Site-specific radiation dosage and implant survival in oral cancer patients: A cohort study.

OBJECTIVES: We assessed the radiation dosages (Dmean ) on implant regions to identify the threshold for implant loss in patients with an intraoral malignancy treated with dental implants to support a mandibular denture during ablative surgery before volumetric-modulated arc therapy (VMAT). MATERIALS AND METHODS: Data was collected prospectively from 28 patients treated surgically for an intraoral malignancy, followed by postoperative radiotherapy (VMAT) and analyzed retrospectively. Patients received 2 implants in the native mandible during ablative surgery. Implant-specific Dmean values were retrieved from the patients' files. Radiographic bone loss was measured 1 year after implant placement and during the last follow-up appointment. Implant survival was analyzed with the Kaplan-Meier method. Univariate logistic regression and Cox-regression analyses were performed to investigate the effect of increasing implant-specific radiation dosages on implant loss. RESULTS: Five out of 56 placed implants were lost during follow-up (median 36.0 months, IQR 39.0). Radiographically, peri-implant bone loss occurred in implants with a Dmean > 40 Gy. Implant loss occurred only in implants with a Dmean > 50 Gy. CONCLUSION: An implant-specific Dmean higher than 50 Gy is related to more peri-implant bone loss and, eventually, implant loss.

Patients with advanced periodontal disease before intensity-modulated radiation therapy are prone to develop bone healing problems: a 2-year prospective follow-up study.

PURPOSE: Intensity-modulated radiation therapy (IMRT) has changed radiation treatment of head and neck cancer (HNC). However, it is still unclear if and how IMRT changes oral morbidity outcomes. In this prospective study, we assessed the outcome of reducing post-IMRT sequelae by means of pre-radiation dental screening and eliminating oral foci. METHODS: All consecutive dentate patients > 18 years, diagnosed with primary oral or oropharyngeal carcinoma, referred for pre-treatment dental screening between May 2011 and May 2013, were included and followed for 2 years. Patients were treated with IMRT or IMRT with chemotherapy (CHIMRT). Dental screening data, demographic data, and data on oral sequelae during follow-up were recorded. Diagnosed oral foci were treated before start of the radiation therapy. RESULTS: Oral foci were found in 44/56 (79%) patients, consisting predominantly of periodontal breakdown. Bone healing problems after radiotherapy occurred more often in patients with periodontal pockets ≥ 6 mm at baseline (19 vs. 4% in patients with pockets < 6 mm). Osteoradionecrosis developed in 4/56 patients (7%) during follow-up. In line with this observation, multiple logistic regression analysis showed that the periodontal inflamed surface area, which is higher in patients with more severe periodontal disease, predicted that a patient has a higher risk on developing osteoradionecrosis or bone healing problems (p = 0.028). CONCLUSIONS: Patients with severe periodontal disease before IMRT/CHIMRT are more prone to develop bone healing problems post-radiotherapy.

Predictors for trismus in patients receiving radiotherapy.

BACKGROUND: Trismus, a restricted mouth opening in head and neck cancer patients may be caused by tumor infiltration in masticatory muscles, radiation-induced fibrosis or scarring after surgery. It may impede oral functioning severely. The aims of our study were to determine: (1) the incidence of trismus at various time points; and (2) the patient, tumor, and treatment characteristics that predict the development of trismus after radiotherapy in head and neck cancer patients using a large database (n = 641). METHODS: Maximal mouth opening was measured prior to and 6, 12, 18, 24, 36, and 48 months after radiotherapy. Patient, tumor, and treatment characteristics were analyzed as potential predictors for trismus using a multivariable logistic regression analysis. RESULTS: At six months after radiotherapy, 28.1% of the patients without trismus prior to radiotherapy developed trismus for the first time. At subsequent time points the incidence declined. Over a total period of 48 months after radiotherapy, the incidence of trismus was 3.6 per 10 person years at risk. Patients who had tumors located in the oral cavity, oropharynx or nasopharynx, and the salivary glands or ear, and who had a longer overall treatment time of radiotherapy, were more likely to develop trismus in the first six months after radiotherapy. Maximal mouth opening was a predictor for developing trismus at all time points. CONCLUSION: Incidence of trismus is 3.6 per 10 person years at risk. Tumor localization and overall treatment time of radiotherapy are predictors for developing trismus the first six months after radiotherapy. Maximal mouth opening is a significant predictor for developing trismus at all time points. Regular measurements of maximal mouth opening are needed to predict trismus.

