Tim Dijkema

Parotid Gland Function after Radiotherapy: The Combined Michigan and Utrecht Experience

PURPOSE To analyze the combined and updated results from the University of Michigan and University Medical Center Utrecht on normal tissue complication probability (NTCP) of the parotid gland 1 year after radiotherapy (RT) for head-and-neck (HN) cancer. PATIENTS AND METHODS A total of 222 prospectively analyzed patients with various HN malignancies were treated with conventional and intensity-modulated RT. Stimulated individual parotid gland flow rates were measured before RT and 1 year after RT using Lashley cups at both centers. A flow ratio <25% of pretreatment was defined as a complication. The data were fitted to the Lyman-Kutcher-Burman model. RESULTS A total of 384 parotid glands (Michigan: 157; Utrecht: 227 glands) was available for analysis 1 year after RT. Combined NTCP analysis based on mean dose resulted in a TD(50) (uniform dose leading to 50% complication probability) of 39.9 Gy and m (steepness of the curve) of 0.40. The resulting NTCP curve had good qualitative agreement with the combined clinical data. Mean doses of 25-30 Gy were associated with 17-26% NTCP. CONCLUSIONS A definite NTCP curve for parotid gland function 1 year after RT is presented, based on mean dose. No threshold dose was observed, and TD(50) was equal to 40 Gy.

A COMPARISON OF DOSE-RESPONSE MODELS FOR THE PAROTID GLAND IN A LARGE GROUP OF HEAD-AND-NECK CANCER PATIENTS

PURPOSE The dose-response relationship of the parotid gland has been described most frequently using the Lyman-Kutcher-Burman model. However, various other normal tissue complication probability (NTCP) models exist. We evaluated in a large group of patients the value of six NTCP models that describe the parotid gland dose response 1 year after radiotherapy. METHODS AND MATERIALS A total of 347 patients with head-and-neck tumors were included in this prospective parotid gland dose-response study. The patients were treated with either conventional radiotherapy or intensity-modulated radiotherapy. Dose-volume histograms for the parotid glands were derived from three-dimensional dose calculations using computed tomography scans. Stimulated salivary flow rates were measured before and 1 year after radiotherapy. A threshold of 25% of the pretreatment flow rate was used to define a complication. The evaluated models included the Lyman-Kutcher-Burman model, the mean dose model, the relative seriality model, the critical volume model, the parallel functional subunit model, and the dose-threshold model. The goodness of fit (GOF) was determined by the deviance and a Monte Carlo hypothesis test. Ranking of the models was based on Akaikes information criterion (AIC). RESULTS None of the models was rejected based on the evaluation of the GOF. The mean dose model was ranked as the best model based on the AIC. The TD(50) in these models was approximately 39 Gy. CONCLUSIONS The mean dose model was preferred for describing the dose-response relationship of the parotid gland.

Large cohort dose-volume response analysis of parotid gland function after radiotherapy: intensity-modulated versus conventional radiotherapy.

PURPOSE To compare parotid gland dose-volume response relationships in a large cohort of patients treated with intensity-modulated (IMRT) and conventional radiotherapy (CRT). METHODS AND MATERIALS A total of 221 patients (64 treated with IMRT, 157 with CRT) with various head-and-neck malignancies were prospectively evaluated. The distribution of tumor subsites in both groups was unbalanced. Stimulated parotid flow rates were measured before and 6 weeks, 6 months, and 1 year after radiotherapy. Parotid gland dose-volume histograms were derived from computed tomography-based treatment planning. The normal tissue complication probability (NTCP) model proposed by Lyman was fit to the data. A complication was defined as stimulated parotid flow ratio <25% of the pretreatment flow rate. The relative risk of complications was determined for IMRT vs. CRT and adjusted for the mean parotid gland dose using Poisson regression modeling. RESULTS One year after radiotherapy, NTCP curves for IMRT and CRT were comparable with a TD(50) (uniform dose leading to a 50% complication probability) of 38 and 40 Gy, respectively. Until 6 months after RT, corrected for mean dose, different complication probabilities existed for IMRT vs. CRT. The relative risk of a complication for IMRT vs. CRT after 6 weeks was 1.42 (95% CI 1.21-1.67), after 6 months 1.41 (95% CI; 1.12-1.77), and at 1 year 1.21 (95% CI 0.87-1.68), after correcting for mean dose. CONCLUSIONS One year after radiotherapy, no difference existed in the mean dose-based NTCP curves for IMRT and CRT. Early after radiotherapy (up to 6 months) mean dose based (Lyman) models failed to fully describe the effects of radiotherapy on the parotid glands.

