Table of Contents 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 274

Doke Buurman

THE IMPACT OF THE MASTICATORY SYSTEM ON FUNCTIONAL REHABILITATION AND QUALITY OF LIFE IN PATIENTS WITH HEAD AND NECK CANCER Doke J.M. Buurman

THE IMPACT OF THE MASTICATORY SYSTEM ON FUNCTIONAL REHABILITATION AND QUALITY OF LIFE IN PATIENTS WITH HEAD AND NECK CANCER Doke J.M. Buurman

ISBN: 978-94-6483-466-6 Cover design: © evelienjagtman.com Layout: © evelienjagtman.com Printing: Ridderprint | www.ridderprint.nl © Doke Buurman, Maastricht, The Netherlands, 2023 The research presented in this dissertation was performed in cooperation with GROW-School for Oncology and Reproduction, at Maastricht University Medical Center+. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording or otherwise, without the written permission of the author and the publisher holding the copyright of the published articles. The printing and distribution of this thesis was financially supported by GROW - School for Oncology and Reproduction, Nederlandse Vereniging voor Gnathologie en Prothetische Tandheelkunde (NVGPT), Nederlandse Vereniging voor Orale Implantologie (NVOI), Koninklijke Nederlandse Maatschappij tot bevordering der Tandheelkunde (KNMT), BioComp Industries b.v., Straumann Group, Southern Implants / ProScan, MDL-Euregio and Digitalepoli.nl.

THE IMPACT OF THE MASTICATORY SYSTEM ON FUNCTIONAL REHABILITATION AND QUALITY OF LIFE IN PATIENTS WITH HEAD AND NECK CANCER De impact van het kauwstelsel op de functionele revalidatie en kwaliteit van leven bij patiënten met hoofd-halskanker DISSERTATION to obtain the degree of Doctor at Maastricht University, on the authority of the Rector Magnificus, Prof. dr. Pamela Habibović in accordance with the decision of the Board of Deans to be defended in public on Wednesday 6 December 2023, at 16:00 hours by Doke Johanna Maria Buurman born 24th March 1977 in Gendt

Supervisor: Prof. dr. P.A.W.H. Kessler Co-supervisors: Dr. C.M. Speksnijder (UMCU) Dr. F.J. Hoebers Assessment Committee: Prof. dr. P.M. Steijlen (Chair) Prof. dr. M.A.W. Merkx (Radboudumc) Prof. dr. E.J.M. Speel Prof. dr. V. Tjan-Heijnen Prof. dr. A. Visser (UMCG)

Contents Chapter 1 General introduction 9 Aims and outline of this thesis 23 Chapter 2 Prosthetic rehabilitation of head and neck cancer patients focusing on mandibular dentures in irradiated patients. 27 Chapter 3 Translation, cross-cultural adaptation, and validation of the Liverpool Oral Rehabilitation Questionnaire (LORQ) into the Dutch language. 43 Chapter 4.1 Masticatory performance and oral health-related quality of life in edentulous maxillectomy patients: A crosssectional study to compare implant-supported obturators and conventional obturators. 57 Chapter 4.2 Mastication in maxillectomy patients: A comparison between reconstructed maxillae and implant supported obturators: A cross-sectional study. 85 Chapter 5 The extent of unnecessary tooth loss due to extractions prior to radiotherapy based on radiation field and dose in patients with head and neck cancer. 105 Chapter 6 Tooth extractions prior to chemoradiation or bioradiation are associated with weight loss during treatment for locally advanced oropharyngeal cancer. 191 Chapter 7 General discussion 213 Chapter 8 Summary in English and Dutch 235 Chapter 9 Impact Paragraph 249 Appendix List of publications 255 Acknowledgement / Dankwoord 261 Curriculum Vitae 269

CHAPTER 1 GENERAL INTRODUCTION

8 Chapter 1

9 General introduction 1 General Introduction Head and Neck Cancer Head and neck cancer (HNC) includes malignancies of the upper aerodigestive tract above the level of the clavicles [1]. It encompasses the lip and oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, nasal cavity and paranasal sinuses, salivary glands, lymph node metastases from unknown primary tumors, ear canal/middle ear carcinomas (lateral skull base), and various skin tumors in the head and neck region. To this are added: thyroid carcinomas with involvement of the larynx, cervical esophagus and tracheal tumors, malignant orbital, non-ocular tumors and HNC in children [2]. The vast majority of HNCs are squamous cell carcinomas [1]. The complex head and neck region is responsible for many different functions such as eating, speaking and swallowing. At the same time, the appearance of the face plays a very important role in social interaction. HNC and its treatment affects these important functions in most patients and regularly also the appearance. Epidemiology and etiology Head and neck cancer is the seventh most common cancer worldwide. In 2020, there were 930,000 new patients with HNC and 470,000 related deaths [3, 4]. In the Netherlands, HNC accounts for about three percent of the total number of malignant neoplasms, making it one of the ten most common forms of cancer. The incidence of HNC in the Netherlands has ranged from 3000 to 3250 new cases per year over the past 10 years, with an increase in the incidence of oral cavity and oropharyngeal tumors and a decrease in laryngeal cancer [5]. This increase in the incidence of oropharyngeal cancer is consistent with global figures, in which the increased incidence of human papilloma virus (HPV) related oropharyngeal squamous cell carcinoma accounts for most of this growth [6]. While tobacco and alcohol use remain the leading causes of HNC, the incidence of laryngeal cancer is slowly declining, in part due to decreased tobacco use [3]. Treatment of head and neck cancer Due to the complexity of diagnostic procedures and therapeutic modalities, HNC treatment is centralized in dedicated multidisciplinary HNC centers [7]. According to the Dutch Cooperative Head & Neck Group, treatment should start within 30 calendar days after the first consultation in 80% of the patients [2]. To minimize the time between the first consultation and the start of treatment, a multidisciplinary consultation on the first day has been introduced in several

