation Weight loss

health care providers. Unfortunately, HNCPs often underestimate trigger symptoms, thus, clinicians should inquire about swallowing issues and investigate any signs and symptoms that herald dysphagia or aspiration at each visit pre, during and after treatment [3,50–53] (Table 2). 4.3. Preventive swallowing dysfunction evaluation 4.3.1 It is recommended that nutritionists and deglutologists evaluate patients before starting treatment and at any time there is a clinical indication of swallowing impairment. HNCPs benefit from an early evaluation by both deglutologists [32,53–60] and nutritionists [20] at the time of diagnosis in order to identify any issues that need to be addressed prior to initiation of therapy. In addition, such an evaluation should be undertaken at any point along the treatment and recovery trajectory if patients are found to have any signs or symptoms of swallowing difficulty or nutritional deficits.

4.4.2 Instrumental evaluation: In order to identify swallowing abnormalities, instrumental testing, such as fibreoptic endoscopic examination of swallowing (FEES) and/or swallowing video-fluorography (SVF), can be recommended on the basis of the deglutologist’s prescription. Based on the clinical swallowing evaluation, the deglutologist may recommend instrumental assessment of the swallowing function using the Modified Barium Swallowing Study (MBSS) procedure with video-fluorography (SVF) and fibreoptic endoscopic examination of swallowing (FEES). Both procedures have been shown to identify patients at risk for aspiration pneumonia outcomes in patients with neurological-disease-related dysphagia [61]. During SVF the patient is required to swallow barium-labelled elements of different volumes and densities. SVF is entirely recorded and each phase of swallowing (oral, pharyngeal and oesophageal) is analyzed and timed. Thus, SVF allows transit abnormalities of different viscosity bolus, intra- and extra-luminal structural abnormalities, hyoid–laryngeal activity and reduced upper oesophageal sphincter (UOES) opening to be assessed [64,65]. During FEES, the evaluation of swallowing by transnasal endoscopy allows for the evaluation of various viscosity substances during phonation, spontaneous deglutition and voluntary swallowing. Hence, FEES cannot provide information on the oral stages of swallowing, but it has the advantage over SVF of allowing for the direct observation of anatomical structures (especially the vocal cord dysfunction), and for sensory tests (touching the pharynx with the tip of the endoscope, and if necessary using air-pulse stimuli) [66–68]. Furthermore, it is less expensive and is repeatable as needed, in considering the fact that there is no radiation exposure [61,68]. Determination of whether to use FEES or MBSS is based on the clinical scenario.

4.4. Deglutologist’s evaluation 4.5. Radiotherapic precautions 4.4.1 The detailed swallowing evaluation by a deglutologist aims to (1) identify swallowing abnormalities, (2) prescribe additional testing (clinical/radiological tests) in order to assess inhalation/aspiration risks, and (3) develop an appropriate treatment plan (correction of swallowing mechanisms through patient education and exercises). The primary role of the deglutologist is to identify swallowing abnormalities [32,53–60]. Data from the swallowing assessment will allow for: (1) the identification of aspiration risk [61,62], (2) recommendations for compensatory manoeuvres and dietary modifications [59], and (3) treatment planning (e.g. swallowing preservation exercises during RT ± CT/TT) [63]. The risk of aspiration may be eliminated by the use of postures, manoeuvres, and modifications to bolus size and consistency. The choice between FEES or SVF can be guided on the basis of the opinion of the deglutologist and of test availability/accessibility.

4.5.1 Simulation Computerized Tomography (S-CT)-based delineation of DARS and the collection of dosimetric parameters are suggested and encouraged, although available data from literature are not yet consolidated for routine use in clinical practice. 4.5.2 A multimetric model (more than one parameter: e.g. Dmean , different DVHs) should be considered in order to evaluate DARS dose constraints. Christianen’s predictive model for swallowing dysfunction can help ROs to predict the risk in non-operated patients without pre-treatment dysphagia. 4.5.3 It is recommended that the dose to the main DARS (i.e. swallowing muscles, Parotid glands, and oral mucosa outside Planning Target Volume or PTV) be minimized as far as possible. 4.5.4 Acute mucositis can worsen dysphagia; therefore dose distribution through oral mucosa (outside PTV) needs to be kept as low as possible (≤30 Gy in 6/7 weeks).