Sparing the contralateral submandibular gland in oropharyngeal cancer patients: a planning study.

BACKGROUND AND PURPOSE The submandibular glands are proposed to be important in preventing xerostomia in head-and-neck cancer patients. We investigated the feasibility of sparing the contralateral submandibular gland (cSMG) by reducing the dose to the contralateral planning target volume (PTV) and by reducing the clinical target volume (CTV)-to-PTV margin. MATERIALS AND METHODS Ten oropharyngeal cancer patients with a contralateral elective PTV were included in this planning study, using intensity modulated radiotherapy (IMRT). The effect on the mean dose to the cSMG of reducing the dose coverage to the contralateral elective PTV from 95 to 90% of the prescribed dose (54Gy in 1.8Gy daily fractions) was determined. The influence of reducing the margin for position uncertainty from 5 to 2mm was investigated. RESULTS The mean dose to the cSMG was reduced from 54Gy to approximately 40Gy if the dose coverage to the contralateral PTV was reduced to 90% of the prescribed dose. The estimated normal tissue complication probability (NTCP) was reduced below 50%. Reducing the margin from 5 to 2mm resulted in a decrease in the mean dose to the cSMG of approximately 6Gy. CONCLUSIONS Reducing the mean dose to the cSMG below 40Gy is possible with a reasonable dose coverage of the contralateral elective PTV.

Xerostomia: A day and night difference

PURPOSE To compare patient-reported xerostomia during daytime and during nighttime with objectively measured parotid and submandibular gland function in a cohort of head-and-neck cancer (HNC) patients treated with RT. MATERIALS AND METHODS A cohort of 138 HNC patients underwent objective measurements of parotid (PF) and submandibular (SMF) gland function and completed a xerostomia questionnaire (XQ) before RT, at 6 weeks, 6 months and 1 year after RT. No attempt was made to spare the submandibular gland(s). The XQ contained specific questions concerning the sensation of dry mouth during day- (XD) and nighttime (XN), scored on a 5-point Likert scale. Patients with no or mild (grade 1-3) xerostomia and patients with more severe (grade 4-5) complaints were grouped together. RESULTS Before RT, no association existed between dry mouth complaints and PF or SMF. At 6 weeks, 6 months and 1 year after RT; 37%, 51% and 36% had grade 4-5 XD and 65%, 64% and 56% had grade 4-5 XN, respectively. Patients with grade 4-5 XD and XN had significantly worse SMF at all time points after RT compared to patients with grade 1-3 XD and XN, while PF was significantly worse only at 6 weeks after RT. In multivariate analyses, SMF was consistently the most important factor related to XN after treatment. PF significantly influenced XD at 6 weeks and 1 year after RT. CONCLUSIONS Differentiating between complaints during day- and nighttime in xerostomia research is necessary. Dry mouth at night is a frequent problem after (parotid-sparing) RT for HNC and is explained by submandibular gland dysfunction. Sparing of the contralateral submandibular gland, in addition to parotid gland sparing, may result in improved patient-reported xerostomia.

