Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer.

PURPOSE: To determine the relationships between the three-dimensional dose distributions in parotid glands and their saliva production, and to find the doses and irradiated volumes that permit preservation of the salivary flow following irradiation (RT). METHODS AND MATERIALS: Eighty-eight patients with head and neck cancer irradiated with parotid-sparing conformal and multisegmental intensity modulation techniques between March 1994 and August 1997 participated in the study. The mean dose and the partial volumes receiving specified doses were determined for each gland from dose-volume histograms (DVHs). Nonstimulated and stimulated saliva flow rates were selectively measured from each parotid gland before RT and at 1, 3, 6, and 12 months after the completion of RT. The data were fit using a generalized linear model and the normal tissue complication probability (NTCP) model of Lyman-Kutcher. In the latter model, a "severe complication" was defined as salivary flow rate reduced to < or =25% pre-RT flow at 12 months. RESULTS: Saliva flow rates data were available for 152 parotid glands. Glands receiving a mean dose below or equal to a threshold (24 Gy for the unstimulated and 26 Gy for the stimulated saliva) showed substantial preservation of the flow rates following RT and continued to improve over time (to median 76% and 114% of pre-RT for the unstimulated and stimulated flow rates, respectively, at 12 months). In contrast, most glands receiving a mean dose higher than the threshold produced little saliva with no recovery over time. The output was not found to decrease as mean dose increased, as long as the threshold dose was not reached. Similarly, partial volume thresholds were found: 67%, 45%, and 24% gland volumes receiving more than 15 Gy, 30 Gy, and 45 Gy, respectively. The partial volume thresholds correlated highly with the mean dose and did not add significantly to a model predicting the saliva flow rate from the mean dose and the time since RT. The NTCP model parameters were found to be TD50 (the tolerance dose for 50% complications rate for whole organ irradiated uniformly) = 28.4 Gy, n (volume dependence parameter) = 1, and m (the slope of the dose/response relationship) = 0.18. Clinical factors including age, gender, pre-RT surgery, chemotherapy, and certain medical conditions were not found to be significantly associated with the salivary flow rates. Medications (diuretics, antidepressants, and narcotics) were found to adversely affect the unstimulated but not the stimulated flow rates. CONCLUSIONS: Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model. A parotid gland mean dose of < or =26 Gy should be a planning goal if substantial sparing of the gland function is desired.     

A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: initial results

OBJECTIVES: In a prospective clinical study, we tested the hypothesis that sparing the parotid glands may result in significant objective and subjective improvement of xerostomia in patients with head-and-neck cancers. The functional outcome 6 months after the completion of radiation therapy is presented. METHODS AND MATERIALS: From February 1997 to February 1999, 41 patients with head-and-neck cancers were enrolled in a prospective salivary function study. Inverse-planning intensity-modulated radiation therapy (IMRT) was used to treat 27 patients, and forward-planning three-dimensional radiation therapy in 14. To avoid potential bias in data interpretation, only patients whose submandibular glands received greater than 50 Gy were eligible. Attempts were made to spare the superficial lobe of the parotid glands to avoid underdosing tumor targets in the parapharyngeal space; however, the entire parotid volume was used to compute dose-volume histograms (DVHs) for this analysis. DVHs were computed for each gland separately. Parotid function was assessed objectively by measuring stimulated and unstimulated saliva flow before and 6 months after the completion of radiation therapy. Measurements were converted to flow rate (mL/min) and normalized relative to that before treatment. The corresponding quality-of-life (QOL) outcome was assessed by five questions regarding the patient's oral discomfort and eating/speaking problems. RESULTS: We observed a correlation between parotid mean dose and the fractional reduction of stimulated saliva output at 6 months after the completion of radiation therapy. We further examined whether the functional outcome could be modeled as a function of dose. Two models were found to describe the dose-response data well. The first model assumed that each parotid gland is comprised of multiple independent parallel functional subunits (corresponding to computed tomography voxels) and that each gland contributes equally to overall flow, and that saliva output decreases exponentially as a quadratic function of irradiation dose to each voxel. The second approach uses the equivalent uniform dose (EUD) metrics, which assumes loss of salivary function with increase in EUD for each parotid gland independently. The analysis suggested that the mean dose to each parotid gland is a reasonable indicator for the functional outcome of each gland. The corresponding exponential coefficient was 0.0428/Gy (95% confidence interval: 0.01, 0.09). The QOL questions on eating/speaking function were significantly correlated with stimulated and unstimulated saliva flow at 6 months. In a multivariate analysis, a toxicity score derived from the model based on radiation dose to the parotid gland was found to be the sole significant predictive factor for xerostomia. Neither radiation technique (IMRT vs. non-IMRT) nor chemotherapy (yes or no) independently influenced the functional outcome of the salivary glands. CONCLUSION: Sparing of the parotid glands translates into objective and subjective improvement of both xerostomia and QOL scores in patients with head-and-neck cancers receiving radiation therapy. Modeling results suggest an exponential relationship between saliva flow reduction and mean parotid dose for each gland. We found that the stimulated saliva flow at 6 months after treatment is reduced exponentially, for each gland independently, at a rate of approximately 4% per Gy of mean parotid dose.     