Please cite this article in press as: Schindler A, et al. Dysphagia in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.06.005

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Table 3 Dose–volume Data for different DARS and different dysphagia dysfunctions. Dmean Dysphagia

V30Gy

V40Gy

V50Gy

V55Gy

V60Gy

Pureed food

Solid food

33% [1]

80% [15,78] 69 Gy [80] 50 Gy [80] 53 (47–60) Gy [74] 36 Gy [81]–59 Gy [74] 41 Gy [1]

DARS PC SPC SGL SPC MPC IPC SPC MPC IPC MPC IPC PC PC SPC IPC UES

30% [77]

36 Gy [81] 55 Gy [80] 51 Gy [80] 37 Gy [80] 62 Gy [80] 61 Gy [80] 47 Gy [80] 52 Gy [80] 47 Gy [80] 33 Gy [80]

Aspiration

SGL

50% [15,78] 85% [15,78]

Stricture

GT

V70Gy

52–55 Gy [81] 80% [77]

Liquids

V65Gy

70% [15,78]

<51 Gy [1]

<65% [1]

<48% [1]

<21% [1]

<51 Gy [1]

<65% [1]

<41% [1]

<37% [1] >80% [77]

Decreased OPSE 65% [77]

<15% [1] 8% [88] <33% [1]

33% [80] 75% [1] 42% [89] <6% [1] <29% [1]

53% [1]

<10% [1]

SGL + GL PC SPC MPC IPC UES SGL + GL SC Ant. OC

DARS, dysphagia/aspiration related structures; Dmean , mean dose (Gy); GL, glottic larynx; GT, gastric tube, PC, pharyngeal constrictor muscle; SPC, superior pharyngeal constrictor muscle; MPC, middle pharyngeal constrictor muscle; IPC, inferior pharyngeal constrictor muscle; OPSE, oropharyngeal swallowing efficiency; SGL, supraglottic larynx; UES, upper esophageal sphincter; Vx , volume of an organ at risk of receiving ≥x Gy (%).

The functional changes after RT [3,7] are due to a poor synchronization between pharyngeal contractions, the opening of the UOES and larynx closure. Indeed, a decreased pharyngeal peristalsis and a defective posterior movement of the tongue base towards the posterior pharyngeal wall, an altered closure of the laryngeal sphincters, a decreased inversion of the epiglottis and decreased elevation of the hyoid bone and larynx, and a delayed opening of the crico-pharyngealUOESs [7,12,15,69,70] have all been demonstrated. All these alterations are due to radio-induced inflammatory oedema or fibrosis of structures involved in the swallowing process (such as mucosa, laryngeal and pharyngeal constrictors, masticator muscles, connective tissue of intra-visceral spaces, terminal afferent and efferent nerve fibres present in mucosa, etc.). All these abnormalities can be responsible for an altered swallowing process and for a post-swallowing residue in the oropharynx, valleculae and hypo-pharynx, which may subsequently be aspirated. Radio-induced dysphagia can often be associated to altered sensitivity, which may cause a silent aspiration and deficient cough reflex [15,70–74]. The results of various studies, which have investigated the correlation between the dose delivered to organs involved in

