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1.  Evaluation of radiation-induced changes to parotid glands following conventional radiotherapy in patients with nasopharygneal carcinoma 
The British Journal of Radiology  2011;84(1005):843-849.
Objectives
Xerostomia is a common post-radiotherapy (post-RT) complication in nasopharyngeal carcinoma (NPC) patients. This study evaluated the relation of post-RT parotid gland changes with the dose received.
Methods
Data from 18 NPC patients treated by radiotherapy between 1997 and 2001 were collected. Parotid gland volumes were measured and compared between their pre-RT and post-RT CT images; both sets of CT were conducted with the same scanning protocol. Doppler ultrasound was used to assess the haemodynamic condition of the glands after radiotherapy. Doppler ultrasound results were compared against 18 age-matched normal participants. A questionnaire was used to evaluate the patients' comments of xerostomia condition. Radiotherapy treatment plans of the participants were retrieved from the Eclipse treatment planning system from which the radiation doses delivered to the parotid glands were estimated. The correlations of parotid gland doses and the post-RT changes were evaluated.
Results
The post-RT parotid glands were significantly smaller (p<0.001) than the pre-RT ones. They also demonstrated lower vascular velocity, resistive and pulsatility indices (p<0.05) than normal participants. The degree of volume shrinkage and subjective severity of xerostomia demonstrated dose dependence, but such dependence was not definite in the haemodynamic changes.
Conclusion
It was possible to predict the gland volume change and subjective severity of xerostomia based on the dose to the parotid glands for NPC patients. However, such prediction was not effective for the vascular changes. The damage to the gland was long lasting and had significant effects on the patients' quality of life.
doi:10.1259/bjr/55873561
PMCID: PMC3473791  PMID: 21224300
2.  Metabolic Imaging Biomarkers of Post-Radiotherapy Xerostomia 
Purpose
Xerostomia is a major complication of head and neck radiotherapy. Available xerostomia measures remain flawed. FDG-PET/CT is routinely used for staging and response assessment of head and neck cancer. We investigated quantitative measurement of parotid gland FDG uptake as a potential biomarker for post-radiotherapy xerostomia.
Methods and Materials
Ninety-eight locally advanced head and neck cancer patients receiving definitive radiotherapy underwent baseline and post-radiotherapy FDG-PET/CT on a prospective imaging trial. A separate validation cohort of 14 patients underwent identical imaging while prospectively enrolled onto a second trial collecting sialometry and patient-reported outcomes. Radiation dose and pre/post-RT SUVs for all voxels contained within parotid gland regions-of-interest were deformably registered.
Results
Average whole gland or voxel-by-voxel models incorporating parotid DMet (defined as the pre-treatment parotid SUV weighted by dose) accurately predicted post-treatment changes in parotid FDG uptake (e.g. fractional parotid SUV). Fractional loss of parotid FDG uptake closely paralleled early parotid toxicity defined by post-treatment salivary output (p < 0.01) and RTOG/EORTC xerostomia scores (p < 0.01).
Conclusions
In this pilot series, loss of parotid FDG uptake strongly associates with acute clinical post-radiotherapy parotid toxicity. DMet may potentially be used to guide function-sparing treatment planning. Prospective validation of FDG-PET/CT as a convenient, quantifiable imaging biomarker of parotid function is warranted and ongoing.
doi:10.1016/j.ijrobp.2011.10.074
PMCID: PMC4271834  PMID: 22658215
Radiotherapy; IMRT; PET/CT; imaging; biomarker; normal tissue toxicity; xerostomia
3.  Parotid gland-recovery after radiotherapy in the head and neck region - 36 months follow-up of a prospective clinical study 
Background
The aim of the present study was to evaluate the recovery potential of the parotid glands after using either 3D-conformal-radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) by sparing one single parotid gland.
Methods
Between 06/2002 and 10/2008, 117 patients with head and neck cancer were included in this prospective, non-randomised clinical study. All patients were treated with curative intent. Salivary gland function was assessed by measuring stimulated salivary flow at the beginning, during and at the end of radiotherapy as well as 1, 6, 12, 24, and 36 months after treatment. Measurements were converted to flow rates and normalized relative to rates before treatment. Mean doses (Dmean) were calculated from dose-volume histograms based on computed tomographies of the parotid glands.
Results
Patients were grouped according to the Dmean of the spared parotid gland having the lowest radiation exposure: Group I - Dmean < 26 Gy (n = 36), group II - Dmean 26-40 Gy (n = 45), and group III - Dmean > 40 Gy (n = 36). 15/117 (13%) patients received IMRT. By using IMRT as compared to 3D-CRT the Dmean of the spared parotid gland could be significantly reduced (Dmean IMRT vs. 3D-CRT: 21.7 vs. 34.4 Gy, p < 0.001). The relative salivary flow rates (RFSR) as a function of the mean parotid dose after 24 and 36 months was in group I 66% and 74%, in group II 56% and 49%, and in group III 31% and 24%, respectively. Multiple linear regression analyses revealed that the parotid gland dose and the tumor site were the independent determinants 12 and 36 months after the end of RT. Patients of group I and II parotid gland function did recover at 12, 24, and 36 months after the end of RT.
Conclusions
If a Dmean < 26 Gy for at least one parotid gland can be achieved then this is sufficient to reach complete recovery of pre-RT salivary flow rates. The radiation volume which depends on tumor site did significantly impact on the Dmean of the parotids, and thus on the saliva flow and recovery of parotid gland.
doi:10.1186/1748-717X-6-125
PMCID: PMC3201902  PMID: 21951317
head and neck cancer; irradiation; saliva; hyposalivation; parotid gland sparing; recovery
4.  EFFECT OF IRRADIATION ON MICROVASCULAR ENDOTHELIAL CELLS OF PAROTID GLANDS IN THE MINIATURE PIG 
Purpose
To evaluate the effect of irradiation on microvascular endothelial cells in miniature pig parotid glands.