10 Chapter 1 institutions [8]. At the Comprehensive Cancer Center of Maastricht University Medical Center (MUMC+) and the Maastro Clinic, the patient is seen during the first consultation by a head and neck surgeon in oral and maxillofacial surgery (OMS), a head and neck surgeon in otolaryngology (ENT) and a head and neck radiation-oncologist. On the same day, the patient is examined by an oral hygienist, a maxillofacial prosthodontist and, if necessary, an anaplastologist. If a biopsy has not yet been performed, it will also be scheduled on the day of the initial consultation. Day 2 is primarily used for imaging, including CT or MRI and ultrasound of the neck. On day 3, the multidisciplinary tumor board (MDT) of the head and neck working group is held, in which the patient is discussed including all the results of the diagnostic tests. The TNM-staging system is used for classification and a proposal for the therapeutic concept is determined based on this [3, 9, 10]. The multidisciplinary team is complemented by plastic surgery, medical oncology, dermatology, oncology nursing care, dietetics, speech therapy, physiotherapy and psychosocial care to achieve structural and functional preservation, improve morbidity when possible and maintain longterm quality of life (QoL) [3]. Following the MDT, the recommended treatment plan is discussed with the patient. For early-stage cancers of the oral cavity and paranasal sinuses, surgery is the treatment of choice with high cure rates and limited morbidity. Early-stage oropharyngeal cancer can be treated by primary surgery or radiotherapy (RT), with RT playing an important role in preserving the larynx in patients with laryngeal cancer [3]. In locally advanced disease, the preferred therapy depends largely on the size and anatomic location of the primary tumor, disease stage, patient age, patient preferences, performance status, and coexisting diseases. For cancer of the oral cavity surgical resection remains the treatment of choice, followed by adjuvant RT, which may be combined with chemotherapy (CRT). At other anatomical sites, surgical resection would likely result in poor longterm functional outcomes, and RT combined with chemotherapy (CRT) is the curative standard of care. CRT is reserved for nonelderly patients who do not have serious comorbidities. RT is usually administered five days per week for seven weeks in fractions of 2Gy up to 66Gy in 33 fractions or 70Gy in 35 fractions in case of postoperative and primary RT, respectively. This is combined with cisplatin administered intravenously every three weeks at a dose of 100 mg/m2 [11, 12]. Cetuximab is considered in patients ineligible for cisplatin and consists of a loading dose of 400 mg/m2 followed by 250 mg/m2 weekly, combined with accelerated fractionated RT up to 68Gy in 34 fractions in 38 days [13].

11 General introduction 1 Side-effects of the treatment Surgical resection can be mutilating and result in altered oral anatomy, tooth loss, reduction in maximum mouth opening (MMO), and soft tissue and bone defects. These side-effects can have an impact on patients’ outer appearance, social interaction and oral functions, such as mastication, deglutition, and phonetics [14-17]. For example, treatment of malignant diseases of the tongue and/or floor of mouth can significantly worsen tongue function, masticatory performance, bite force, and dental status [17-20]. Treatment of malignant diseases of the maxilla and midface, can lead to leakage through the nose, impaired speech intelligibility due to loss of air, and impaired masticatory performance [21, 22]. RT also causes damage to normal tissues located within the radiation field, e.g. skin, soft tissues of the neck, salivary glands, oral mucosa, bones, dentition, chewing and swallowing muscles, and the temporomandibular joint. The clinical consequences of RT can be divided in acute and late (lifelong) side effects. Acute side effects include mucositis, hyposalivation, loss of taste, dermatitis, pain, hair loss, and dysphagia. Late side effects include soft tissue fibrosis, xerostomia, osteoradionecrosis (ORN), radiation caries, and trismus [23]. Hyposalivation leads to a deterioration of the lubrication of the oral cavity. This can cause radiation caries, an increase in periodontal problems, dysphagia, speech problems and problems wearing dentures. These side effects impact QoL and may persist forever [16, 24-26]. The most feared side effect is ORN [27]. ORN is defined as ‘irradiated bone that becomes devitalized and is exposed through the overlying skin or mucosa, without tumor recurrence, and does not heal within 3 months’ [28]. Although the risk of ORN has decreased to nearly 5% today [27, 29] due to careful patient selection, improved pre- and post-treatment dental care and individualized RT dose calculation algorithms, the impact of ORN on oral function and QoL remains catastrophic [30-33]. CRT or bioradiotherapy (BRT) can cause severe toxicity both during treatment (acute symptoms) and in the longer term. In addition to the acute symptoms of RT itself, dysphagia, oral pain, taste (dysgeusia or hypogeusia) and smell (dysosmia or hyposmia) disturbances, nausea, and vomiting are more common when chemotherapy or biotherapy is added to RT. These symptoms interfere

12 Chapter 1 with oral intake and often lead to weight loss and dehydration during and immediately after CRT [34]. Unintentional weight loss and low muscle mass, the clinical features of cachexia [35], negatively impact treatment-related toxicity and oncologic outcome. Patients with HNC and unintentional weight loss and/ or low muscle mass experience higher toxicity, more unplanned hospitalizations, and poorer overall survival [36-38]. Worldwide, patients with HNC cite fear of the cancer relapse as by far the greatest concern after cancer treatment [39, 40]. However, this main concern is closely followed by the side effects of cancer treatment, with the most important side effects being: Dry mouth, chewing/eating, swallowing, speech/voice/being understood, and dental health/teeth [40]. Young age at diagnosis combined with a better prognosis for HPV-positive HNC and thus a longer life expectancy has increased awareness of late treatment-related toxicity [41]. Consequences of the loss of dental functions Teeth may be lost due to surgical resection of an oral cavity tumor, but also due to the removal of potential oral sources of infection prior to RT, CRT or BRT to prevent ORN [42, 43]. Tooth extractions result in a reduced number of functional units and impair the ability to chew and swallow [44, 45]. The implications of disrupting our masticatory system are great. Qualitative studies have shown that this multiple tooth loss negatively affects patients’ ability to chew and eat, and thus their quality of life [46-48]. Specifically, a greater number of missing teeth is associated with a reduced maximum bite force (MBF), decreased masticatory performance, and self-perceived oral health status [44, 49, 50]. Compared to the non-cancer general dental practitioners group, patients with HNC rated oral function issues as more important than other domains. Other issues such as pain, appearance, activity, recreation, mood, and anxiety were considered less important [51]. Despite the fact that masticatory performance can often return to pre-treatment levels after surgery, even in patients who survive for five years, some degree of masticatory impairment persists and may affect the ability to eat [17, 44]. RT and its side effects on the quantity and quality of saliva, oral mucosa, and masticatory muscles, exacerbate masticatory problems [17]. The masticatory performance of patients with oral cavity cancer is positively affected by having full dentures or better, a higher number of occlusal units (OU), an increased MMO, and an increased maximum bite force (MBF). The location of the tumor also plays an important role [44].