Long-term parotid gland function after radiotherapy

PURPOSE: Irradiation of the parotid glands causes salivary dysfunction, resulting in reduced salivary flow. Recovery can be seen with time; however, long-term prospective data are lacking. The objective of this study was to analyze the long-term parotid gland function after irradiation for head-and-neck cancer. METHODS AND MATERIALS: A total of 52 patients with head-and-neck cancer and treated with radiotherapy (RT) were prospectively evaluated. Stimulated bilateral parotid salivary flow rates were measured before RT and 6 weeks, 6 months, 12 months, and at least 3.5 years after RT completion. A complication was defined as a stimulated parotid flow rate of <25% of the pre-RT flow rate. The normal tissue complication probability model proposed by Lyman was fit to the data. Multilevel techniques were used to model the patterns of flow rates with time. RESULTS: The mean stimulated flow rate of the parotid glands before RT was 0.31 mL/min (standard deviation [SD], 0.21). This was reduced to 0.14 mL/min (SD, 0.15) at 6 weeks after RT and recovered to 0.20 mL/min (SD, 0.22) at 6 months and 0.19 mL/min (SD, 0.21) at 12 months after RT. The mean stimulated flow rate was 0.25 mL/min (SD, 0.28) 5 years after RT. The mean dose to the parotid gland resulting in a 50% complication probability increased from 34 Gy at 6 weeks to 40 Gy at 6 months, 42 Gy at 12 months, and 46 Gy at 5 years after RT. Multilevel modeling indicated that both dose and time were significantly associated with the flow ratio. CONCLUSION: Salivary output can still recover many years after RT. At 5 years after RT, we found an increase in the salivary flow rate of approximately 32% compared with at 12 months after RT.     

Parotid-gland-sparing 3D conformal radiotherapy in patients with bilateral radiotherapy of the head and neck region--results in clinical practice

The aim was to improve the prediction rate of hyposalivation after using a modern 3D-conformal-radiotherapy-technique (3D-CRT) by sparing of the contralateral parotid gland. Between June 2002 and October 2006, 107 patients (90 male, 17 female, average age: 58 years) with squamous cell carcinoma of the head and neck were included in a prospective, non-randomized study. All patients were treated using 3D-CRT. Parotid function was assessed by measuring stimulated salivary flow before, during and at the end of radiotherapy, as well as 1, 6 and 12 months after radiotherapy. Measurements were converted to flow rates and normalized relative to that before treatment. Mean doses (D(mean)) were calculated from dose-volume histograms (DVHs) based on computed tomographies (CTs) for the left and right parotid gland separately. Patients were grouped according to the D(mean) of the lowest irradiated parotid gland. Group I included all patients who received a D(mean)<26Gy (n=23), group II D(mean) 26-40Gy (n=38) and group III D(mean)>40Gy (n=46). By the time of 6 months after irradiation, salivary flow rates decreased continuously during the therapy. In group I the flow rate decreased to 59%, in group II to 40% and in group III to 14%, p<0.05. One year after irradiation a recovery effect could be measured in all groups. A sufficient saliva flow rate can be proven if one parotid gland is spared with a D(mean) dose <26Gy. Approximately, one quarter of the participants showed a significant improvement.     