Methods and Materials
A single 25-Gy dose of irradiation (IR) was delivered to parotid glands of 6 miniature pigs. Three other animals served as non-IR controls. Local blood flow rate in glands was measured pre- and post-IR with an ultrasonic Doppler analyzer. Samples of parotid gland tissue were taken at 4 h, 24 h, 1 week, and 2 weeks after IR for microvascular density (MVD) analysis and sphingomyelinase (SMase) assay. Histopathology and immunohistochemical staining (anti-CD31 and anti-AQP1) were used to assess morphological changes. MVD was determined by calculating the number of CD31- or AQP1-stained cells per field. A terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay was used to detect apoptotic cells. The activity of acid and neutral Mg2+-dependent SMase (ASMase and NSMase, respectively) was also assayed.
Results
Local parotid gland blood flow rate decreased rapidly at 4 h post-IR and remained below control levels throughout the 14-day observation period. Parotid MVD also declined from 4 to 24 hours and remained below control levels thereafter. The activity levels of ASMase and NSMase in parotid glands increased rapidly from 4 to 24 h post-IR and then declined gradually. The frequency of detecting apoptotic nuclei in the glands followed similar kinetics.
Conclusions
Single-dose IR led to a significant reduction of MVD and local blood flow rate, indicating marked damage to microvascular endothelial cells in miniature pig parotid glands. The significant and rapid increases of ASMase and NSMase activity levels may be important in this IR-induced damage.
doi:10.1016/j.ijrobp.2010.05.048
PMCID: PMC3655408  PMID: 20832188
Salivary glands; Radiotherapy; Microvessel density; Endothelial cells; Sphingomyelinase
5.  Changes in parotid gland morphology and function in patients treated with intensity-modulated radiotherapy for nasopharyngeal and oropharyngeal tumors 
Oral Radiology  2013;30(2):135-141.
Objective
To evaluate the morphological changes of the parotid glands in patients treated with intensity-modulated radiotherapy (IMRT) for nasopharyngeal and oropharyngeal tumors and the correlations with parotid function.
Methods
Ten patients with nasopharyngeal and oropharyngeal tumors treated with IMRT between May 2009 and January 2010 at Hokkaido University Hospital were included in this study. In the morphological assessment of the parotid glands, the sizes and computed tomography (CT) numbers of the bilateral parotid glands before and after IMRT with CT were calculated. For functional assessment of the parotid glands, we conducted the Saxon test and used a visual analog scale (VAS) for xerostomia evaluation.
Results
Reductions in saliva secretion were observed in the patients treated with IMRT for nasopharyngeal and oropharyngeal tumors, and there was a significant correlation between the reduction in saliva secretion and the VAS. The reductions in the parotid gland size and CT number were larger on the ipsilateral side than on the contralateral side. The reduction in saliva secretion was not significantly correlated with the reduction in parotid gland size, but was significantly correlated with the reduction in CT number.
Conclusions
Morphological and functional changes of the parotid glands were observed after IMRT for nasopharyngeal and oropharyngeal tumors, and preservation of the contralateral parotid glands was only partly achieved. Among the morphological changes of the parotid glands, the CT number may be considered a predictor of parotid function after radiotherapy.
doi:10.1007/s11282-013-0151-3
PMCID: PMC4009139  PMID: 24817788
Intensity-modulated radiotherapy (IMRT); Parotid gland; Nasopharyngeal and oropharyngeal tumors; Morphological and functional changes
6.  Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial 
The Lancet Oncology  2011;12(2):127-136.
Summary
Background
Xerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia.
Methods
We undertook a randomised controlled trial between Jan 21, 2003, and Dec 7, 2007, that compared conventional radiotherapy (control) with parotid-sparing IMRT. We randomly assigned patients with histologically confirmed pharyngeal squamous-cell carcinoma (T1–4, N0–3, M0) at six UK radiotherapy centres between the two radiotherapy techniques (1:1 ratio). A dose of 60 or 65 Gy was prescribed in 30 daily fractions given Monday to Friday. Treatment was not masked. Randomisation was by computer-generated permuted blocks and was stratified by centre and tumour site. Our primary endpoint was the proportion of patients with grade 2 or worse xerostomia at 12 months, as assessed by the Late Effects of Normal Tissue (LENT SOMA) scale. Analyses were done on an intention-to-treat basis, with all patients who had assessments included. Long-term follow-up of patients is ongoing. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN48243537.
Findings
47 patients were assigned to each treatment arm. Median follow-up was 44·0 months (IQR 30·0–59·7). Six patients from each group died before 12 months and seven patients from the conventional radiotherapy and two from the IMRT group were not assessed at 12 months. At 12 months xerostomia side-effects were reported in 73 of 82 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the IMRT group than in the conventional radiotherapy group (25 [74%; 95% CI 56–87] of 34 patients given conventional radiotherapy vs 15 [38%; 23–55] of 39 given IMRT, p=0·0027). The only recorded acute adverse event of grade 2 or worse that differed significantly between the treatment groups was fatigue, which was more prevalent in the IMRT group (18 [41%; 99% CI 23–61] of 44 patients given conventional radiotherapy vs 35 [74%; 55–89] of 47 given IMRT, p=0·0015). At 24 months, grade 2 or worse xerostomia was significantly less common with IMRT than with conventional radiotherapy (20 [83%; 95% CI 63–95] of 24 patients given conventional radiotherapy vs nine [29%; 14–48] of 31 given IMRT; p<0·0001). At 12 and 24 months, significant benefits were seen in recovery of saliva secretion with IMRT compared with conventional radiotherapy, as were clinically significant improvements in dry-mouth-specific and global quality of life scores. At 24 months, no significant differences were seen between randomised groups in non-xerostomia late toxicities, locoregional control, or overall survival.