The association of frailty and outcomes of geriatric assessment with acute radiation-induced toxicity in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Geriatric impairments and frailty are highly prevalent in patients with head and neck cancer (HNC). This study investigated the association of frailty and outcomes of geriatric assessment (GA) with radiation-induced toxicity (RIT) in patients undergoing (chemo)radiotherapy ((C)RT) for HNC. MATERIALS AND METHODS: Between October 2014 and April 2016, patients with HNC were prospectively included in OncoLifeS, an institutional data-biobank. Before treatment initiation, patients underwent GA and frailty screening (Groningen Frailty Indicator and Geriatric 8). The main outcome of this study was RIT (weight loss, mucositis, salivary gland inflammation, oral pain, sore throat, hoarseness, dry mouth, dysgeusia, dysphagia and general pain) according to the common terminology criteria of adverse events (CTCAE) version 4.0. Linear mixed models were performed, to analyse factors associated with increasing mean RIT over time during the treatment period. RESULTS: 160 patients were included. 114 (71.3%) were male and the mean age was 66.1 years. Age ≥ 65 (ß = 0.03(95 %CI = 0.01;0.05), p = 0.01), regional RT (ß = 0.05(95 %CI = 0.02;0.09), p = 0.004), and concurrent chemotherapy (ß = 0.04(95 %CI = 0.02;0.07), p = 0.001), were independent factors associated with increasing toxicity during the 7-week treatment period, adjusted for relevant covariates. None of the single items of GA, as well as the frailty screening instruments, were associated with increasing RIT. CONCLUSION: In this study, frailty and GA were not associated with additional RIT during treatment. These results suggest that (C)RT is equally tolerated in frail and non-frail patients, with respect to acute RIT. RT could be a suitable alternative to surgery in selected frail patients.

Reduced radiation-induced toxicity by using proton therapy for the treatment of oropharyngeal cancer.

Patients with squamous cell carcinoma of the oropharynx are generally treated with (chemo) radiation. Patients with oropharyngeal cancer have better survival than patients with squamous cell carcinoma of other head and neck subsites, especially when related to human papillomavirus. However, radiotherapy results in a substantial percentage of survivors suffering from significant treatment-related side-effects. Late radiation-induced side-effects are mostly irreversible and may even be progressive, and particularly xerostomia and dysphagia affect health-related quality of life. As the risk of radiation-induced side-effects highly depends on dose to healthy normal tissues, prevention of radiation-induced xerostomia and dysphagia and subsequent improvement of health-relatedquality of life can be obtained by applying proton therapy, which offers the opportunity to reduce the dose to both the salivary glands and anatomic structures involved in swallowing.This review describes the results of the first cohort studies demonstrating that proton therapy results in lower dose levels in multiple organs at risk, which translates into reduced acute toxicity (i.e. up to 3 months after radiotherapy), while preserving tumour control. Next to reducing mucositis, tube feeding, xerostomia and distortion of the sense of taste, protons can improve general well-being by decreasing fatigue and nausea. Proton therapy results in decreased rates of tube feeding dependency and severe weight loss up to 1 year after radiotherapy, and may decrease the risk of radionecrosis of the mandible. Also, the model-based approach for selecting patients for proton therapy in the Netherlands is described in this review and future perspectives are discussed.

Development of Normal Tissue Complication Probability Model for Trismus in Head and Neck Cancer Patients Treated With Radiotherapy: The Role of Dosimetric and Clinical Factors.