The impact of dose on parotid salivary recovery in head and neck cancer patients treated with radiation therapy

PURPOSE: A common side effect experienced by head and neck cancer patients after radiation therapy (RT) is impairment of the parotid glands' ability to produce saliva. Our purpose is to investigate the relationship between radiation dose and saliva changes in the 2 years after treatment. METHODS AND MATERIALS: The study population includes 142 patients treated with conformal or intensity-modulated radiotherapy. Saliva flow rates from 266 parotid glands are measured before and 1, 3, 6, 12, 18, and 24 months after treatment. Measurements are collected separately from each gland under both stimulated and unstimulated conditions. Bayesian nonlinear hierarchical models were developed and fit to the data. RESULTS: Parotids receiving higher radiation produce less saliva. The largest reduction is at 1-3 months after RT followed by gradual recovery. When mean doses are lower (e.g., <25 Gy), the model-predicted average stimulated saliva recovers to pretreatment levels at 12 months and exceeds it at 18 and 24 months. For higher doses (e.g., >30 Gy), the stimulated saliva does not return to original levels after 2 years. Without stimulation, at 24 months, the predicted saliva is 86% of pretreatment levels for 25 Gy and <31% for >40 Gy. We do not find evidence to support that the overproduction of stimulated saliva at 18 and 24 months after low dose in 1 parotid gland is the result of low saliva production from the other parotid gland. CONCLUSIONS: Saliva production is affected significantly by radiation, but with doses <25-30 Gy, recovery is substantial and returns to pretreatment levels 2 years after RT.     

Scintigraphy in prediction of the salivary gland function after gland-sparing intensity modulated radiation therapy for head and neck cancer

BACKGROUND AND PURPOSE: To evaluate salivary gland scintigraphy in prediction of salivary flow following radiation therapy. PATIENTS AND METHODS: Twenty patients diagnosed with head and neck cancer were treated with intensity modulated radiation therapy with an intention to spare the salivary gland function. The total quantitative saliva secretion was measured prior to and 6 and 12 months after therapy, and the function of the major salivary glands was monitored using Tc-99m-pertechnetate scintigraphy. Two models were designed for prediction of the post-treatment salivary flow: an average model, based on the average proportions of saliva produced by each of the four major glands in healthy subjects, and an individual model, based on saliva produced by each gland as measured by scintigraphy prior to therapy. These models were compared with volume-based (Lyman) normal tissue complication probability models using two published sets of model parameters. RESULTS: The D(50) for the parotid and the submandibular gland function assessed at 6 and 12 months after radiotherapy was approximately 39Gy. The scintigraphy-based individual model predicted well the measured post-treatment saliva flow rates. The correlation coefficient between the predicted stimulated and the measured saliva flow rate was 0.77 (p<0.0001) at 6 months and 0.55 (p=0.034) at 12 months after completion of radiotherapy. The relative changes in unstimulated and stimulated salivary flow rates showed similar dependency on the cumulative radiation dose. CONCLUSIONS: Salivary gland function assessed by scintigraphy prior to radiotherapy is useful in prediction of the residual salivary flow after radiotherapy.     

Intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: a prospective study on disease control and preservation of salivary function

BACKGROUND: Xerostomia is a uniform complication after radiotherapy (RT) for nasopharyngeal carcinoma (NPC). Dosimetric studies suggested that intensity-modulated RT (IMRT) can spare part of the parotid glands from high-dose radiation. Disease control and salivary function after IMRT for early-stage NPC was studied prospectively. METHODS: Thirty-three patients with T1,N0-N1,M0 NPC were treated with IMRT from 2000 to 2002. The prescribed dose was 68-70 grays (Gy) in 34 fractions to gross tumor volume, 64-68 Gy to the planning target volume, and 70 Gy to enlarged cervical lymph nodes. Nineteen patients had stimulated whole salivary (SWS) flow assessment and stimulated parotid salivary (SPS) flow assessment at baseline and at 2 months, 6 months, 12 months, 18 months, and 24 months after the completion of IMRT. RESULTS: At a median follow-up of 2 years, only 1 neck failure was observed. The 2-year and 3-year local control, distant metastases-free, and overall survival rates all were 100%. The lymph node control and progression-free survival rates were 100% at 2 years and 92.3% at 3 years, respectively. The average mean dose to the parotid gland was 38.8 Gy. The SWS and SPS flow showed continuous recovery: 60% and 47.1% of patients recovered at least 25% of their baseline SPS flow and SWS flow, respectively, at 1 year after completion of IMRT, and the proportions rose to 85.7% and 71.4%, respectively, by 2 years. The pH and buffering capacity of saliva also improved with time. CONCLUSIONS: Parotid-sparing IMRT achieved good locoregional control, and there was continuous recovery of salivary flow, pH, and buffering capacity in the first 2 years after IMRT in patients with NPC.     