Interpretation
Sparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life, and thus strongly supports a role for IMRT in squamous-cell carcinoma of the head and neck.
Funding
Cancer Research UK (CRUK/03/005).
doi:10.1016/S1470-2045(10)70290-4
PMCID: PMC3033533  PMID: 21236730
7.  Pattern and predictors of volumetric change of parotid glands during intensity modulated radiotherapy 
The British Journal of Radiology  2013;86(1031):20130363.
Objective:
To describe the pattern and predictors of volumetric change of parotid glands during intensity modulated radiotherapy (IMRT) for oropharyngeal cancer.
Methods:
A cohort of patients undergoing weekly CT scans during dose-painted IMRT was considered. The parotid glands were contoured at the time of treatment planning (baseline) and on all subsequent scans. For a given patient, the parotid glands were labelled as higher (H) and lower (L), based on the mean dose at planning. The volume of each gland was determined for each scan and the percent change from baseline computed. Data were fit to both linear and quadratic functions. The role of selected covariates was assessed with both logistic regression and pair-wise comparison between the sides. The analyses were performed considering the whole treatment duration or each separate half.
Results:
85 patients, 170 glands and 565 scans were analysed. For all parotids except one, the quadratic function provided a better fit than the linear one. Moreover, according to both the logistic regression and pair-wise comparison, the cumulative mean dose of radiation is independently correlated with the parotid shrinkage during the first but not the second half of the treatment. Conversely, age and weight loss are predictors of relative parotid shrinkage during the entire course of the treatment.
Conclusion:
Parotid gland shrinkage during IMRT is not linear. Age, weight loss and radiation dose independently predict parotid shrinkage during a course of IMRT.
Advances in knowledge:
The present study adds to the pathophysiology of parotid shrinkage during radiotherapy.
doi:10.1259/bjr.20130363
PMCID: PMC3830435  PMID: 24029628
8.  Dosimetric evaluation of an ipsilateral intensity modulated radiotherapy beam arrangement for parotid malignancies 
Radiology and Oncology  2013;47(4):411-418.
Background
We conducted a dosimetric comparison of an ipsilateral beam arrangement for intensity modulated radiotherapy (IMRT) with off-axis beams.
Patients and methods
Six patients who received post-operative radiotherapy (RT) for parotid malignancies were used in this dosimetric study. Four treatment plans were created for each CT data set (24 plans): 1) ipsilateral 4-field off-axis IMRT (4fld-OA), 2) conventional wedge pair (WP), 3) 7 field co-planar IMRT (7fld), and 4) ipsilateral co-planar 4-field quartet IMRT (4fld-CP). Dose, volume statistics for the planning target volumes (PTVs) and planning risk volumes (PRVs) were compared for the four treatment techniques.
Results
Wedge pair plans inadequately covered the deep aspect of the PTV. The 7-field IMRT plans delivered the largest low dose volumes to normal tissues. Mean dose to the contralateral parotid was highest for 7 field IMRT. Mean dose to the contralateral submandibular gland was highest for 7 field IMRT and WP. 7 field IMRT plans had the highest dose to the oral cavity. The mean doses to the brainstem, spinal cord, ipsilateral temporal lobe, cerrebellum and ipsilateral cochlea were similar among the four techniques.
Conclusions
For postoperative treatment of the parotid bed, 4-field ipsilateral IMRT techniques provided excellent coverage while maximally sparing the contralateral parotid gland and submandibular gland.
doi:10.2478/raon-2013-0010
PMCID: PMC3814288  PMID: 24294188
intensity modulated radiotherapy; parotid; dosimetry
9.  Superficial parotid lobe–sparing delineation approach: a better method of dose optimization to protect the parotid gland in intensity-modulated radiotherapy for nasopharyngeal carcinoma 
Current Oncology  2013;20(6):e577-e584.
Purpose
We used a superficial parotid lobe–sparing delineation approach for dose optimization with better protection for the parotid glands in intensity-modulated radiotherapy (imrt) for nasopharyngeal carcinoma (npc) patients.
Methods
Compared with traditional contouring of the entire parotid glands as organs at risk (oars) in imrt for npc, we used a superficial parotid lobe–sparing delineation approach of contouring the superficial parotid lobes as oars. Changes in dose to the parotid glands, the targets, and other oars were evaluated.
Results
The mean dose to the parotid glands overall decreased by more than 4 Gy in the test plans. Impressively, the mean dose to the superficial parotid lobes in the test plans was not more than 30 Gy, regardless of clinical stage. In T1–3 npc patients, the dose distributions for targets were not significantly different in the control plans and the test plans. However, for some T4 patients, the dose distributions for targets and brainstem in the test plans could not meet clinical requirements.
Conclusions
The superficial parotid lobe–sparing delineation approach can significantly lower the mean dose to the entire parotid and to the superficial parotid lobe in T1–3 npc patients, which would be expected to result in less xerostomia and better quality of life for those patients.
doi:10.3747/co.20.1485
PMCID: PMC3851355  PMID: 24311959
Intensity-modulated radiotherapy; nasopharyngeal carcinoma; superficial parotid lobes
10.  Changes of parotid and submandibular glands caused by radiotherapy—an ultrasound evaluation 
Dentomaxillofacial Radiology  2012;41(5):379-384.