BACKGROUND/AIM: The aim of this study was to develop a normal tissue complication probability (NTCP) model for trismus in head and neck cancer (HNC) patients treated with radiotherapy (RT). PATIENTS AND METHODS: Prospective measurements of maximum inter-incisal opening (MIO) were performed at baseline and 6 months after definitive RT in 132 HNC patients. The primary endpoint of this study was defined when a patient fulfilled both of the following criteria: 1) MIO at 6 months after RT ≤35 mm and 2) MIO at 6 months after RT ≤80% of baseline MIO. Eleven clinical factors and a wide range of dosimetric factors (mean dose, maximum dose, V5, V10, V20, and V40) in twelve organs at risk (OARs) were chosen as candidate prognostic variables. RESULTS: Thirty out of 132 patients (23%) developed the primary endpoint. Multivariate logistic regression analysis revealed that the mean dose to the contralateral mandible joint (p=0.001) and baseline MIO (p=0.027) were independent prognostic factors. CONCLUSION: A multivariable NTCP model for trismus in HNC patients treated with RT was established including the mean dose to contralateral mandible joint and baseline MIO.

Functional Swallowing Units (FSUs) as organs-at-risk for radiotherapy. PART 1: Physiology and anatomy.

BACKGROUND AND PURPOSE: When optimising radiotherapy treatments today, the pharyngeal constrictor muscles and the larynx are usually regarded as the swallowing organs at risk (SWOARs). The purpose of this study was to identify and describe additional, previously undefined groups of muscles (functional units) involved in crucial components of swallowing (hyolaryngeal elevation (HLE), tongue base retraction (TBR) and tongue motion), and to emphasise their relevance in radiation-induced dysphagia. MATERIAL AND METHODS: Based on available literature on human anatomy and swallowing physiology, the functional units of muscles involved in HLE, TBR and tongue motion have been identified and described. RESULTS AND CONCLUSION: Functional swallowing units (FSUs) were defined as groups of swallowing muscles sharing their function, that are in close proximity to each other. Seven FSUs involved in HLE, TBR and tongue motion were identified: floor of mouth, thyrohyoid muscles, posterior digastric/stylohyoid muscles complex, longitudinal pharyngeal muscles, hyoglossus/styloglossus muscles complex, genioglossus muscles, intrinsic tongue muscles. The swallowing physiology and anatomy of the FSUs described in this paper will lead to a greater understanding of radiation-induced dysphagia mechanisms and, consequently, to an improvement in the development of swallowing sparing strategies. This article (PART 1) serves as the theoretical foundation for a subsequent article (PART 2), which provides detailed delineation guidelines for FSUs.

Prevalence and prediction of trismus in patients with head and neck cancer: A cross-sectional study.

BACKGROUND: Trismus occurs frequently in patients with head and neck cancer. Determining the prevalence and associated factors of trismus would enable prediction of the risk of trismus for future patients. METHODS: Based on maximal mouth opening measurements, we determined the prevalence of trismus in 730 patients with head and neck cancer. Associated factors for trismus were analyzed using univariate analyses and multivariate logistic regression analyses. Based on the regression model, a calculation tool to predict trismus was made. RESULTS: Prevalence of trismus was 23.6%. Factors associated with trismus were: advanced age; partial or full dentition; tumors located at the maxilla; mandible; cheek; major salivary glands; oropharynx; an unknown primary; a free soft tissue transfer after surgery; reirradiation; and chemotherapy. CONCLUSION: About one-fourth of patients with head and neck cancer develop trismus. Based on prevalence and associated factors of trismus, a simple calculation tool predicts the risk of trismus in these patients.

Parameters Associated With Mandibular Osteoradionecrosis.

The objective of this review is to discuss factors related to the risk of osteoradionecrosis (ORN) and how to minimize the likelihood of this complication. A PubMed search for publications pertaining to ORN within the last 3 years was conducted revealing 44 publications. The bibliographies of these publications were reviewed to identify additional references spanning a longer time period. The incidence of ORN is 5% to 10% with a median latency period of 1 to 2 years or less. The likelihood of ORN depends on a number of factors including primary site and extent of disease, dental status, treatment modality, radiotherapy (RT) dose, volume of mandible included in the planning target volume, RT fractionation schedule and technique, and teeth extractions. The risk of ORN may be reduced by limiting the RT dose and volume of mandible irradiated without increasing the risk of a local-regional recurrence due to a marginal miss.

Unilateral versus bilateral irradiation in squamous cell head and neck cancer in relation to patient-rated xerostomia and sticky saliva.