Dose and volume impact on radiation-induced xerostomia

Radiation-induced xerostomia consists in the chronic dryness of the mouth caused by parotid gland irradiation. Parotid glands produce approximately 60% of saliva while the rest is secreted by submandibular and accessory salivary glands. Methods of measuring the salivary output are essentially represented by 99mTc-pertechnate scintigraphy or simpler albeit less accurate methods in stimulated or unstimulated saliva. There are subjective and objective criteria of classification and grading of the secretion of saliva. Radiation-induced xerostomia, namely the residual salivary gland function is evidently associated with the mean dose absorbed. The salivary output tends to decrease after the end of radiotherapy. The partial dose-volume is substantially correlated with the mean dose to the whole gland. As for ipsilateral irradiation for head and neck cancer, conformal RT or IMRT allow to spare the contralateral parotid gland without increasing the risk of contralateral nodal recurrences. The monitoring system of late toxicity used by the authors is presented.     

Scintigraphic assessment of early and late parotid gland function after radiotherapy for head-and-neck cancer: a prospective study of dose-volume response relationships

PURPOSE: To investigate the value of scintigraphy as an indirect measurement of parotid function after radiotherapy (RT). METHODS AND MATERIALS: Ninety-six patients with primary or postoperative RT for various malignancies in the head-and-neck region were prospectively evaluated. Parotid gland scintigraphy was performed before RT and 6 weeks and 1 year after RT. The uptake, excretion fraction of the saliva from the parotid gland to the oral cavity (SEF), and the ratios of uptake and SEF after and before treatment were calculated. CT-based treatment planning was used to derive dose-volume histograms of the parotid glands. To establish the effects of both the radiation dose and the volume of the parotid gland irradiated, the normal tissue complication probability model proposed by Lyman was fit to the data. RESULTS: The mean maximal uptake of 192 parotid glands decreased significantly from 3329 counts (ct)-/s before RT to 3084 ct/s and 3005 ct/s at 6 weeks and 1 year after RT. The SEF before treatment was 44.7%. The SEF decreased to 18.7% at 6 weeks after RT, but recovered to a SEF of 32.4% at 1 year after RT. A significant correlation was found between the uptake 1 year after RT and the mean parotid dose. The reduction in post-RT SEF correlated significantly with the mean parotid gland dose. The normal tissue complication probability model parameter TD50 was found to be 29 and 43 Gy at 6 weeks and 1 year after RT, respectively, when a complication was defined as a posttreatment SEF parotid ratio of <45%. CONCLUSIONS: The effects of radiation on parotid gland function using scintigraphy could be well established. A statistically significant correlation between the SEF ratio and the mean parotid dose was shown, with some recovery of function at 1 year after RT, comparable with the flow results. When direct flow measurements are not feasible, parotid scintigraphy appears to be a good indicator of gland function.     

Intensity modulated radiotherapy for head and neck cancer: evidence for preserved salivary gland function.