Objective
Radiotherapy may alter the normal morphology of salivary glands located in the radiation field. These changes could be evaluated safely by sonography; however, there have been few studies in this regard. This study is aimed at evaluating the sonographic changes of the parotid and submandibular glands in patients undergoing radiotherapy for head and neck malignancies.
Methods
20 patients (16 males and 4 females) with head and neck malignancies who had been referred for radiotherapy to the Qaem Hospital in Mashhad, Iran, entered the study. Length, height, depth, echotexture, echogenicity and margins of parotid and submandibular glands were evaluated in three stages (I, before radiotherapy; II, 2 weeks after radiotherapy; and III, 6–7 weeks after radiotherapy) using sonography. Peak systolic velocity (PSV), end diastolic velocity (EDV) and resistive index (RI) were also evaluated by Doppler sonography.
Results
Significant differences in length, height and depth (p = 0.000, p = 0.000, and p = 0.39, respectively) and also echotexture, echogenicity and gland margins (p = 0.000) were observed before and after radiotherapy. Doppler sonography results showed no significant differences regarding PSV, EDV and RI between sonographic stages. Echotexture and echogenicity were the only independent parameters that showed significant differences in sonographic stages I and II (p = 0.000). Length in stage I and II (p = 0.000) and echogenicity in stage III (p = 0.038) were the only parameters that showed significant differences between the two glands.
Conclusion
Radiotherapy may change the echotexture, echogenicity and margins of the salivary glands from homogenic to heterogenic, hyperechoic to hypoechoic and regular to irregular, respectively, and may reduce their size.
doi:10.1259/dmfr/17113005
PMCID: PMC3520350  PMID: 22241872
radiotherapy; sonography; salivary gland; Doppler sonography; head and neck malignancies
11.  ULTRASOUND HISTOGRAM ASSESSMENT OF PAROTID GLAND INJURY FOLLOWING HEAD-AND-NECK RADIOTHERAPY: A FEASIBILITY STUDY 
Ultrasound in medicine & biology  2012;38(9):1514-1521.
Xerostomia (dry mouth), resulting from radiation damage to the parotid glands, is one of the most common and distressing side effects of head-and-neck cancer radiotherapy. A noninvasive, objective imaging method to assess parotid injury is lacking, but much needed in the clinic. Therefore, we investigated echo histograms to quantitatively evaluate the morphologic and microstructural integrity of the parotid glands. Six sono-graphic features were derived from the echo-intensity histograms to assess the echogenicity, homogeneity and heterogeneity of the parotid gland: (1) peak intensity value (Ipeak), (2) −3-dB intensity width (W3-dB), (3) the low (<50% Ipeak) intensity width (Wlow), (4) the high (>50% Ipeak) intensity width (Whigh), (5) the area of low intensity (Alow) and (6) the area of high intensity (Ahigh). In this pilot study, 12 post-radiotherapy patients and seven healthy volunteers were enrolled. Significant differences (p < 0.05) were observed in four sonographic features between 24 irradiated and 14 normal parotid glands. In summary, we developed a family of sonographic features derived from echo histograms and demonstrated the feasibility of quantitative evaluation of radiation-induced parotid-gland injury.
doi:10.1016/j.ultrasmedbio.2012.05.005
PMCID: PMC3633493  PMID: 22766120
Xerostomia; Ultrasound; Parotid gland; Radiation toxicity; Echo histogram; Head-and-neck cancer; Sonographic features
12.  Parotid gland sparing effect by computed tomography-based modified lower field margin in whole brain radiotherapy 
Radiation Oncology Journal  2013;31(1):12-17.
Purpose
Parotid gland can be considered as a risk organ in whole brain radiotherapy (WBRT). The purpose of this study is to evaluate the parotid gland sparing effect of computed tomography (CT)-based WBRT compared to 2-dimensional plan with conventional field margin.
Materials and Methods
From January 2008 to April 2011, 53 patients underwent WBRT using CT-based simulation. Bilateral two-field arrangement was used and the prescribed dose was 30 Gy in 10 fractions. We compared the parotid dose between 2 radiotherapy plans using different lower field margins: conventional field to the lower level of the atlas (CF) and modified field fitted to the brain tissue (MF).
Results
Averages of mean parotid dose of the 2 protocols with CF and MF were 17.4 Gy and 8.7 Gy, respectively (p < 0.001). Mean parotid dose of both glands ≥20 Gy were observed in 15 (28.3%) for CF and in 0 (0.0%) for MF. The whole brain percentage volumes receiving >98% of prescribed dose were 99.7% for CF and 99.5% for MF.
Conclusion
Compared to WBRT with CF, CT-based lower field margin modification is a simple and effective technique for sparing the parotid gland, while providing similar dose coverage of the whole brain.
doi:10.3857/roj.2013.31.1.12
PMCID: PMC3633226  PMID: 23620864
Whole brain radiotherapy; Parotid gland sparing; Xerostomia; Normal tissue complication probability
13.  Parotid Glands Dose-Effect Relationships Based on Their Actually Delivered Doses: Implications for Adaptive Re-Planning in Radiotherapy of Head and Neck Cancer 
Purpose
Doses actually delivered to the parotid glands during radiotherapy often exceed planned doses. We hypothesized that the delivered doses correlate better with parotid salivary output than the planned doses, used in all previous studies, and that determining these correlations will help decisions regarding adaptive re-planning (ART) aimed at reducing the delivered doses.
Methods and Materials
Prospective study: oropharyngeal cancer patients treated definitively with chemo-irradiation underwent daily cone beam CT (CBCT) with clinical set-up alignment based on C2 posterior edge. Parotid glands in the CBCTs were aligned by deformable registration to calculate cumulative delivered doses. Stimulated salivary flow rates were measured separately from each parotid gland pretherapy and periodically posttherapy.