BACKGROUND AND PURPOSE: To investigate the association between radiation technique with patient-rated moderate and severe xerostomia and sticky saliva. MATERIALS AND METHODS: One hundred and fifty patients treated with bilateral or unilateral irradiation for head and neck cancer were included. The salivary glands and the oral cavity were delineated on plannings-CT scans. Xerostomia and sticky saliva were assessed using the EORTC QLQ-H&N35 questionnaire at baseline and 6 and 12 months. RESULTS: At 6 months a significant association between radiation technique and the mean parotid dose (MD(parb)) and xerostomia was observed (Odds ratio (OR)-technique: 2.55; p=0.04 and OR-MD(parb): 1.04; p=0.009). Considering the individual salivary glands, only the mean dose in the contralateral parotid gland (MD(parcl)) is associated with xerostomia (OR: 1.04; p<0.0001). Moreover, the threshold dose for a 50% probability (P50) on xerostomia increased from 21 Gy with bilateral to 44 Gy for unilateral irradiation. CONCLUSIONS: Both technique and MD(parb) influence the risk of xerostomia in irradiated patients. Of all individual salivary glands, only MD(parcl) is of utmost importance for xerostomia. The shift in the P50 observed for xerostomia suggests that sparing of the contralateral parotid gland is compensated by hyperfunction of the contralateral parotid gland.

Quality of life after surgical treatment for oral and oropharyngeal cancer: a prospective longitudinal assessment of patients reconstructed by a microvascular flap.

The aim of this study was to document changes from baseline to 6 and 12 months after treatment in health-related quality of life (HRQOL) in relation to sociodemographic and clinical parameters among advanced oral/oropharyngeal cancer patients treated with reconstructive surgery and adjuvant radiotherapy. The HRQOL of 80 consecutive patients was assessed by the EORTC QLQ-C30 and QLQ-H&N35 questionnaires, pretreatment and 6 and 12 months posttreatment. Several patterns of HRQOL changes were distinguished: most general HRQOL issues do not change after treatment or improve compared to baseline scores (emotional functioning, pain, insomnia, constipation) and most head and neck specific issues deteriorate after treatment but return to pretreatment levels at 12 months, except for senses, opening mouth, sticky saliva, and coughing which remain deteriorated in the long term. Although improvement to baseline levels was noted, it should be kept in mind that baseline levels of patients are often deviant from "normal" scores from the general population. Tumour site and stage, comorbidity, and extensive resections were significantly associated with HRQOL outcomes, as were marital status and age. These results, obtained in a homogenous group of patients, may serve as HRQOL benchmarks for future studies investigating surgical and other treatment modalities.

Treatment of late sequelae after radiotherapy for head and neck cancer.

Radiotherapy (RT) is used to treat approximately 80% of patients with cancer of the head and neck. Despite enormous advances in RT planning and delivery, a significant number of patients will experience radiation-associated toxicities, especially those treated with concurrent systemic agents. Many effective management options are available for acute RT-associated toxicities, but treatment options are much more limited and of variable benefit among patients who develop late sequelae after RT. The adverse impact of developing late tissue damage in irradiated patients may range from bothersome symptoms that negatively affect their quality of life to severe life-threatening complications. In the region of the head and neck, among the most problematic late effects are impaired function of the salivary glands and swallowing apparatus. Other tissues and structures in the region may be at risk, depending mainly on the location of the irradiated tumor relative to the mandible and hearing apparatus. Here, we review the available evidence on the use of different therapeutic strategies to alleviate common late sequelae of RT in head and neck cancer patients, with a focus on the critical assessment of the treatment options for xerostomia, dysphagia, mandibular osteoradionecrosis, trismus, and hearing loss.

CT image biomarkers to improve patient-specific prediction of radiation-induced xerostomia and sticky saliva.