13 General introduction 1 Role of the maxillofacial prosthodontists in rehabilitation Therefore, there is a need and demand among patients for dental rehabilitation aimed at restoring orofacial form and function as well as overall well-being. Dental rehabilitation begins at the time of diagnosis, and a multidisciplinary approach is critical for optimal treatment outcomes [49]. Dental and prosthodontic rehabilitation and the planning required to achieve it are preferably performed by a maxillofacial prosthodontist and should preferably begin on the day of the initial admission [52]. Rehabilitation is performed in concert with reconstructive surgical options and requires cooperation with oral and maxillofacial surgeons, head and neck oncologists, radiation oncologists, anaplastologists, general and differentiated dentists, and allied health care providers. Maxillofacial prosthodontics is a differentiation of dentistry that involves rehabilitation of patients with defects or disabilities that were present when born or acquired due to disease or trauma. The patients with HNC belong to the group of acquired defects. The rehabilitation consists of replacing missing bone and other tissues and restoring oral functions such as chewing, swallowing, and speaking. Often this rehabilitation is combined with traditional dental therapy to restore oral health, function and esthetics, especially when the oral cavity is compromised by RT [53, 54]. During the initial consultation, a comprehensive assessment of the patients and their oral condition is critical. A thorough pretreatment oral and dental screening, including the patient’s medical and dental history and clinical and radiographic examination, should be performed considering patient-related factors such as age, patient preferences, dental awareness, level of oral hygiene, and cancer treatment-related factors such as clinical staging and tumor location, cure or palliation decisions, treatment modality, type, dose, and range of RT, and immediacy of treatment [17, 42, 43]. The dentate patient In patients with remaining natural teeth, removal of teeth with limited prognosis identified as potential cause of oral cavity infection before head and neck RT is associated with a lower risk of developing ORN than tooth extractions after or during RT [55]. In the Netherlands, oral health recommendations prior to RT are based on a 1992 protocol, which was revised in 2018 [42, 43, 56]. To give extraction wounds sufficient time (at least 10 to 14 days) to heal before starting RT, decisions

14 Chapter 1 are made based on the expected radiation dose. Because the risk of developing ORN begins at an RT dose of approximately 40Gy [27], it is desirable to eliminate oral sources of infection that are likely to be within the radiation field and receive a cumulative dose of ≥40Gy [43, 57]. Ideally, the dentition should be preserved as much as possible to allow optimal rehabilitation of masticatory function and QoL, but treatment plans should be based on basic principles of prosthodontics, including a philosophy of preventive and conservative restorative dentistry [17]. This includes the role of natural teeth as an anchor point for a removable partial denture or as a pillar for (semi)fixed prosthetic rehabilitation [49]. The edentulous patient In a completely edentulous patient, successful prosthetic rehabilitation depends on the existing anatomical base. The hard palate in the upper jaw provides a stable base for this prosthetic rehabilitation. In de mandible, only a horseshoeshaped base is available, so the tongue, lips and cheeks play an important role in stabilizing the prosthesis. When oral anatomy changes due to HNC treatment, it can be very difficult to place a stable and retentive prosthesis. In addition, altered lubrication of the oral cavity may cause the prosthesis to damage the mucosa [23]. Implant-retained dentures (IODs) are a standard treatment for patients with HNC and appear to contribute to successful overall treatment [58-60]. However, the percentage of patients in HNC therapy who receive dental implants varies widely from 22% to 91% [25]. In the maxilla, the stable prosthetic base of the hard palate may be lost due to trauma, infection or tumor resection. This can lead to leakage through the nose, impaired speech intelligibility due to loss of air and inability to chew resulting in enormous limitations in daily life [21, 22, 61]. Reconstruction of these defects remains a challenge for both surgeons and prosthodontists due to the complex three-dimensional anatomy of the maxilla and midface and is controversial [62-65]. Valid arguments have been presented for choosing the best reconstruction and rehabilitation method based on parameters such as QoL and functional outcomes [66-69]. Regardless of the rehabilitation method, defects that encompass a significant portion of the alveolus must be rehabilitated to allow optimal masticatory behavior and appearance of teeth [64]. A significant number of surgically reconstructed patients will remain excluded from dental rehabilitation and will not return to normal eating [70].

15 General introduction 1 Therefore, prosthetic obturation seems to be the preferred treatment modality for many patients, generally leading to an improvement in masticatory function [22, 71, 72]. However, this prosthetic treatment is challenging due to insufficient retention, among other reasons [71]. As in the mandible, implant retention, especially in edentulous patients, has also proven successful in prosthetic rehabilitation in the maxilla [64, 73-76].