Results
36 parotid glands of 18 patients were analyzed. Average mean planned doses was 32 Gy and differences from planned to delivered mean gland doses were −4.9 to +8.4 Gy, median difference +2.2 Gy in glands whose delivered doses increased relative to planned. Both planned and delivered mean doses were significantly correlated with post-treatment salivary outputs at almost all post-therapy time points, without statistically significant differences in the correlations. Large dispersions [on average, standard deviation (SD) 3.6 Gy] characterized the dose/effect relationships for both. The differences between the cumulative delivered doses and planned doses were evident already at first fraction (r=0.92, p<0.0001) due to complex set-up deviations, e.g. rotations and neck articulations, uncorrected by the translational clinical alignments.
Conclusions
After daily translational set-up corrections, differences between planned and delivered doses in most glands were small relative to the SDs of the dose/saliva data, suggesting that ART is not likely to gain measurable salivary output improvement in most cases. These differences were observed already at first treatment, indicating potential benefit for more complex set-up corrections or adaptive interventions in the minority of patients with large deviations detected very early by CBCT.
doi:10.1016/j.ijrobp.2013.07.040
PMCID: PMC3805710  PMID: 24035328
parotid; head neck cancer; IMRT; IGRT; Adaptive radiotherapy
14.  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 radiotherapy (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 two years following 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. <25Gy), the model-predicted average stimulated saliva recovers to pre-treatment levels at 12 months and exceeds it at 18 and 24 months. For higher doses (e.g. >30Gy), the stimulated saliva does not return to original levels after two years. Without stimulation, at 24 months, the predicted saliva is 86% of pre-treatment levels for 25Gy and <31% for >40Gy. We do not find evidence to support that the over-production of stimulated saliva at 18 and 24 months after low dose in one parotid gland is due to low saliva production from the other parotid gland.
Conclusions
Saliva production is impacted significantly by radiation, but with doses <25–30Gy, recovery is substantial and returns to pre-treatment levels two years after RT.
doi:10.1016/j.ijrobp.2006.09.021
PMCID: PMC2001308  PMID: 17141973
Head and neck cancer; Intensity modulated radiation therapy; Parotid salivary glands; Radiation dose; Bayesian analysis
15.  Extended parotidectomy 
Summary
Malignant tumours of the parotid gland represent a group of relatively rare lesions. The medical records of 363 patients with parotid swelling treated between 1974 and 2003 at the “G. Ferreri” Department of Otorhinolaryngology, “La Sapienza” University in Rome were retrospectively analysed. Clinical presentation, pre-operative investigations, surgical procedure, histopathology report, post-operative complications, and the oncological results of 19 patients who underwent extended radical parotidectomy for malignant neoplasm of the parotid gland are discussed. Extended radical parotidectomy, reserved for neoplasms in an advanced stage, involves the removal of the entire parotid gland, with sacrifice of the facial nerve and the resection en bloc of the adjacent structures affected by neoplastic infiltration, such as the temporal bone, the mandibular bone, the skin, blood vessels and nerves. In addition to this surgical treatment, a cycle of adjuvant radiotherapy is also necessary. The overall rate of survival at 10 years depends mainly on the histological characteristics of the tumour, and, in this series, is reported to be approximately 58%. These data indicate that total extended radical parotidectomy combined with post-operative radiotherapy, represents the best therapeutic approach with regard both to quality of life and life expectancy, in patients with an advanced stage of malignant neoplasm of the parotid gland.
PMCID: PMC2639865  PMID: 16450772
Parotid gland; Malignant tumours; Treatment; Extended parotidectomy
16.  Effects of radiotherapy on parotid salivary sialochemistry in head and neck cancer patients 
Aim
To determine the effects of high dose irradiation on parotid salivary sodium and pH concentration at subsequent duration of 1.5, 3 and 6 months following radiotherapy.
Materials and methods
Eighty parotid glands of head and neck cancer patients were irradiated with mean dose of 66 Gy. The stimulated parotid flow (PF) was collected by a cannulation of Stenson’s duct followed by analysis of sodium (PF sodium) by Easylyte Sodium/Potassium auto analyzer and pH by litmus narrow band pH paper.
Results
A steep elevation of PF sodium was found in post-RT period after 1.5 months of starting RT followed by gradual increase up to 6 months and pH changed towards acidity.
Conclusions
A high dose of 66 Gy causes irreversible damage to parotid salivary duct system.
doi:10.1007/s12070-009-0084-7
PMCID: PMC3450082  PMID: 23120652
Radiotherapy; Head and neck cancer; Parotid gland; Sodium
17.  Effect of Same-dose Single or Dual Field Irradiation on Damage to Miniature Pig Parotid Glands 
Aim
To evaluate the effect of single or dual field irradiation (IR) with the same dose on damage to miniature pig parotid glands.
Methodology
Sixteen miniature pigs were divided into two IR groups (n=6) and a control group (n=4). The irradiation groups were subjected to 20 Gy X-radiation to one parotid gland using single-field or dual-field modality by linear accelerator. The dose-volume distributions between two IR groups were compared. Saliva from parotid glands and blood were collected at 0, 4, 8 and 16 weeks after irradiation. Parotid glands were removed at 16 weeks to evaluate tissue morphology.
Results
The irradiation dose volume distributions were significantly different between single and dual field irradiation groups (t=4.177, P=0.002), although dose volume histogramin (DVH) indicated the equal maximal dose in parotid glands. Saliva flow rates from IR side decreased dramatically at all time points in IR groups, especially in dual field irradiation group. The radiation caused changes of white blood cell count in blood, lactate dehydrogenase and amylase in serum, calcium, potassium and amylase in saliva. Morphologically, more severe radiation damage was found in irradiated parotid glands from dual field irradiation group than that from single field irradiation group.