BACKGROUND AND PURPOSE: Current models for the prediction of late patient-rated moderate-to-severe xerostomia (XER12m) and sticky saliva (STIC12m) after radiotherapy are based on dose-volume parameters and baseline xerostomia (XERbase) or sticky saliva (STICbase) scores. The purpose is to improve prediction of XER12m and STIC12m with patient-specific characteristics, based on CT image biomarkers (IBMs). METHODS: Planning CT-scans and patient-rated outcome measures were prospectively collected for 249 head and neck cancer patients treated with definitive radiotherapy with or without systemic treatment. The potential IBMs represent geometric, CT intensity and textural characteristics of the parotid and submandibular glands. Lasso regularisation was used to create multivariable logistic regression models, which were internally validated by bootstrapping. RESULTS: The prediction of XER12m could be improved significantly by adding the IBM "Short Run Emphasis" (SRE), which quantifies heterogeneity of parotid tissue, to a model with mean contra-lateral parotid gland dose and XERbase. For STIC12m, the IBM maximum CT intensity of the submandibular gland was selected in addition to STICbase and mean dose to submandibular glands. CONCLUSION: Prediction of XER12m and STIC12m was improved by including IBMs representing heterogeneity and density of the salivary glands, respectively. These IBMs could guide additional research to the patient-specific response of healthy tissue to radiation dose.

Head and neck intensity modulated radiation therapy leads to an increase of opportunistic oral pathogens.

OBJECTIVES: The introduction of intensity modulated radiation therapy (IMRT) has led to new possibilities in the treatment of head and neck cancer (HNC). Limited information is available on how this more advanced radiation technique affects the oral microflora. In a prospective study we assessed the effects of various advanced treatments for HNC on the oral microflora, as well as the effects of elimination of oral foci of infection. MATERIALS AND METHODS: All consecutive dentate patients >18years, diagnosed with a primary oral or oropharynx carcinoma and seen for a pre-treatment dental screening (May 2011-May 2013) were included. Patients were grouped by oncologic treatment: surgery (SURG), IMRT (IMRT) or IMRT+chemotherapy (CHIMRT). Dental screening data, demographic data, subgingival biofilm samples, oral lavages and whole saliva samples were obtained to microbiologically analyze the effects of cancer treatments (1-year follow-up). RESULTS: This study included 82 patients (29 SURG, 26 IMRT and 27 CHIMRT). The trends in changes in prevalence and proportions of microorganisms were comparable in the IMRT and CHIMRT group. However, relative to the SURG group, increased prevalence of enteric rods, staphylococci and Candida species was observed in the IMRT and CHIMRT groups. In these groups, elimination of oral foci decreased the frequency of detection of pathogens such as Porphyromonas gingivalis, Tannerella forsythia and Streptococcus mutans. CONCLUSION: Different treatments in HNC patients result in different changes in the oral microflora. Opportunistic pathogens such as staphylococci, enteric rods and Candida sp. tend to increase in prevalence after IMRT with or without chemotherapy, but not after surgical intervention.

Quality-of-life after radiotherapy for advanced laryngeal cancer: Results of a phase III trial of the Dutch Head and Neck Society.

BACKGROUND/PURPOSE: To report on health-related quality-of-life (HRQoL) of patients with laryngeal cancer, treated in a randomized trial comparing accelerated radiotherapy with carbogen and nicotinamide (ARCON) against accelerated radiotherapy alone (AR). MATERIAL/METHODS: HRQoL was assessed using the HRQoL Questionnaire-C30 (QLQ-C30) and the Head & Neck cancer module (QLQ-H&N35) at baseline, at completion of radiotherapy and at 6, 12, and 24months post-baseline. RESULTS: From 269/345 patients (AR: 136/174; ARCON: 133/171) data on HRQoL were available for analysis. Moderate to severe clinical impact of the treatment was observed for nearly all items of the QLQ-C30 and QLQ-H&N35 between baseline and end-of-treatment. At 6months, scores returned to baseline level with exception of dry mouth, sticky saliva, and taste/smell. No difference between AR and ARCON was observed. At 2years from baseline, the percentage of patients reporting moderate to severe complaints of dry mouth, sticky saliva, or changes in taste/smell was 30%, 22% and 18%, respectively, while the majority of patients had no or few complaints of swallowing (79%) or speech (64%). CONCLUSIONS: With accelerated radiotherapy, high local tumor control was obtained while maintaining good speech and swallowing function. Long-term dry mouth, sticky saliva and changes in taste/smell are limited to one quarter of patients. (ClinicalTrials.gov number, NCT00147732).