16 Chapter 1 References 1. Rettig, E.M. and G. D’Souza, Epidemiology of head and neck cancer. Surg Oncol Clin N Am, 2015. 24(3): p. 379-96. 2. Federatie Medisch Specialisten, Werkgroep normen voor oncologienetwerken, SONCOS NORMERINGSRAPPORT versie 10 (2022). Available from: https://demedischspecialist. nl/normeringsrapport-van-soncos. 3. Chow, L.Q.M., Head and Neck Cancer. N Engl J Med, 2020. 382(1): p. 60-72. 4. Ferlay, J., et al. Global Cancer Observatory: Cancer Today. Available from: https://gco. iarc.fr/today, accessed on [28.03.2023]. 5. IKNL. Nederlandse Kankerregistratie (NKR). Available from: iknl.nl/nkr-cijfers, accessed on [07-09-2022]. 6. Auperin, A., Epidemiology of head and neck cancers: an update. Curr Opin Oncol, 2020. 32(3): p. 178-186. 7. Dutch Cooperative Head & Neck Group (NWHHT), Policy head and neck cancer care 2013. (BELEIDSNOTITIE HOOFD-HALS ONCOLOGISCHE ZORG 2013). Available from: https://www.nwhht.nl/. 8. van Huizen, L.S., et al., Multidisciplinary first-day consultation accelerates diagnostic procedures and throughput times of patients in a head-and-neck cancer care pathway, a mixed method study. BMC Health Serv Res, 2018. 18(1): p. 820. 9. Edge, S.B. and C.C. Compton, The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol, 2010. 17(6): p. 1471-4. 10. Huang, S.H. and B. O’Sullivan, Overview of the 8th Edition TNM Classification for Head and Neck Cancer. Curr Treat Options Oncol, 2017. 18(7): p. 40. 11. Blanchard, E.M., et al., Comparison of platinum-based chemotherapy in patients older and younger than 70 years: an analysis of Southwest Oncology Group Trials 9308 and 9509. J Thorac Oncol, 2011. 6(1): p. 115-20. 12. Blanchard, P., et al., Meta-analysis of chemotherapy in head and neck cancer (MACHNC): a comprehensive analysis by tumour site. Radiother Oncol, 2011. 100(1): p. 33-40. 13. Bonner, J.A., et al., Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med, 2006. 354(6): p. 567-78. 14. Tang, J.A., J.M. Rieger, and J.F. Wolfaardt, A review of functional outcomes related to prosthetic treatment after maxillary and mandibular reconstruction in patients with head and neck cancer. Int J Prosthodont, 2008. 21(4): p. 337-54. 15. Vissink, A., et al., Prevention and treatment of the consequences of head and neck radiotherapy. Crit Rev Oral Biol Med, 2003. 14(3): p. 213-25. 16. Speksnijder, C.M., et al., Oral function after oncological intervention in the oral cavity: a retrospective study. J Oral Maxillofac Surg, 2010. 68(6): p. 1231-7. 17. Pace-Balzan, A., R.J. Shaw, and C. Butterworth, Oral rehabilitation following treatment for oral cancer. Periodontol 2000, 2011. 57(1): p. 102-17. 18. Speksnijder, C.M., et al., Mastication in patients treated for malignancies in tongue and/or floor of mouth: A 1-year prospective study. Head Neck, 2011. 33(7): p. 1013-20.

17 General introduction 1 19. Speksnijder, C.M., et al., Tongue function in patients treated for malignancies in tongue and/or floor of mouth; a one year prospective study. Int J Oral Maxillofac Surg, 2011. 40(12): p. 1388-94. 20. Wetzels, J.W., et al., Maximum mouth opening and trismus in 143 patients treated for oral cancer: a 1-year prospective study. Head Neck, 2014. 36(12): p. 1754-62. 21. Umino, S., et al., Speech intelligibility following maxillectomy with and without a prosthesis: an analysis of 54 cases. J Oral Rehabil, 1998. 25(2): p. 153-8. 22. Vero, N., et al., Assessment of swallowing and masticatory performance in obturator wearers: a clinical study. J Adv Prosthodont, 2015. 7(1): p. 8-14. 23. Vissink, A., et al., Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med, 2003. 14(3): p. 199-212. 24. Braam, P.M., et al., Quality of life and salivary output in patients with head-and-neck cancer five years after radiotherapy. Radiat Oncol, 2007. 2: p. 3. 25. Korfage, A., et al., Five-year follow-up of oral functioning and quality of life in patients with oral cancer with implant-retained mandibular overdentures. Head Neck, 2011. 33(6): p. 831-9. 26. Dirix, P., et al., The influence of xerostomia after radiotherapy on quality of life: results of a questionnaire in head and neck cancer. Support Care Cancer, 2008. 16(2): p. 171-9. 27. Spijkervet, F.K.L., et al., Research Frontiers in Oral Toxicities of Cancer Therapies: Osteoradionecrosis of the Jaws. J Natl Cancer Inst Monogr, 2019. 2019(53). 28. Lyons, A. and N. Ghazali, Osteoradionecrosis of the jaws: current understanding of its pathophysiology and treatment. Br J Oral Maxillofac Surg, 2008. 46(8): p. 653-60. 29. Burns, M. and V. Patel, Osteonecrosis of the jaw in primary dental care: Recognition and referral. Prim Dent J, 2022. 11(3): p. 108-116. 30. Patel, V., et al., Presenting pre-radiotherapy dental status of head and neck cancer patients in the novel radiation era. Br Dent J, 2020. 228(6): p. 435-440. 31. Nabil, S. and N. Samman, Risk factors for osteoradionecrosis after head and neck radiation: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol, 2012. 113(1): p. 54-69. 32. Schuurhuis, J.M., et al., Efficacy of routine pre-radiation dental screening and dental follow-up in head and neck oncology patients on intermediate and late radiation effects. A retrospective evaluation. Radiother Oncol, 2011. 101(3): p. 403-9. 33. Irie, M.S., et al., Periodontal therapy for patients before and after radiotherapy: A review of the literature and topics of interest for clinicians. Med Oral Patol Oral Cir Bucal, 2018. 23(5): p. e524-e530. 34. Bressan, V., et al., The effects of swallowing disorders, dysgeusia, oral mucositis and xerostomia on nutritional status, oral intake and weight loss in head and neck cancer patients: A systematic review. Cancer Treat Rev, 2016. 45: p. 105-19. 35. Fearon, K., et al., Definition and classification of cancer cachexia: an international consensus. Lancet Oncol, 2011. 12(5): p. 489-95. 36. Cho, Y., et al., Prognostic Significance of Sarcopenia With Inflammation in Patients With Head and Neck Cancer Who Underwent Definitive Chemoradiotherapy. Front Oncol, 2018. 8: p. 457.