Conclusion
Data from this large animal model demonstrated that the radiation damage from the dual field irradiation was more severe than that of the single field irradiation at the same dose, suggesting that dose-volume distribution is an important factor in evaluation of the radiobiology of parotid glands.
doi:10.4248/ijos.08001
PMCID: PMC3735788  PMID: 20690500
irradiation damage; miniature pig; parotid gland
18.  Increase in mast cells and hyaluronic acid correlates to radiation-induced damage and loss of serous acinar cells in salivary glands: the parotid and submandibular glands differ in radiation sensitivity. 
British Journal of Cancer  1994;69(2):320-326.
The detailed mechanisms which can explain the inherent radiosensitivity of salivary glands remain to be elucidated. Although DNA is the most plausible critical target for the lethal effects of irradiation, interactions with other constituents, such as cell membrane and neuropeptides, have been suggested to cause important physiological changes. Moreover, mast cells seem to be closely linked to radiation-induced pneumonitis. Therefore, in the present study the effects of fractionated irradiation on salivary glands have been assessed with special regard to the appearance of mast cells and its correlation with damage to gland parenchyma. Sprague-Dawley strain rats were unilaterally irradiated to the head and neck with the salivary glands within the radiation field. The irradiation was delivered once daily for 5 days to a total dose of 20, 35 and 45 Gy. The contralateral parotid and submandibular glands served as intra-animal controls and parallel analysis of glands was performed 2, 4, 10 or 180 days following the last radiation treatment. Morphological analysis revealed no obvious changes up to 10 days after the irradiation. At 180 days a radiation dose-dependent loss of gland parenchyma was seen, especially with regard to serious acinar cells in parotid gland and acinar cells and serous CGT (convoluted granular tubule) cells in the submandibular gland. These changes displayed a close correlation with a concomitant dose-dependent enhanced density of mast cells and staining for hyaluronic acid. This cell population seems to conform with the features of the connective tissue mast cell type. The parotid seems to be more sensitive to irradiation than the submandibular gland. Thus, the present results further strengthen the role of and the potential interaction of mast cells with radiation-induced tissue injury and alterations in normal tissue integrity.
Images
PMCID: PMC1968701  PMID: 8297728
19.  Comparative study of four advanced 3d-conformal radiation therapy treatment planning techniques for head and neck cancer 
For the head-and-neck cancer bilateral irradiation, intensity-modulated radiation therapy (IMRT) is the most reported technique as it enables both target dose coverage and organ-at-risk (OAR) sparing. However, during the last 20 years, three-dimensional conformal radiotherapy (3DCRT) techniques have been introduced, which are tailored to improve the classic shrinking field technique, as regards both planning target volume (PTV) dose conformality and sparing of OAR’s, such as parotid glands and spinal cord. In this study, we tested experimentally in a sample of 13 patients, four of these advanced 3DCRT techniques, all using photon beams only and a unique isocentre, namely Bellinzona, Forward-Planned Multisegments (FPMS), ConPas, and field-in-field (FIF) techniques. Statistical analysis of the main dosimetric parameters of PTV and OAR’s DVH’s as well as of homogeneity and conformity indexes was carried out in order to compare the performance of each technique. The results show that the PTV dose coverage is adequate for all the techniques, with the FPMS techniques providing the highest value for D95%; on the other hand, the best sparing of parotid glands is achieved using the FIF and ConPas techniques, with a mean dose of 26 Gy to parotid glands for a PTV prescription dose of 54 Gy. After taking into account both PTV coverage and parotid sparing, the best global performance was achieved by the FIF technique with results comparable to that of IMRT plans. This technique can be proposed as a valid alternative when IMRT equipment is not available or patient is not suitable for IMRT treatment.
doi:10.4103/0971-6203.111331
PMCID: PMC3683308  PMID: 23776314
Head and neck; 3DCRT techniques; dosimetric comparison
20.  3D-conformal-intensity modulated radiotherapy with compensators for head and neck cancer: clinical results of normal tissue sparing 
Background
To investigate the potential of parotic gland sparing of intensity modulated radiotherapy (3D-c-IMRT) performed with metallic compensators for head and neck cancer in a clinical series by analysis of dose distributions and clinical measures.
Materials and methods
39 patients with squamous cell cancer of the head and neck irradiated using 3D-c-IMRT were evaluable for dose distribution within PTVs and at one parotid gland and 38 patients for toxicity analysis. 10 patients were treated primarily, 29 postoperatively, 19 received concomittant cis-platin based chemotherapy, 20 3D-c-IMRT alone. Initially the dose distribution was calculated with Helax ® and photon fluence was modulated using metallic compensators made of tin-granulate (n = 22). Later the dose distribution was calculated with KonRad ® and fluence was modified by MCP 96 alloy compensators (n = 17). Gross tumor/tumor bed (PTV 1) was irradiated up to 60–70 Gy, [5 fractions/week, single fraction dose: 2.0–2.2 (simultaneously integrated boost)], adjuvantly irradiated bilateral cervical lymph nodes (PTV 2) with 48–54 Gy [single dose: 1.5–1.8]). Toxicity was scored according the RTOG scale and patient-reported xerostomia questionnaire (XQ).