BACKGROUND AND PURPOSE: To investigate the salivary gland function following intensity modulated radiotherapy (IMRT) for head and neck cancer. PATIENTS AND METHODS: Seventeen patients with oropharyngeal (n=11) or nasopharyngeal (n=6) carcinoma located adjacent to the major salivary glands were treated with IMRT with an emphasis to spare the salivary glands from high-dose irradiation and to reduce the risk of postirradiation xerostomy. Three patients had stage 2, 4 stage III, and 10 stage IVA cancer. The total basal and stimulated saliva flow rates were measured before the treatment, and 6 and 12 months after radiotherapy. RESULTS: The median basal saliva flow rate measured before radiation treatment was 0.13 mL/min, and at 6 and 12 months after the completion of IMRT 0.04 mL/min and 0.07 mL/min, respectively. The corresponding median stimulated saliva flow rates were 0.49 mL/min, 0.33 mL/min, and 0.45 mL, respectively. The D50 for an impaired stimulated parotid gland saliva flow rate was 25.5 Gy. Only two (12%) patients developed grade 3 and none grade 4 xerostomia during a median follow-up of 24 months (range, 12-40 months). No patients had locoregional cancer recurrence following IMRT. CONCLUSIONS: The results suggest that much of the salivary gland function can be maintained with IMRT without jeopardizing the local control rate in the treatment of locally advanced oropharynx or nasopharynx carcinoma.     

Quantitative dose-volume response analysis of changes in parotid gland function after radiotherapy in the head-and-neck region.

PURPOSE: To study the radiation tolerance of the parotid glands as a function of dose and volume irradiated. METHODS AND MATERIALS: One hundred eight patients treated with primary or postoperative radiotherapy for various malignancies in the head-and-neck region were prospectively evaluated. Stimulated parotid flow rate was measured before radiotherapy and 6 weeks, 6 months, and 1 year after radiotherapy. Parotid gland dose-volume histograms were derived from CT-based treatment planning. The normal tissue complication probability model proposed by Lyman was fit to the data. A complication was defined as stimulated parotid flow rate <25% of the preradiotherapy flow rate. RESULTS: The mean stimulated preradiotherapy flow rate of 174 parotid glands was 0.34 mL/min. The mean flow rate reduced to 0.12 mL/min 6 weeks postradiotherapy, but recovered to a mean flow rate of 0.20 mL/min at 1 year after radiotherapy. Reduction in postradiotherapy flow rate correlated significantly with mean parotid dose. No threshold dose was found. Increasing the irradiated volume of parotid glands from 0%-40% to 90-100% in patients with a mean parotid dose of 35-45 Gy resulted in a decrease in flow ratio from, respectively, approximately 100% to less than 10% 6 weeks after radiation. The flow ratio of the 90%-100% group partially recovered to 15% at 6 months and to 30% at 1 year after radiotherapy. The normal tissue complication probability model parameter TD(50) (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 postradiotherapy, respectively. The volume dependency parameter n was around 1, which means that the mean parotid dose correlates best with the observed complications. There was no steep dose-response curve (m = 0.45 at 1 year postradiotherapy). CONCLUSIONS: This study on dose/volume/parotid gland function relationships revealed a linear correlation between postradiotherapy flow ratio and parotid gland dose and a strong volume dependency. No threshold dose was found. Recovery of parotid gland function was shown at 6 months and 1 year after radiotherapy. In radiation planning, attempts should be made to achieve a mean parotid gland dose at least below 39 Gy (leading to a complication probability of 50%).     

Factors influencing the parotid function in nasopharyngeal carcinoma treated with parotid-sparing radiotherapy

BACKGROUND: To evaluate the factors influencing post-irradiation parotid gland function in nasopharyngeal cancer treated with parotid-sparing radiotherapy. METHODS: This study consisted of 45 patients with nasopharyngeal cancer treated with radiotherapy including 3D conformal radiotherapy, intensity-modulated radiotherapy and high-dose-rate brachytherapy. The mean follow-up time was 37.5 months (range: 15-50 months). Objective parotid gland function was assessed by series sialoscintigraphy pre-irradiation and post-irradiation at 1, 6, 12 and 18 months. Subjective salivary function was recorded by the LENT/SOMA system. Wilcoxon signed-rank test was used to compare the secretion ratio (SR) of parotid gland before and after treatment. Mann-Whitney rank-sum test was used to determine the factors influencing the post-irradiated SR. Chi-square test was used to compare the correlation between subjective grading of xerostomia and objective grading of parotid glands. RESULTS: There was a significant difference between the pre-irradiation and post-irradiation parotid gland's SR at 1 (0.30 versus 0.01, P < 0.05) and 6 months (0.03 versus 0.08, P < 0.05). However, there was no significant difference compared with the pre-irradiation SR at 12 (0.30 versus 0.20, P > 0.05) and 18 months (0.30 versus 0.18, P > 0.05). There was significant correlation between subjective and objective salivary function (P = 0.024) at 12 months after radiotherapy. The factor that impacted the preservation of parotid function was mean dose to the parotid gland >38.0 Gy (P < 0.05). CONCLUSIONS: Our results demonstrated that parotid function could recover 1 year after treatment with parotid-sparing radiotherapy in patients with nasopharyngeal cancer. The most important factor that influenced parotid function was the mean dose to the parotid gland.     