Does radiation dose to the salivary glands and oral cavity predict patient-rated xerostomia and sticky saliva in head and neck cancer patients treated with curative radiotherapy?

BACKGROUND AND PURPOSE: To investigate the association between the mean salivary gland and oral cavity dose, with patient-rated moderate and severe xerostomia and sticky saliva. PATIENTS AND METHODS: One hundred and fifty-seven patients treated with bilateral irradiation for head and neck cancer were included. The parotid and submandibular glands and the oral cavity were delineated on plannings-CT scans. At baseline and 6 and 12 months self-reported xerostomia and sticky saliva were assessed using the EORTC QLQ-H&N35 questionnaire. RESULTS: At 6 months a significant association between the mean parotid (MD(par)) and mean submandibular dose (MD(subm)) and xerostomia was observed (OR - MD(par): 1.17; P=0.002 and OR - MD(subm): 1.08; P = 0.02). Between MD(par) and MD(subm), a significant interaction term was present. No significant association was found with the oral cavity dose. Xerostomia was reversible depending on MD(par) and MD(subm). Considering Sticky saliva, a significant association was found at 6 and 12 months with MD(subm) (OR: 1.03; P < 0.001). The P50 for sticky saliva increased with elapsing time. CONCLUSIONS: Both MD(par) and MD(subm) influence the risk of xerostomia in irradiated patients at 6 months. This probability as a function of the mean parotid dose significantly depended on the mean dose in the submandibular glands. Sticky saliva mainly depends on MD(subm).

Sparing the region of the salivary gland containing stem cells preserves saliva production after radiotherapy for head and neck cancer.

Each year, 500,000 patients are treated with radiotherapy for head and neck cancer, resulting in relatively high survival rates. However, in 40% of patients, quality of life is severely compromised because of radiation-induced impairment of salivary gland function and consequent xerostomia (dry mouth). New radiation treatment technologies enable sparing of parts of the salivary glands. We have determined the parts of the major salivary gland, the parotid gland, that need to be spared to ensure that the gland continues to produce saliva after irradiation treatment. In mice, rats, and humans, we showed that stem and progenitor cells reside in the region of the parotid gland containing the major ducts. We demonstrated in rats that inclusion of the ducts in the radiation field led to loss of regenerative capacity, resulting in long-term gland dysfunction with reduced saliva production. Then we showed in a cohort of patients with head and neck cancer that the radiation dose to the region of the salivary gland containing the stem/progenitor cells predicted the function of the salivary glands one year after radiotherapy. Finally, we showed that this region of the salivary gland could be spared during radiotherapy, thus reducing the risk of post-radiotherapy xerostomia.

Prospective evaluation of health-related quality of life in long-term oral and oropharyngeal cancer survivors and the perceived need for supportive care.

PURPOSE: To evaluate long-term changes in health related quality of life (HRQOL) in oral/oropharyngeal cancer survivors and their need for and use of supportive care. METHODS: Between 1999 and 2001, 80 advanced oral or oropharyngeal cancer patients treated with free-flap reconstruction and postoperative radiotherapy were included in a prospective study of whom 27 patients were long-term survivors (mean 9.2 years, range 8-11 years). The HRQOL of 26 patients (response rate 96%) was assessed with the EORTC QLQ-C30 and QLQ-H&N35 questionnaires at four points in time: pretreatment (baseline), and at 6 months, 12 months (short term) and 8-11 years (long-term) follow up. A study specific questionnaire was developed to evaluate the need for and use of supportive care (allied health services, peer contact, psychosocial care, and complementary care) and was completed at the period of treatment and at long-term follow up. RESULTS: A number of HRQOL domains worsened significantly (p < 0.01) in the long-term: emotional functioning, social functioning, swallowing, speech, taste/smell, dry mouth, sticky saliva and coughing assessed by the mixed effects statistical model. At time of treatment, the need for supportive care was the highest for a dental hygienist (77%), a physical therapist (73%), a speech therapist (42%), a dietician (38%), and a special diet (62%). At long-term follow up, the need for supportive care was limited to a dental hygienist (46%) and a physical therapist (23%). Only small differences were observed between the perceived need for and actual use of supportive care. CONCLUSION: A range of HRQOL domains in head and neck cancer survivors were deteriorated in the long-term compared to baseline and to the first year after treatment. At time of treatment and less frequently at long-term follow up, patients reported needing and using a variety of supportive care services.