18 Chapter 1 37. Findlay, M., et al., The Association Between Computed Tomography-Defined Sarcopenia and Outcomes in Adult Patients Undergoing Radiotherapy of Curative Intent for Head and Neck Cancer: A Systematic Review. J Acad Nutr Diet, 2020. 120(8): p. 1330-1347 e8. 38. Willemsen, A.C.H., et al., Disease-induced and treatment-induced alterations in body composition in locally advanced head and neck squamous cell carcinoma. J Cachexia Sarcopenia Muscle, 2020. 11(1): p. 145-159. 39. Kanatas, A., et al., Issues patients would like to discuss at their review consultation: variation by early and late stage oral, oropharyngeal and laryngeal subsites. Eur Arch Otorhinolaryngol, 2013. 270(3): p. 1067-74. 40. Rogers, S.N., et al., Variations in concerns reported on the patient concerns inventory in patients with head and neck cancer from different health settings across the world. Head Neck, 2020. 42(3): p. 498-512. 41. Ang, K.K., et al., Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med, 2010. 363(1): p. 24-35. 42. Schuurhuis, J.M., et al., Patients with advanced periodontal disease before intensitymodulated radiation therapy are prone to develop bone healing problems: a 2-year prospective follow-up study. Support Care Cancer, 2018. 26(4): p. 1133-1142. 43. Spijkervet, F.K.L., et al., Should oral foci of infection be removed before the onset of radiotherapy or chemotherapy? Oral Dis, 2021. 27(1): p. 7-13. 44. de Groot, R.J., et al., Masticatory function and related factors after oral oncological treatment: A 5-year prospective study. Head Neck, 2019. 41(1): p. 216-224. 45. Brahm, C.O., et al., Patients with head and neck cancer treated with radiotherapy: Their experiences after 6 months of prophylactic tooth extractions and temporary removable dentures. Clin Exp Dent Res, 2021. 46. Parahoo, R.S., et al., The experience among patients with multiple dental loss as a consequence of treatment for head and neck cancer: A qualitative study. J Dent, 2019. 82: p. 30-37. 47. Clough, S., et al., The impact of pre-radiotherapy dental extractions on head and neck cancer patients: a qualitative study. Br Dent J, 2018. 225(1): p. 28-32. 48. Mahmood, R., et al., Characteristics and referral of head and neck cancer patients who report chewing and dental issues on the Patient Concerns Inventory. Br Dent J, 2014. 216(11): p. E25. 49. Pace-Balzan, A. and S.N. Rogers, Dental rehabilitation after surgery for oral cancer. Curr Opin Otolaryngol Head Neck Surg, 2012. 20(2): p. 109-13. 50. Fontijn-Tekamp, F.A., et al., Biting and chewing in overdentures, full dentures, and natural dentitions. J Dent Res, 2000. 79(7): p. 1519-24. 51. Metcalfe, C.W., D. Lowe, and S.N. Rogers, What patients consider important: temporal variations by early and late stage oral, oropharyngeal and laryngeal subsites. J Craniomaxillofac Surg, 2014. 42(5): p. 641-7. 52. Vosselman, N., et al., Prosthodontic rehabilitation of head and neck cancer patientsChallenges and new developments. Oral Dis, 2021. 27(1): p. 64-72. 53. American Academy of Maxillofacial Prosthetics, What is a Maxillofacial Prosthodontist?. Available from: https://www.maxillofacialprosthetics.org/referring_physicians/what_is_ mp/.

19 General introduction 1 54. NVGPT. De tandarts maxillofaciale prothetiek. Available from: https://www.nvgpt.nl/ patienten/de-tandarts-maxillofaciale-prothetiek , accessed on [28.03.2023]. 55. Normando, A.G.C., et al., To extract or not extract teeth prior to head and neck radiotherapy? A systematic review and meta-analysis. Support Care Cancer, 2022. 30(11): p. 8745-8759. 56. Jansma, J., et al., Protocol for the prevention and treatment of oral sequelae resulting from head and neck radiation therapy. Cancer, 1992. 70(8): p. 2171-80. 57. Schuurhuis, J.M., et al., [A PhD completed 9. The value of oral foci screening in oncology patients]. Ned Tijdschr Tandheelkd, 2017. 124(5): p. 279-281. 58. Smolka, K., et al., Fibula free flap reconstruction of the mandible in cancer patients: evaluation of a combined surgical and prosthodontic treatment concept. Oral Oncol, 2008. 44(6): p. 571-81. 59. Korfage, A., et al., Benefits of dental implants installed during ablative tumour surgery in oral cancer patients: a prospective 5-year clinical trial. Clin Oral Implants Res, 2010. 21(9): p. 971-9. 60. Nelson, K., S. Heberer, and C. Glatzer, Survival analysis and clinical evaluation of implant-retained prostheses in oral cancer resection patients over a mean follow-up period of 10 years. J Prosthet Dent, 2007. 98(5): p. 405-10. 61. Reitemeier, B., et al., Clinical test of masticatory efficacy in patients with maxillary/ mandibular defects due to tumors. Onkologie, 2012. 35(4): p. 170-4. 62. Santamaria, E. and P.G. Cordeiro, Reconstruction of maxillectomy and midfacial defects with free tissue transfer. J Surg Oncol, 2006. 94(6): p. 522-31. 63. Hanasono, M.M., et al., A comprehensive algorithm for oncologic maxillary reconstruction. Plast Reconstr Surg, 2013. 131(1): p. 47-60. 64. Brown, J., A. Schache, and C. Butterworth, Liverpool Opinion on Unfavorable Results in Microsurgical Head and Neck Reconstruction: Lessons Learned. Clin Plast Surg, 2016. 43(4): p. 707-18. 65. Mertens, C., et al., Reconstruction of the maxilla following hemimaxillectomy defects with scapular tip grafts and dental implants. J Craniomaxillofac Surg, 2016. 44(11): p. 1806-1811. 66. Brandao, T.B., et al., Obturator prostheses versus free tissue transfers: A systematic review of the optimal approach to improving the quality of life for patients with maxillary defects. J Prosthet Dent, 2016. 115(2): p. 247-253 e4. 67. Sharaf, M.Y., et al., Prosthetic versus surgical rehabilitation in patients with maxillary defect regarding the quality of life: systematic review. Oral Maxillofac Surg, 2018. 22(1): p. 1-11. 68. Dos Santos, D.M., et al., Oral rehabilitation of patients after maxillectomy. A systematic review. Br J Oral Maxillofac Surg, 2018. 56(4): p. 256-266. 69. Cao, Y., et al., Obturators versus flaps after maxillary oncological ablation: A systematic review and best evidence synthesis. Oral Oncol, 2018. 82: p. 152-161. 70. Triana, R.J., Jr., et al., Microvascular free flap reconstructive options in patients with partial and total maxillectomy defects. Arch Facial Plast Surg, 2000. 2(2): p. 91-101. 71. Andrades, P., et al., Current strategies in reconstruction of maxillectomy defects. Arch Otolaryngol Head Neck Surg, 2011. 137(8): p. 806-12. 72. Sharma, A.B. and J. Beumer, 3rd, Reconstruction of maxillary defects: the case for prosthetic rehabilitation. J Oral Maxillofac Surg, 2005. 63(12): p. 1770-3.