Partial irradiation of the parotid gland

Recent efforts to reduce xerostomia associated with irradiation (RT) of head and neck cancer include the use of conformal and intensity-modulated RT (IMRT) to partly spare the major salivary glands, notably the parotid glands, from a high radiation dose while treating adequately all the targets at risk of disease. Knowledge of the dose-volume-response relationships in the salivary glands would determine treatment planning goals and facilitate optimization of the RT plans. Recent prospective studies of salivary flows following inhomogeneous irradiation of the parotid glands have utilized dose-volume histograms (DVHs) and various models to assess these relationships. These studies found that the mean dose to the gland is correlated with the reduction of the salivary output. This is consistent with a pure parallel architecture of the functional subunits (FSUs) of the salivary glands. The range of the mean doses, which have been found in these studies to cause significant salivary flow reduction is 26 to 39 Gy.     

Influence of parotid-sparing radiotherapy on xerostomia in head and neck cancer patients

Radiotherapy (RT) for head and neck cancers causes permanent salivary gland dysfunction (SGD) and xerostomia. We have previously demonstrated the effectiveness of parotid-sparing RT on salivary function. The aim of this was to characterize the relationship between radiation dosages to parotid glands, SGD, xerostomia, and impaired quality of life (QOL). Ninety-three patients received unilateral (n=38) and bilateral (n=44) neck RT with parotid-sparing techniques, or standard three-field technique RT (n=11). Unstimulated and stimulated parotid saliva was collected pre-RT and 1 year post-RT. Assessment of QOL and xerostomia was conducted with three questionnaires. The results demonstrated that reduced radiation dosages to parotid glands were strongly associated with percentage of baseline parotid flow rates measured at 1 year post-RT. Unilateral and bilateral neck RT with parotid-sparing techniques were successful in preserving salivary output, compared to standard three beam RT techniques. Lower radiation dose to contralateral parotid glands was associated with greater percentage of baseline salivary flow rates at 1 year post-RT, fewer xerostomic complaints, and an enhanced QOL.     

Preservation of oral health-related quality of life and salivary flow rates after inverse-planned intensity- modulated radiotherapy (IMRT) for head-and-neck cancer