Role of minor salivary glands in developing patient-rated xerostomia and sticky saliva during day and night.

PURPOSE: The purpose of this prospective study was to investigate the relationship between xerostomia during the day (XERday) and night (XERnight) and sticky saliva during the day (STICday) and night (STICnight) and dose distributions in different major and minor salivary glands among head and neck cancer (HNC) patients treated with primary radiotherapy (RT) or chemoradiation (CHRT). METHODS AND MATERIALS: The study population was composed of 201 consecutive HNC patients treated with intensity modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3D-CRT). All patients were included in a standard follow up programme in which acute and late side effects and quality of life (QoL) were prospectively assessed, prior to, during and after treatment. The primary endpoints were XERday, XERnight, STICday, STICnight as assessed by the Groningen Radiotherapy Induced Xerostomia questionnaire (GRIX) six months after completion of treatment. Organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, buccal mucosa and lips. Patients with moderate-to-severe xerostomia or moderate-to-severe sticky saliva, respectively, at baseline were excluded. In order to determine which salivary glands were most important, a multivariate logistic regression analysis with an extended bootstrapping technique was used. RESULTS: In total, 29% and 19% of the cases suffered from XERday and XERnight, respectively. The multivariate analysis showed that baseline xerostomia and the mean parotid gland dose were the most important predictors for XERday and XERnight. At 6months after (CH)RT, 10% and 12% of the cases reported STICday and STICnight respectively. We were not able to identify prognostic factors related to dose distributions with regard to STICday. The mean submandibular gland dose was associated with STICnight. Baseline xerostomia and sticky saliva scores on the GRIX were associated with XERday, XERnight, STICday. Increasing age was correlated with both XERnight and STICnight. CONCLUSION: Organs at risk for XERday and STICday are similar to organs at risk for XERnight and STICnight.

External validation of three dimensional conformal radiotherapy based NTCP models for patient-rated xerostomia and sticky saliva among patients treated with intensity modulated radiotherapy.

PURPOSE: The purpose of this study was to investigate the ability of predictive models for patient-rated xerostomia (XER(6M)) and sticky saliva (STIC(6M)) at 6 months after completion of primary (chemo)radiation developed in head and neck cancer patients treated with 3D-conformal radiotherapy (3D-CRT) to predict outcome in patients treated with intensity modulated radiotherapy (IMRT). METHODS AND MATERIALS: Recently, we published the results of a prospective study on predictive models for patient-rated xerostomia and sticky saliva in head and neck cancer patients treated with 3D-CRT (3D-CRT based NTCP models). The 3D-CRT based model for XER(6M) consisted of three factors, including the mean parotid dose, age, and baseline xerostomia (none versus a bit). The 3D-CRT based model for STIC(6M) consisted of the mean submandibular dose, age, the mean sublingual dose, and baseline sticky saliva (none versus a bit). In the current study, a population consisting of 162 patients treated with IMRT was used to test the external validity of these 3D-CRT based models. External validity was described by the explained variation (R(2) Nagelkerke) and the Brier score. The discriminative abilities of the models were calculated using the area under the receiver operating curve (AUC) and calibration (i.e. the agreement between predicted and observed outcome) was assessed with the Hosmer-Lemeshow "goodness-of-fit" test. RESULTS: Overall model performance of the 3D-CRT based predictive models for XER(6M) and STIC(6M) was significantly worse in terms of the Brier score and R(2) Nagelkerke among patients treated with IMRT. Moreover the AUC for both 3D-CRT based models in the IMRT treated patients were markedly lower. The Hosmer-Lemeshow test showed a significant disagreement for both models between predicted risk and observed outcome. CONCLUSION: 3D-CRT based models for patient-rated xerostomia and sticky saliva among head and neck cancer patients treated with primary radiotherapy or chemoradiation turned out to be less valid for patients treated with IMRT. The main message from these findings is that models developed in a population treated with a specific technique cannot be generalised and extrapolated to a population treated with another technique without external validation.