swallowing and the reduction of the swallowing function after RT [10,25,75–87], are concordant in showing a strong correlation between swallowing disorders and the dose received by the pharyngeal constrictors, larynx, and crico-pharyngeal and/or UOESs. Thus, irradiated patients could have a significantly reduced oral and pharyngeal swallowing performance, with longer oral transit times, lower oropharyngeal swallowing efficiency, increased pharyngeal residue, and reduced cricopharyngeal opening duration [3,88]. Recent reports and the “Quantitative Analysis of Normal Tissue Effects in the Clinic” (QUANTEC) guidelines suggested minimizing the volume of DARS. DARS were first described by Eisbruch et al. [7], and, successively, various authors tried to outline them in planning CT data sets. Yet, they were not defined in the same way. For instance, the pharyngeal/oesophageal sphincter region has been described by some authors as the whole cervical oesophagus “outlined from the level of the inferior edge of the cricoid cartilage through the most distal axial CT image containing targets in the low neck” without mentioning any difference between the crico-pharyngeal muscle and the oesophagus inlet muscle [15,81,85], whereas others only

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Table 4 Swallowing exercises. Exercise

Target

Procedure

Tongue resistance

To improve range and strength of the tongue

Tongue base retraction

Improve tongue base to posterior pharyngeal wall contact and therefore improve pharyngeal propulsion of the bolus

Masako o tongue hold

Glossopharyngeal muscle responsible for tongue base retraction and medialization of pharyngeal constrictors To increase the extent and duration of laryngeal elevation and prolong crico-pharyngeal opening times Provide volitional airway protection

Patient is to move side to side up and down in/out the tongue also against resistance (spatula) Pull the back of your tongue as far back as you can. Pretend you are trying to scratch the back wall of your throat with the back of your tongue. Hold for a few seconds Gently hold your tongue in between your front teeth and swallow your saliva Patients swallow when the larynx reaches the highest level then hold few seconds and then relax Patient is to take deep breath, hold the breath while they swallow then exhale forcefully Inhale and hold your breath very tightly, bearing down Keep holding your breath and bearing down as you swallow Cough when you are finished The patient is instructed to lie on their back, lift their head up so that they can see their toes, but do not lift up their shoulders. Hold for a minute and then rest for 1 min

Mendelson Supraglottic swallow or breath hold Super-supraglottic swallow

Technique facilitates closure of the airway entrance before and during the swallow and also increases tongue base motion and speed and extent of laryngeal elevation.

Shaker

To strengthened the supra-hyoid muscle complex

Jaw exercises

To improve and retain movement of mandible

considered the crico-pharyngeal muscle [80,83,89] or the UOES (defined as the first centimetre of the oesophagus below the crico-pharyngeal muscle [74,80,83]) or both without distinction between them [87]. Furthermore, the pharyngeal superior constrictor has been contoured differently by different authors [74,86,87]. Finally, Alterio et al. reported that MRI-derived contouring can ameliorate operator-related variability [90]. All this variability in contouring the various DARS undermines the reliability of the relationship between DARS dosimetric parameters and the predictive models of swallowing dysfunction. Thus, a single dose parameter such as the mean dose to a specified DARS or the dose given to a percentage of an irradiated DARS volume (defined as VxGy ) gives neither a reliable constraint [91] nor an ideal representation of the 3D dose distribution through the DARS [90,92]. Consequently, the panel prudently advised adopting a multimetric model (more than one index: e.g. Dmean and more than one VxGy value) in clinical practice (Table 3). At any rate, a recent systematic review of dose–volume constraints for DARS [91] suggested that dose–volume constraints for the pharyngeal constrictors are in the same range as those proposed by the QUANTEC group [93] and Einsbruch [81] (i.e. reducing the mean doses to the non-involved pharyngeal constrictors from 61–64 Gy to 52–55 Gy, as well as lowering the mean doses to the supraglottic larynx from 48–54 to 36–38 Gy). Furthermore, the panel suggested that Christianen’s predictive model for swallowing dysfunction (see Christianen’s appendix [83]) could help ROs to predict the risk in non-operated patients without pre-treatment dysphagia. The guideline for delineations of DARS based on CT image are also provided [90,92].