PURPOSE: To assess whether comprehensive bilateral neck intensity-modulated radiotherapy (IMRT) for head-and-neck cancer results in preserving of oral health-related quality of life and sparing of salivary flow in the first year after therapy. METHODS AND MATERIALS: Twenty-three patients with head-and-neck cancer (primary sites: nasopharynx [5], oral cavity [12], oropharynx [3], and all others [3]) were accrued to a Phase I-II trial. Inverse planning was carried out with the following treatment goals: at least 1 spared parotid gland (defined as the volume of parotid gland outside the planning target volume [PTV]) to receive a median dose of less than 20 Gy; spinal cord, maximum 45 Gy; PTV(1) to receive a median dose of 50 Gy; PTV(2) to receive a median dose of 60 Gy (postoperative setting, n = 15) or 66-70 Gy (definitive radiotherapy setting, n = 8). Treatment was delivered with 6 and 15 MV photons using a "step-and-shoot" technique on a Varian 2300 EX linac with 120-leaf Millenium MLC. Unstimulated and stimulated whole-mouth salivary flow rates were measured, and patients completed the University of Washington instrument (UWQOL) and a separate xerostomia questionnaire (XQOL) in follow-up. RESULTS: Early functional outcome end point data are available at the 1-, 3-, and 12-month follow-up time points for 22, 22, and 18 patients, respectively. The combined mean parotid dose was 30.0 Gy (95% confidence interval: 26.9-33.1). The differences from baseline in mean overall UWQOL scores at 1, 3, and 12 months postradiotherapy were -0.24, 0.32, and 4.28, not significantly different from zero (p = 0.89, p = 0.87, p = 0.13). None of the UWQOL individual domain scores related to oral health (pain, eating-chewing, eating-swallowing, and speech) at 1, 3, or 12 months were significantly different from baseline. Both unstimulated and stimulated whole-mouth flow was variably preserved. Unstimulated salivary flow at 1 and 12 months was inversely correlated with combined mean parotid dose (p = 0.014, p = 0.0007), whereas stimulated salivary flow rates at 3 and 12 months were also correlated with combined mean parotid dose (p = 0.025, p = 0.0016). Combined maximum parotid dose was correlated with unstimulated flow rate at 12 months (p = 0.02, r = -0.56) and stimulated flow rate at 1 and 12 months (p = 0.036, r = -0.45; p = 0.0042, r = -0.66). The proportion of patients reporting total XQOL scores of 0 or 1 (no or mild xerostomia) did not diminish significantly from baseline at 1, 3, or 12 months (p = 0.72, p = 0.51, p = 1.0). Unstimulated and stimulated flow at 1 month was inversely correlated with total XQOL score at 12 months (p = 0.025, p = 0.029). CONCLUSIONS: Oral health-related quality of life (HRQOL) was highly preserved in the initial 12 months after IMRT, as assessed with separate, validated instruments for xerostomia-specific quality of life and oral HRQOL. In general, patients with better-preserved unstimulated salivary flow rates tended to report lower xerostomia scores. Whole-mouth salivary flow rates post IMRT were inversely correlated with combined mean parotid doses. Longer follow-up is required to assess to what extent HRQOL is favorably maintained.     

Dose-response relationships within the parotid gland after radiotherapy for head and neck cancer.

BACKGROUND AND PURPOSE: To determine the salivary function, after parotid-sparing radiotherapy (RT), of different regions within the parotid gland and to evaluate dose-function relationships within the parotid glands and between patients. PATIENTS AND METHODS: Sixteen head and neck cancer patients, irradiated between September 1999 and November 2000 using a conformal parotid-sparing technique, were included in this study. Before RT and 7 months after RT (range 6-10 months), a salivary gland scintigraphy was performed in all patients combined with a single photon emission computed tomography (SPECT). The salivary excretion fraction (SEF) was measured, after stimulation, in 8-12 transverse 5mm SPECT slices of each parotid. Loss of salivary excretion fraction (dSEF %) of these slices was calculated as the proportion of SEF after RT as compared to SEF before RT. Since the planning CT-scan and the SPECT-scintigraphy were performed in the same treatment position, the dose to a transverse slice within the parotid gland could be matched to the loss of salivary excretion fraction of that respective slice. A non-linear model was fitted to the dose-loss of function data and the dose resulting in 50% loss of salivary excretion fraction (D50) was calculated. RESULTS: Before RT, all but one patient presented with normal salivary excretion fractions (SEF) of both parotid glands. Within the same parotid gland, the SEF's of the different slices were almost equal. Seven months after RT, the reduction in SEF was statistically significant (P-value<0.0001). A significant difference in loss of salivary excretion fraction (dSEF) was also observed between both parotid glands (P<0.0001) as a result of the parotid-sparing technique. When plotting the dSEF of a slice versus the dose given to that slice, doses as low as 10-15 Gy could result in a serious loss of function (dSEF>50%). After fitting a non-linear model to these plots, the mean dose resulting in 50% loss of salivary excretion fraction (D50) 7 months after RT was 22.5 Gy. A large inter-patient variability was found in D50. CONCLUSIONS: Salivary SPECT is a useful tool for the evaluation of the salivary function of different slices within the parotid gland. Before irradiation, the different slices within one parotid gland act as functional sub-units contributing equally to the function of the entire gland. Seven months after an average dose of 22.5 Gy (D50) the functional sub-unit has lost 50% of its excretion fraction. The high inter-patient variability in D50 and the observation that low doses (10-15 Gy) can induce serious loss of function should prompt us in the clinic to reduce the dose to the parotids even lower than the threshold of 22.5 Gy.     