Results
Mean of the median doses at the parotid glands to be spared was 25.9 (16.3–46.8) Gy, for tin graulate 26 Gy, for MCP alloy 24.2 Gy. Tin-granulate compensators resulted in a median parotid dose above 26 Gy in 10/22, MCP 96 alloy in 0/17 patients. Following acute toxicities were seen (°0–2/3): xerostomia: 87%/13%, dysphagia: 84%/16%, mucositis: 89%/11%, dermatitis: 100%/0%. No grade 4 reaction was encountered. During therapy the XQ forms showed °0–2/3): 88%/12%. 6 months postRT chronic xerostomia °0–2/3 was observed in 85%/15% of patients, none with °4 xerostomia.
Conclusion
3D-c-IMRT using metallic compensators along with inverse calculation algorithm achieves sufficient parotid gland sparing in virtually all advanced head and neck cancers. Since the concept of lower single (and total) doses in the adjuvantly treated volumes reduces acute morbidity 3D-c-IMRT nicely meets demands of concurrent chemotherapy protocols.
doi:10.1186/1748-717X-1-18
PMCID: PMC1524966  PMID: 16790059
21.  Feasibility of image-guided radiotherapy based on helical tomotherapy to reduce contralateral parotid dose in head and neck cancer 
BMC Cancer  2012;12:175.
Background
To evaluate the feasibility of image-guided radiotherapy based on helical Tomotherapy to spare the contralateral parotid gland in head and neck cancer patients with unilateral or no neck node metastases.
Methods
A retrospective review of 52 patients undergoing radiotherapy for head and neck cancers with image guidance based on daily megavoltage CT imaging with helical tomotherapy was performed.
Results
Mean contralateral parotid dose and the volume of the contralateral parotid receiving 40 Gy or more were compared between radiotherapy plans with significant constraint (SC) of less than 20 Gy on parotid dose (23 patients) and the conventional constraint (CC) of 26 Gy (29 patients). All patients had PTV coverage of at least 95% to the contralateral elective neck nodes. Mean contralateral parotid dose was, respectively, 14.1 Gy and 24.7 Gy for the SC and CC plans (p < 0.0001). The volume of contralateral parotid receiving 40 Gy or more was respectively 5.3% and 18.2% (p < 0.0001)
Conclusion
Tomotherapy for head and neck cancer minimized radiotherapy dose to the contralateral parotid gland in patients undergoing elective node irradiation without sacrificing target coverage.
doi:10.1186/1471-2407-12-175
PMCID: PMC3411401  PMID: 22578076
Head and neck cancer; Tomotherapy; Parotid sparing
22.  Dosimetric variations of target volumes and organs at risk in nasopharyngeal carcinoma intensity-modulated radiotherapy 
Zhang, X | Li, M | Cao, J | Luo, J-W | Xu, G-Z | Gao, L | Yi, J | Huang, X | Xiao, J | Li, S | Dai, J
The British Journal of Radiology  2012;85(1016):e506-e513.
Objective
The aim of this study was to evaluate the actual dose variability to the targets and organs at risk (OARs) during nasopharyngeal carcinoma (NPC) intensity-modulated radiotherapy (IMRT) and to investigate the significance of replanning.
Methods
11 NPC patients were included in this study. Each patient had both a planning CT and weekly repeated CT. Simulated plans that were generated by using the same beam configurations mapped to the repeated CT represented the actual delivered doses to the target volumes and OARs. An IMRT replanning was performed with the fifth week CT scan. Doses among the initial plan, the simulated plans and replanning were compared.
Results
There were no significant dosimetric differences in the gross tumour volume, clinical target volume (CTV) 1 or CTV2 for either the simulated plans or the replanning compared with the initial plan. Dosimetric variability of both parotid glands and the brain stem were unique to each individual, and doses to the spinal cord were always maintained within the limit. Replanning in the fifth week had significantly decreased the doses delivered to both parotids (p-values of the mean dose were 0.015 and 0.026 for the left and right parotid, respectively), whereas it did not reduce the doses to the brain stem and spinal cord. There was no relationship between dose variability and weight loss.
Conclusions
There are no significant dose changes for target volumes and spinal cord, and doses to the brain stem and both parotid glands changed individually during NPC IMRT. Replanning helps to spare bilateral parotids.
doi:10.1259/bjr/20695672
PMCID: PMC3587088  PMID: 22096217
23.  99mTc Hynic-rh-Annexin V scintigraphy for in vivo imaging of apoptosis in patients with head and neck cancer treated with chemoradiotherapy 
Purpose
The purpose of this study was to determine the value of 99mTc Hynic-rh-Annexin-V-Scintigraphy (TAVS), a non-invasive in vivo technique to demonstrate apoptosis in patients with head and neck squamous cell carcinoma.
Methods
TAVS were performed before and within 48 h after the first course of cisplatin-based chemoradiation. Radiation dose given to the tumour at the time of post-treatment TAVS was 6–8 Gy. Single-photon emission tomography data were co-registered to planning CT scan. Complete sets of these data were available for 13 patients. The radiation dose at post-treatment TAVS was calculated for several regions of interest (ROI): primary tumour, involved lymph nodes and salivary glands. Annexin uptake was determined in each ROI, and the difference between post-treatment and baseline TAVS represented the absolute Annexin uptake: Delta uptake (ΔU).
Results
In 24 of 26 parotid glands, treatment-induced Annexin uptake was observed. Mean ΔU was significantly correlated with the mean radiation dose given to the parotid glands (r = 0.59, p = 0.002): Glands that received higher doses showed more Annexin uptake. ΔU in primary tumour and pathological lymph nodes showed large inter-patient differences. A high correlation was observed on an inter-patient level (r = 0.71, p = 0.006) between the maximum ΔU in primary tumour and in the lymph nodes.