Regarding the relationship between xerostomia and dysphagia, there is some evidence for dose–volume relationships linking the major salivary gland dose to mouth dryness [16] and consequently the reduced salivary flow to an impaired swallowing function [74,94–96]. Clear dose limits exist for the parotid glands [16,97–99], but there are also limits for the submandibular and minor salivary glands, which influence the moistening of oral tissues [79,100–103]. To prevent or reduce salivary gland hypo-function and xerostomia, parotid-sparing intensitymodulated radiation therapy [16] (IMRT) is recommended as a standard approach in HNCPs. In addition, treatment should focus on approaches to further reduce the radiation dose to the submandibular and minor salivary glands [79,100–103]. Furthermore, the mucosa-sparing IMRT can impact on swallowing dysfunction due to reduced mucosa fibrosis and the reduced negative effect on minor salivary glands [79,104]. Finally, Sanguineti reported that PEG use was drastically reduced when the weekly dose–volume histogram (DVH) (V9.5Gy ) of oral mucosa was <64 cm3 . These results need to be validated [79]. In conclusion, the DARS-sparing IMRT should prioritize in the following order: salivary glands, swallowing muscles, and oral mucosa (outside PTV). This order takes into account the varying strengths of evidence. In any case, DARS-sparing IMRT has to be optimized without compromising target doses [15].

4.6. Preventative and therapeutic swallowing exercises 4.6.1 Patients may benefit from strategies aimed at the prevention of swallowing dysfunction after curative RT ± CT/TT such as preventative swallowing

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exercises during treatment. Swallowing exercises should be prescribed and supervised by an SLP; 4.6.2 Two types of exercises can be suggested for patients with dysphagia, both of which are to be performed at the beginning, during and after treatment: indirect (exercises to strengthen swallowing muscles) and direct (postural exercises to be performed while swallowing); Swallowing exercises are designed to increase the range of movement of the tongue, lips, and jaw. Exercising swallowing muscles seems to improve and/or maintain the ability to swallow [29,30] (Table 4). For each group of swallowing muscles, patients will be guided to perform a range of motion and resistance exercises. Physicians or deglutologists will select tailored exercises for each patient: i.e. the number of repetitions, the duration of each exercise, and the interval between them should be customized. 4.6.3 If enteral nutrition is adopted, patients should be encouraged to continue to swallow and to wean from artificial nutrition as quickly and safely as is feasible, regardless of the method (e.g. nasogastric tube, PEG, and parenteral nutrition);

Conflict of interest statement

Initial malnutrition affects the response to treatment and the prognosis of HNCPs treated with RT(±CT/TT) [105]. This cohort of patients might therefore benefit from nutritional support and/or prophylactic gastrostomy before the beginning of treatment. Once a feeding tube is placed, either prophylactically or in response to treatment-related toxicity, patients should be encouraged to continue swallowing exercises as prescribed by the SLP in order to retain the swallowing function and prevent long term swallowing impairment. Sometimes, the pain control is crucial in order to keep the patient swallowing and to maintain the functionality of swallowing muscles. Every effort should be adopted to support the patient with an adequate and personalized antalgic therapy. Patients should move to oral intake when safe.

References

5. Conclusions Dysphagia in HNCPs has often been misunderstood, under-diagnosed, and improperly treated. Adequate treatment of dysphagia is fundamental to plan a correct oncological programme, by reducing the side effects that negatively impact on HRQoL and might affect overall survival. Recommendations for dysphagia assessment and management during RT(±CT/TT) for HNCPs have been defined with a recognized methodology, in an area where high quality evidence is lacking. The consensus highlighted the need for interdisciplinary collaboration, accurate and early diagnostic workup and effective and therapeutic strategies to manage dysphagia successfully.

9

The authors have no financial and personal relationships with other people or organisations that could inappropriately influence (bias) this work.

Funding This study was partly supported by Lega Tumori sezione di Cuneo.