Dose de tolérance à l’irradiation des tissus sains : les glandes salivaires

Xerostomia is one of the most a common complication of radiotherapy for head and neck cancers, affecting quality of life. Parotid glands produce approximately 60% of saliva and submandibular glands 20% of saliva while the rest is secreted by sublingual and accessory salivary glands. Methods of measuring the salivary output are collection of unstimulated or stimulated saliva or 99mTc-pertechnate scintigraphy. Several studies demonstrated that late salivary dysfunction after radiotherapy has been correlated to the mean parotid gland dose, with recovery occurring with time. Severe xerostomia could be avoided if at one parotid gland is spared to a mean dose of less than approximately 25–30 Gy. Clinical benefit of submandibular gland sparing is more controversial. A mean dose less than 39 Gy could preserve submandibular gland function. This paper aims to review main studies evaluating tolerance dose of salivary glands.     

Protection of salivary function by concomitant pilocarpine during radiotherapy: a double-blind, randomized, placebo-controlled study

PURPOSE: To investigate the effect of concomitant administration of pilocarpine during radiotherapy for head-and-neck squamous cell carcinoma (HNSCC) on postradiotherapy xerostomia. METHODS AND MATERIALS: A prospective, double blind, placebo-controlled randomized trial including 170 patients with HNSCC was executed to study the protective effect of pilocarpine on radiotherapy-induced parotid gland dysfunction. The primary objective endpoint was parotid flow rate complication probability (PFCP) scored 6 weeks, 6 months, and 12 months after radiotherapy. Secondary endpoints included Late Effects of Normal Tissue/Somatic Objective Management Analytic scale (LENT SOMA) and patient-rated xerostomia scores. For all parotid glands, dose-volume histograms were assessed because the dose distribution in the parotid glands is considered the most important prognostic factor with regard to radiation-induced salivary dysfunction. RESULTS: Although no significant differences in PFCP were found for the two treatments arms, a significant (p = 0.03) reduced loss of parotid flow 1 year after radiotherapy was observed in those patients who received pilocarpine and a mean parotid dose above 40 Gy. The LENT SOMA and patient-rated xerostomia scores showed similar trends toward less dryness-related complaints for the pilocarpine group. CONCLUSIONS: Concomitant administration of pilocarpine during radiotherapy did not improve the PFCP or LENT SOMA and patient-rated xerostomia scores. In a subgroup of patients with a mean dose above 40 Gy, pilocarpine administration resulted in sparing of parotid gland function. Therefore, pilocarpine could be provided to patients in whom sufficient sparing of the parotid is not achievable.     

Diffusion-weighted magnetic resonance imaging to evaluate major salivary gland function before and after radiotherapy

PURPOSE: To evaluate diffusion-weighted (DW)-MRI as a noninvasive tool to investigate major salivary gland function before and after radiotherapy (RT) for head and neck cancer (HNC). METHODS AND MATERIALS: DW-MRI was performed in 8 HNC patients before and after parotid-sparing RT (mean dose to the contralateral parotid gland <26 Gy). A DW sequence was performed once at rest and then repeated continuously during salivary stimulation. Apparent diffusion coefficient (ADC) maps for both parotid and submandibular glands were calculated. Findings were compared with salivary gland scintigraphy. RESULTS: Before RT, the mean ADC value at rest was significantly lower in the parotid than in the submandibular glands. During the first 5 min of stimulation, the ADC value of the salivary glands showed a decrease, followed by a steady increase until a peak ADC, significantly higher than the baseline value, was reached after a median of 17 min. The baseline ADC value at rest was significantly higher after RT than before RT in the nonspared salivary glands but not in the spared parotid glands. In the contralateral parotid glands, the same response was seen as before RT. This pattern was completely lost in the nonspared glands. These results corresponded with remaining or loss of salivary function, respectively, as confirmed by salivary gland scintigraphy. CONCLUSIONS: Diffusion-weighted-MRI allows noninvasive evaluation of functional changes in the major salivary glands after RT and is a promising tool for investigating radiation-induced xerostomia.