20 Chapter 1 73. Goiato, M.C., et al., Implants in the zygomatic bone for maxillary prosthetic rehabilitation: a systematic review. Int J Oral Maxillofac Surg, 2014. 43(6): p. 748-57. 74. Huang, W., et al., Long-term results for maxillary rehabilitation with dental implants after tumor resection. Clin Implant Dent Relat Res, 2014. 16(2): p. 282-91. 75. Boyes-Varley, J.G., et al., A protocol for maxillary reconstruction following oncology resection using zygomatic implants. Int J Prosthodont, 2007. 20(5): p. 521-31. 76. Butterworth, C.J., Immediately Loaded Zygomatic Implant Retained Maxillary Obturator used in Management of a Patient following Total Maxillectomy. Int J Head Neck Surg, 2018. 9(2): p. 94-100.

22 Chapter 1

23 Aims and outline of this thesis 1 Aims and outline of this thesis With the changing head and neck cancer (HNC) population, advances in surgical techniques and innovative radiation systems, the focus is shifting from survival to survival with the best possible quality of life (QoL). As a result, attention to the side effects of cancer treatment is increasing. Fear of cancer recurrence is now closely followed by concerns about dry mouth, chewing, swallowing, speach, and dental health. Therefore, it is becoming increasingly important to optimize each patient’s masticatory system to improve QoL. Patient-related factors such as age, patient preferences, dental awareness and factors related to cancer treatment should be considered. The overall aim of this thesis is to evaluate the masticatory function after prosthetic rehabilitation of edentulous HNC patients and to assess the accuracy and possible consequences of tooth extractions prior to radiotherapy (RT). The first section of this thesis focuses on the prosthetic rehabilitation of edentulous patients with an acquired defect and/or side effects after RT (Chapters 2-4). The second section examines the initial steps in the search for optimal preservation of the existing masticatory system of the patient with HNC (Chapters 5-6). In Chapter 2 we examined the overall percentage of functioning mandibular prostheses with and without implant retention in irradiated patients with HNC. In addition, we determined patient satisfaction with dental rehabilitation in terms of QoL. The available general QoL questionnaires, such as the EORTC QLQ-C30 en QLQH&N35, lack the discriminating ability to measure the effect of prosthodontic treatment on chewing, swallowing, speech, aesthetics, retention, and pain. In 2004 the Liverpool Oral Rehabilitation Questionnaire (LORQ) was developed to provide a more sophisticated measure of the impact of prosthetic treatment on QoL in patients with HNC. In order to be able to use the LORQv3 for Dutchspeaking patients we translated the questionnaire into Dutch and evaluated the internal consistency, reliability, and validity of the resulting LORQv3-NL in Chapter 3. Mastication with an obturator prosthesis is challenging, especially when retention is limited, as in edentulous patients. In Chapter 4, we evaluated the potential benefits of implant placement on masticatory performance and

24 Chapter 1 QoL of edentulous maxillectomy patients after prosthetic obturation (4a), and compared the objective and subjective masticatory function of patients with implant-supported obturators with patients with surgically reconstructed maxillae (4b). Removal of teeth with limited prognosis, identified as a potential cause of oral cavity infection prior to head and neck RT, is associated with a lower risk of developing osteoradionecrosis (ORN). At the same time, tooth extractions result in a reduced number of functional units and impair both chewing and swallowing. To ensure that extraction wounds have adequate time to heal (at least 10 to 14 days) before starting RT, the decision of whether extraction is warranted is made based on the expected radiation dose. However, for some of the extracted teeth, it may be found after completion of RT that the extraction was not indicated due to the RT dose received being lower than expected. In Chapter 5 we examined the number and patient and tumor characteristics associated with this number of redundantly extracted teeth. After HNC treatment, sufficient time must be allowed for adequate wound healing before successful prosthetic rehabilitation can begin. This means that patients who have to undergo RT have a deteriorated masticatory system during this RT. This impairment in mastication has been associated with oropharyngeal dysphagia, and oropharyngeal dysphagia is significantly related to involuntary weight loss. In Chapter 6, we examined the effects of incomplete dentition and tooth extractions on weight loss during RT combined with chemotherapy (CRT) or biotherapy (BRT) and the need for tube feeding during CRT or BRT for patients with oropharyngeal carcinoma.

CHAPTER 2 PROSTHETIC REHABILITATION OF HEAD AND NECK CANCER PATIENTS FOCUSING ON MANDIBULAR DENTURES IN IRRADIATED PATIENTS. Doke J.M. Buurman Lauretta A. Vaassen Roland Böckmann Peter Kessler Published in The International Journal of Prosthodontics. November/December 2013

28 Chapter 2 Abstract Purpose: This retrospective study assessed treatment outcomes and patient satisfaction of irradiated head and neck cancer patients treated with mandibular implant overdentures (IODs) or conventional dentures (CDs). Materials and Methods: Fifty-one irradiated head and neck cancer patients, out of a total of 158 patients included, completed the standardized questionnaire and underwent a clinical assessment. Nineteen patients were treated with removable CDs and 32 patients received IODs between January 2006 and January 2011. The mean follow up of the patients after diagnosis was 5.75 years (range: 1 to 23 years). Results: A total of 45 (88,3%) mandibular dentures were in function at the time of assessment. The overall denture satisfaction was 7.3 (range 1 to 10, SD: 2.14). Patients being treated with adjuvant concepts, including surgical tumor ablation, scored worse than patients after radiation therapy alone. Edentulous patients seem to benefit from implants, especially with respect to prosthesis retention. Men take more benefit from IODs compared to women. Conclusions: The results are comparable to other studies in head and neck cancer patients and also of healthy individuals. Surgical interventions in adjuvant therapy concepts lead to reduced denture satisfaction. The concept of prosthetic rehabilitation as part of oncologic treatment can be judged as successful.