Acknowledgments Airoldi Mario (Turin), Azzarello Giuseppe (Padova), Bolner Andrea (Trento), Cavagnini Roberta (Brescia),Corvò Renzo (Genova), Fiscella Michela (Milan), Gavazzi Cecilia (Milan), Carmine Pinto (Parma), Grisanti Salvatore (Brescia), Magrini Stefano (Brescia), Maurizi Enrici Riccardo (Rome), Orlandi Ester (Milano), Paiar Fabiola (Firenze), Salgarello Stefano (Brescia).

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Biographies Elvio G. Russi, M.D. (corresponding author) earned his M.D. degree at the University of Messina. He completed residency programmes in Radiation Oncology, in Medical Oncology, and in Radiodiagnosis. He is currently Head of the Radiation Oncology department at Teaching Hospital “A.O. S. Croce e Carle” in Cuneo (Italy). Dr. Russi headed the “Head and neck study group” of Italian Association of Radiation Oncologist (AIRO) between 2012 and 2013. He was a board member for AIRO (Italian Association of Radiation Oncologist) between 2010 and 2012. He has authored or co-authored over 80 original articles, book chapters with a predominant emphasis on Head and neck cancer treatment. “Author H index”: 13 (Scopus 2014). Marco C. Merlano, M.D. earned his M.D. degree at the University of Genoa. He is currently Chair of Oncological Department at Teaching Hospital “A.O. S. Croce e Carle” in Cuneo (Italy). Dr. Merlano has authored or co-authored over 135 original articles, book chapters with a predominant

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emphasis on Head and neck cancer treatment. “Author H index”: 20 (Scopus 2014). Lisa Licitra, M.D. is Chief of Head and neck cancer unit – Istituto Nazionale dei Tumori Milano (Italy). She specialized in Medical Oncology at the University of Parma. Dr. Licitra was Chair of Head and neck cancer group of EORTC (European Organisation For Research And Treatment Of Cancer) – member of PDQ (Physician’s Data Query) of the National Cancer Institute USA. She is honorary member of European Society For Therapeutic Radiology And Oncology (ESTRO). Member of the editorial board – Cancer Treatment Reviews (2007–2009). She has authored or co-authored over 135 original articles, book chapters with a predominant emphasis on Head and neck cancer treatment. “Author H index”: 27 (Scopus 2014). Giuseppe Sanguineti, M.D. is currently Head of Department of Radiation Oncology at Istituto Nazionale Tumori Regina Elena, Rome, Italy. He completed his residency programmes at University of Genoa (Italy) in both Radiation Oncology and Clinical Oncology and his fellowship in Radiation Oncology at MD Anderson Cancer Center in Houston, USA between 1994 and 1995. He has been Associate Professor in Radiation Oncology at the University of Texas Medical Branch (2002–2007) and Johns Hopkins University (2007–2011). He has authored or co-authored over 135 original articles, book chapters with a predominant emphasis on Head and neck cancer treatment. “Author H index”: 26 (Scopus 2014). Johannes Albertus Langendijk is Director of Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. He has authored or co-authored over 120 original articles, book chapters with a predominant emphasis on Head and neck cancer treatment. “Author H index”: 33 (Scopus 2014). Barbara A. Murphy, M.D. graduated from the Wake Forest University School of Medicine. Fellowship in medical oncology at Memorial Sloan-Kettering Cancer Center; internal medicine Residency at Greenwich Hospital (Yale University affiliated). She is Professor of Medicine (Hematology/Oncology), Director of Head & Neck Oncology, Program Director of Pain & Symptom Management Program in Vanderbilt University, Nashville, USA. Dr. Murphy has authored or co-authored over 110 original articles, book chapters, with a predominant emphasis on supportive care and on improving survival and quality of life in patients with head and neck treated with chemo-radiation therapy. “Author h-index”: 36 (Scopus 2014).

Please cite this article in press as: Schindler A, et al. Dysphagia in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.06.005