Conclusions
Within the dose range of 0–8 Gy, Annexin-V-scintigraphy showed a radiation-dose-dependent uptake in parotid glands, indicative of early apoptosis during treatment. The inter-individual spread in Annexin uptake in primary tumours could not be related to differences in dose or tumour volume, but the Annexin uptake in tumour and lymph nodes were closely correlated. This effect might represent a tumour-specific apoptotic response.
doi:10.1007/s00259-007-0624-x
PMCID: PMC2275773  PMID: 17994297
Apoptosis; Annexin; Scintigraphy; Head and neck cancer; Parotid gland
24.  Second Cancer Incidence Risk Estimates using BEIR VII Models for Standard and Complex External Beam Radiotherapy for Early Breast Cancer 
Medical physics  2012;39(10):5814-5824.
Purpose
To compare organ specific cancer incidence risks for standard and complex external beam radiotherapy including cone beam CT verification following breast conservation surgery for early breast cancer.
Method
Doses from breast radiotherapy and kilovoltage cone beam CT (CBCT) exposures were obtained from thermoluminescent dosimeter (TLD) measurements in an anthropomorphic phantom in which the positions of radiosensitive organs were delineated. Five treatment deliveries were investigated : (i) conventional tangential field whole breast radiotherapy (WBRT), (ii) non-coplanar conformal delivery applicable to accelerated partial beast irradiation (APBI), (iii) two-volume simultaneous integrated boost (SIB) treatment, (iv) forward planned three-volume SIB, (v) inverse-planned three volume SIB. Conformal and intensity modulated radiotherapy (IMRT) methods were used to plan the complex treatments. Techniques spanned the range from simple methods appropriate for patient cohorts with a low local cancer recurrence risk to complex plans relevant to cohorts with high recurrence risk. Delineated organs at risk included brain, salivary glands, thyroid, contra-lateral breast, left and right lung, oesophagus, stomach, liver, colon and bladder. Biological Effects of Ionising Radiation (BEIR) VII cancer incidence models were applied to the measured mean organ doses to determine Lifetime Attributable Risk (LAR) for ages at exposure from 35 to 80 years according to radiotherapy techniques, and included dose from the CBCT imaging.
Results
All LAR decreased with age at exposure and were lowest for brain, thyroid, liver and bladder (< 0.1%). There was little dependence of LAR on radiotherapy technique for these organs and for colon and stomach. LAR values for the lungs for the three SIB techniques were two to three times those from WBRT and APBI. Uncertainties in the LAR models outweigh any differences in lung LAR between the SIB methods. Constraints in the planning of the SIB methods ensured that contra-lateral breast doses and LAR were comparable to WBRT, despite their added complexity. The smaller irradiated volume of the ABPI plan contributed to a halving of LAR for contralateral breast compared with the other plan types. Daily image guided radiotherapy (IGRT) for a left breast protocol using kilovoltage CBCT contributed <10% to LAR for the majority of organs, and did not exceed 22% of total organ dose.
Conclusion
Phantom measurements and calculations of LAR from the BEIR VII models predict that complex breast radiotherapy techniques do not increase the theoretical risk of second cancer incidence for organs distant from the treated breast, or the contralateral breast where appropriate plan constraints are applied. Complex SIB treatments are predicted to increase the risk of second cancer incidence in the lungs compared to standard whole breast radiotherapy ; this is outweighed by the threefold reduction in 5 year local recurrence risk for patients of high risk of recurrence, and young age, from the use of radiotherapy. APBI may have a favourable impact on risk of second cancer in the contra-lateral breast and lung for older patients at low risk of recurrence. Intensive use of IGRT increased the estimated values of LAR but these are dominated by the effect of the dose from the radiotherapy, and any increase in LAR from IGRT is much lower than the models’ uncertainties.
doi:10.1118/1.4748332
PMCID: PMC3498624  PMID: 23039620
second cancer incidence; breast radiotherapy; image-guided radiotherapy; partial breast
25.  Parotid gland dose in head-and-neck intensity-modulated radiotherapy: Is what you plan what you get? 
Purpose
To quantify the differences between planned and delivered parotid gland and target doses, and to assess the benefits of daily bone alignment for head-and-neck cancer patients treated with intensity-modulated radiotherapy (IMRT).
Methods and Materials
Eleven head-and-neck cancer patients received 2 CT scans/week with an in-room CT scanner over their course of radiotherapy. The clinical IMRT plans, designed with 3–4mm planning margins, were recalculated on the repeat CT images. The plans were aligned using (1) the actual treatment isocenter marked with radiopaque markers (BB) and (2) bone alignment to the cervical vertebrae to simulate image-guided setup. In-house deformable image registration software was used to map daily dose distributions to the original treatment plan and to calculate a cumulative, delivered dose distribution for each patient.
Results
Using conventional BB alignment led to increases in the parotid gland mean dose above the planned dose by 5–7Gy in 45% of the patients (median = 3.0Gy ipsilateral (p=0.026); median = 1.0Gy contralateral (p=0.016)). Use of bone alignment led to reductions relative to BB alignment in 91% of patients (median=2Gy; range=0.3–8.3Gy; 15 of 22 parotids improved). However, the parotid dose from bone alignment was still greater than planned (median=1.0Gy (p=0.007)). Neither approach affected tumor dose coverage.
Conclusions
With conventional BB alignment, the parotid gland mean dose was significantly increased above the planned mean dose. Using daily bone alignment reduced the parotid dose compared to BB alignment in almost all patients. A 3–4 mm planning margin was adequate for tumor dose coverage.
doi:10.1016/j.ijrobp.2007.07.2345
PMCID: PMC2288571  PMID: 17967319
adaptive radiotherapy; IGRT; setup uncertainty; anatomic variation; parotid gland

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