29 Mandibular Dentures in Head and Neck Cancer Patients 2 Introduction Treatment of head and neck cancer has an enormous impact on patients’ lives. Therapy-related functional and esthetic problems directly influence the outer appearance, social interaction and oral functions, such as mastication, swallowing, speech and nutrition of patients [1-3]. Current advances in microsurgery in combination with dental implants have led to better functional and esthetic outcomes [4]. However, radiation therapy and chemotherapy still cause unfavorable side effects such as reduced swallowing ability, xerostomia, and a painful and tender mucosa [2, 3, 5]. These side effects have an impact on the quality of life (QoL) and may last forever [3, 6-8]. In the rehabilitation process, after tumor treatment, prosthetic rehabilitation plays a prominent role in improving oral functions and QoL [7, 9]. Implantretained dentures (IODs) are a standard treatment in head and neck cancer patients. Several studies in irradiated and nonirradiated patients presented high implant survival rates varying from 69% to nearly 99% [4, 10, 11]. However, the percentage of head and neck oncology patients, who are rehabilitated with the use of implants widely varies from 22% to 91% [7]. There are different reasons for this variation. Among others, survival rate, length of follow-up, and financial aspects play important roles depending on local insurance regulations. A positive correlation can be found between denture satisfaction and overall QoL in head and neck cancer patients [12]. There is some evidence regarding better outcomes for IODs in edentulous individuals compared with conventional dentures (CDs) [13, 14]. For irradiated edentulous patients, the same assumptions have been made [10, 11, 15]. This might imply that IODs increase denture satisfaction and the overall QoL in head and neck cancer patients. Thus, prosthetic rehabilitation appears to aid in a successful overall treatment of head and neck cancer. The objectives of this retrospective study were threefold: to assess the overall percentage of functioning IODs and CDs and to determine patient satisfaction with dental rehabilitation with respect to QoL in both the IOD and CD groups. Data acquisition was based on patients treated for primary head and neck cancer at the Maastricht University Medical Center (MUMC) who had to undergo radiation therapy at the Maastro clinic between January 2006 and January 2011.

30 Chapter 2 Materials and Methods One hundred fifty-eight patients suffering from head and neck cancer were extracted from the overall population of head and neck cancer patients of the Department of Cranio-Maxillofacial Surgery, MUMC). The authors made a list of patients for whom dental technician work had been done. Their medical files were then reviewed to determine if they were edentulous, had received an IOD or CD between January 2006 and January 2011, and if radiation therapy had been mentioned. All patients received an invitation and response letter for participation in this study. The total response rate was 68.4% (n = 108). Sixty-nine patients agreed to participate, 30 patients refused, 5 patients were not irradiated for various reasons, 1 patient died, 3 patients moved, and 50 patients did not respond to the letter. All patients ready to participate in the study were invited to visit the clinic to complete a questionnaire. They were assisted by a researcher. Of the 69 people invited by phone, 13 failed to show up for their appointment, 2 fell ill, 1 responded too late to the invitation, and 2 appeared but refused to answer the questions. 51 irradiated patients 32 men (62.7%) 19 women (37.3%) 32 implant-retained mandibular dentures (62.7%) 19 conventional mandibular dentures (37.3%) 22 surgeries for malignancy (71.9%) 10 had no surgery for malignancy (28.1%) 11 surgeries for malignancy (57.9%) 8 had no surgery for malignancy (42.1%) Figure 1 - Classification of the patients who completed the assessment and questionnaires. A total of 51 patients, 32 (62.7%) men and 19 (37.3%) women, completed the questionnaires (Fig 1). All patients were seen by the same researcher (LV). The oncological and medical history, as well as any current medications, were recorded. The following data were obtained: tumor classification according to the TNM classification, tumor location, oncological treatment, and whether or not the patient was irradiated by intense modulated radiation therapy (Table 1). The dimensions of the surgical defect in the mandible were classified as partial defects (box and slice osteotomies) and continuity defects, with or without bony reconstruction. There were five cases of maxillary resections. The center

31 Mandibular Dentures in Head and Neck Cancer Patients 2 of attention, however, was on the mandible as the radiation doses were focused on the lower third of the face and the neck. This region is more susceptible to functional impairment due to the fact that the tongue is situated in the irradiation field and, therefore, speech and swallowing are affected. A dental anamnesis was done followed by an oral examination (Table 2). The oral conditions and the state of the prosthetic rehabilitation were noted. The medical and dental anamnesis were standardized and completed with information from the patients’ medical records. Table 1 - Patient and Tumor Characteristics Patient n Minimum Maximum Mean SD Mean age (y) 51 52 84 67.2 7.586 Edentulous mandibule (y) 50 1 46 12.8 14.739 Follow-up (y) 51 1 23 5.75 4.293 Sex M 32 62.7% F 19 37.3% Tumor location Oral 23 45.1% Oropharynx 14 27.5% Laryngopharynx 11 21.6% Other 3 5.9% Surgery Y 33 64.7% N 18 35.3% Bony defect Without 44 86.3% Partial 0 0% Continuity 7 13.7% The questionnaire entitled “Satisfaction of the denture” was filled in together with the researcher (LV). General QoL was assessed with the Linear Analogue Self-Assessment method (one-item version). Overall denture satisfaction was expressed on a 10-point rating scale, range 1 to 10, 1 being completely dissatisfied and 10 being completely satisfied [9]. More detailed information about denture satisfaction was assessed using a validated questionnaire consisting of eight

32 Chapter 2 separate items focusing on the function of maxillary and mandibular dentures and on specific features such as esthetics, retention and functional comfort. All questions could score 1 to 5, 1 being most satisfied and 5 being most unsatisfied [16]. All data were evaluated using SPSS (IBM, version 18.0 for Mac). Table 2 - Dental Anamnesis and Oral Assessment as Administered Dental anamnesis: Edentulous since? Age at first mandibular denture? Do you wear your mandibular denture? Why not? Oral assessment: Dental status? Maxilla edentulous? Implant status for mandibule? How many implants? Stable implants? Dutch Periodontal Screening Instrument for implants and possible teeth in the maxilla. Condition of oral mucosa? Blister or ulcer by denture? Soft tissue defect?