MUC5B levels in submandibular gland saliva of patients treated with radiotherapy for head-and-neck cancer: A pilot study

BackgroundThe salivary mucin MUC5B, present in (sero)mucous secretions including submandibular gland (SMG) saliva, plays an important role in the lubrication of the oral mucosa and is thought to be related to the feeling of dry mouth. We investigated if MUC5B levels in SMG saliva could distinguish between the presence or absence of severe dry mouth complaints 12 months after radiotherapy (RT) for head-and-neck cancer (HNC).FindingsTwenty-nine HNC patients with a residual stimulated SMG secretion rate of ≥0.2 ml/10 min at 12 months after RT were analyzed. MUC5B (in U; normalized to 1) and total protein levels (mg/ml) were measured in SMG saliva at baseline and 12 months after RT using ELISA and BCA protein assay, respectively. Overall, median MUC5B levels decreased after RT from 0.12 to 0.03 U (p = 0.47). Patients were dichotomized into none/mild xerostomia (n = 12) and severe xerostomia (n = 17) based on a questionnaire completed at 12 months. SMG and whole saliva flow rates decreased after RT but were comparable in both groups. The median MUC5B level was higher in patients with no or mild xerostomia compared to patients with severe xerostomia (0.14 vs 0.01 U, p = 0.22). Half of the patients with severe xerostomia had no detectable MUC5B at 12 months after RT. No differences in total protein levels were observed.ConclusionsQualitative saliva parameters like MUC5B need further investigation in RT-induced xerostomia. This pilot study showed a trend towards lower MUC5B levels in the SMG saliva of patients with severe xerostomia 12 months after RT for HNC.

Parotid gland function after radiotherapy

Radiotherapy is a common treatment for head and neck cancer patients. Unfortunately, it produces serious acute and long-term side effects to the oral cavity. One severe complication is the loss of salivary gland function, which can persists for many years. Saliva has multiple functions relating to speech, taste perception, mastication, and swallowing and bolus formation. Cleansing and dental and mucosal protection are also important functions. In this thesis, a detailed report is given on the effects of radiotherapy on changes in the parotid gland function. Different methods of measuring gland function are described. Moreover, a preventive measure to limit the gland toxicity was investigated in rodents. The radiation field and, in particular, the volume of the parotid gland tissue exposed to radiation is of notable importance with regard to the development of gland damage and hypofunction. Therefore, it is important to achieve detailed information about the size and position of the parotid gland. Great differences in size and position of the parotid glands between the patients were seen. In order to exactly define the localisation of the glands, it is essential to use CT-based simulation of radiation fields. The radiation tolerance of the parotid glands as a function of dose and volume irradiated was accurately described. The best parameter for evaluation of the parotid gland function appeared to be the flow measurement using the Lashley cups. However, if direct flow measurements are not feasible, 99mTc-pertechnetate scintigraphy might be a good alternative. Flow reduction depended on the mean parotid gland dose. For a post treatment parotid flow ratio a 25%, the TD50 (the dose to the whole organ leading to a complication probability of 50%) was found to be 31, 35 and 39 Gy at 6 weeks, 6 months and 1 year after radiotherapy respectively. The consequences of parotid gland injury are still difficult to manage. Prophylactic treatment with sialogogues like the muscarinic receptor agonist pilocarpine has been shown to have radioprotective potential. The effects of preirradiation treatment of pilocarpine on rat parotid gland function were investigated in relation to radiation dose. Pilocarpine induced compensation, which at least underlies the radioprotective effect of the drug. This effect seemed to be dependent on the amount of damage induced. Therefore, the type of fractionation scheme and the volume of the gland that lies within the radiation portal will be crucial for the effectiveness of a prophylactic pilocarpine treatment. With the more detailed knowledge on the dose/volume effects of radiation on parotid function, we can try to focus on sparing the parotid gland function. The prevention of radiation-induced loss of parotid gland function will depend on both optimal sparing radiation therapy techniques and on pharmacological agents, which can selectively interfere with the radiation-induced effects. These preventing strategies will need a joint effort of radiation-oncologists, clinical physicists and radiobiologists.