33 Mandibular Dentures in Head and Neck Cancer Patients 2 Results Of the total number of patients (n = 51), 32 had an IOD and 19 a CD (Fig 1). The patient characteristics are shown in Table 1. In the 32 patients with an IOD, a total of 73 implants were placed in the mandible. Overall implant survival was 97.3% (71/73), and 95.9% (70/73) of the implants were in function after a mean time of 48.6 months (range: 14 to 132 months, SD: 32.1 months). Two implants were lost, one at stage-two surgery and the other due to malpositioning. In one patient, one of three implants was not activated, as it was not needed for the prosthetic rehabilitation. Most of the patients (n = 45, 88.3%) used their mandibular dentures (Table 3). Reasons for being unable to wear the mandibular denture were: anatomical changes in the oral cavity due to ablative surgery, pain, temporomandibular joint dysfunction, and dissatisfaction with design and esthetic aspects of the denture. Table 3 - Frequencies of Patients Wearing Their Dentures Frequency % Yes 39 76.5 Most of the time 6 11.8 Mostly not 4 7.8 Never 2 3.9 Total 51 100 Patients answering “yes” or “most of the time” were scored as “wearing their denture”. Patients answering “mostly not” or “never” were scored as “not wearing their denture”. Table 4 - Denture Satisfaction Scores for the Total Group n Minimum Maximum Mean Overall Denture Satisfaction 49 1 10 7.3 Mandibular Denture Satisfaction 48 1 10 7.4 Range: 0 to 10 with 0 being completely dissatisfied and 10 being completely satisfied. The missing patients were not able to wear their dentures because of changes in anatomy due to recent surgery.

34 Chapter 2 Overall denture satisfaction was obtained separately for the complete prosthetic restoration and for the mandibular denture (Table 4). There was no difference in overall denture satisfaction between the CD group (mean: 7.33, SD: 1.97) and the IOD group (mean: 7.29, SD: 2.26) (Table 5). The slight difference in overall mandibular denture satisfaction between the CD group (mean: 6.88, SD: 1.80) and the IOD group (mean: 7.73, SD: 2.50) was not significant. A detailed analysis showed a significant difference for the item “retention” in favor of the IOD group (mean: 1.77, SD: 0.83) versus de CD group (mean: 2.50, SD: 1.16) (Table 5). Table 5 - Comparing the CD Group with the IOD Group CD mean (n = 18) IOD mean (n = 31) Total (mean) p Overall denture satisfaction 7.3333 7.2903 7.3061 .947 Mandibular denture satisfaction 6.8824 7.7258 7.4271 .227 Retention 2.5000 1.7742 2.0408 .014 For the items “overall denture satisfaction” and “mandibular denture satisfaction” the range was 0 to 10 with 0 being completely dissatisfied and 10 being completely satisfied. For “retention”, 1 = very satisfied, 2 = satisfied, 3 = neutral, 4 = dissatisfied, and 5 = very dissatisfied. In regard to sex, there were no significant differences found in the CD group; however, significant differences were found in the IOD group. Men scored better in “overall denture satisfaction” and “overall mandibular denture satisfaction”, specifically with regard to “mandibular denture” and “appearance”. The items “functional comfort” and “speaking” were also judged more favorably by men than women (Table 6). Regarding men, the difference in “overall mandibular denture satisfaction” became significant in favor of the IOD group, and in addition to the item “retention”, “mandibular denture” also scored significantly better in the IOD group (Table 7). When comparing patients after adjuvant therapy with patients after radiation therapy alone, there was a significantly better score for “appearance and speaking” from the group that underwent radiation therapy alone. For “eating” there was a strong trend in favor of the radiation therapy alone group (Table 8). Patients with mandibular continuity resection scored significantly worse on the items “eating and speaking” (Table 9).

35 Mandibular Dentures in Head and Neck Cancer Patients 2 Table 6 - Mean Scores for the IOD Group Men (n = 20) Women (n = 11) Total p Overall denture satisfaction 8.0250 5.9545 7.2903 .012 Mandibular denture satisfaction 8.4750 6.3636 7.7258 .022 Denture satisfaction General 1.9444 2.7273 2.2414 .076 Maxillary denture 2.1765 2.8000 2.4074 .217 Mandibular denture 1.6000 2.4545 1.9032 .037 Appearance 1.7000 2.5455 2.0000 .017 Retention 1.6500 2.0000 1.7742 .265 Functional comfort 1.8750 2.8182 2.2097 .052 Eating 1.9500 2.6364 2.1935 .109 Speaking 1.8500 2.6364 2.1290 .060 For the items “overall denture satisfaction” and “mandibular denture satisfaction”, the range was 0 to 10 with 0 being completely dissatisfied and 10 being completely satisfied. For items under the “denture satisfaction” heading, 1 = very satisfied, 2 = satisfied, 3 = neutral, 4 = dissatisfied, and 5 = very dissatisfied. Bold numbers indicate statistical significance (p ≤ .05). Table 7 - Significant Differences for Men with CDs versus Men with IODs CD (n = 10) IOD (n = 20) Total p Mandibular denture satisfaction 6.5556 8.4750 7.8793 .003 Mandibular denture 2.4444 1.6000 1.8621 .009 Retention 2.6000 1.6500 1.9667 .016 For the item “mandibular denture satisfaction” the range was 0 to 10 with 0 being completely dissatisfied and 10 being completely satisfied. For “mandibular denture” and “retention”, 1 = very satisfied, 2 = satisfied, 3 = neutral, 4 = dissatisfied, and 5 = very dissatisfied.

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