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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.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  Developing an adaptive radiation therapy strategy for nasopharyngeal carcinoma 
Journal of Radiation Research  2013;55(2):293-304.
Adaptive radiotherapy (ART) has recently been introduced to restore the planned dose distribution by accounting for the anatomic changes during treatment. By quantifying the anatomic changes in nasopharyngeal carcinoma (NPC) patients, this study aimed to establish an ART strategy for NPC cases. A total of 30 NPC patients treated with helical tomotherapy were recruited. In the pretreatment megavoltage CT images, the anatomic changes of the posterolateral wall of nasopharynx (P-NP), neck region and parotid glands were measured and assessed. One-way repeated measure ANOVA was employed to define threshold(s) at any time-point. The presence of a threshold(s) would indicate significant anatomical change(s) such that replanning should be suggested. A pragmatic schedule for ART was established by evaluating the threshold for each parameter. Results showed the P-NP, parotid gland and neck volumes demonstrated significant regressions over time. Respectively, the mean loss rates were 0.99, 1.35, and 0.39 %/day, and the mean volume losses were 35.70, 47.54 and 11.91% (all P < 0.001). The parotid gland shifted medially and superiorly over time by a mean of 0.34 and 0.24 cm, respectively (all P < 0.001). The neck region showed non-rigid posterior displacement, which increased from upper to lower neck. According to the threshold occurrences, three replans at 9th, 19th and 29th fractions were proposed. This ART strategy was able to accommodate the dosimetric consequences due to anatomic deviation over the treatment course. It is clinically feasible and would be recommended for centers where an adaptive planning system was not yet available.
doi:10.1093/jrr/rrt103
PMCID: PMC3951067  PMID: 23988444
adaptive radiotherapy; nasopharyngeal carcinoma; tomotherapy; replanning schedule
12.  Interobserver variation in parotid gland delineation: a study of its impact on intensity-modulated radiotherapy solutions with a systematic review of the literature 
The British Journal of Radiology  2012;85(1016):1070-1077.
Objectives
This study evaluates the interobserver variation in parotid gland delineation and its impact on intensity-modulated radiotherapy (IMRT) solutions.
Methods
The CT volumetric data sets of 10 patients with oropharyngeal squamous cell carcinoma who had been treated with parotid-sparing IMRT were used. Four radiation oncologists and three radiologists delineated the parotid gland that had been spared using IMRT. The dose–volume histogram (DVH) for each study contour was calculated using the IMRT plan actually delivered for that patient. This was compared with the original DVH obtained when the plan was used clinically.
Results
70 study contours were analysed. The mean parotid dose achieved during the actual treatment was within 10% of 24 Gy for all cases. Using the study contours, the mean parotid dose obtained was within 10% of 24 Gy for only 53% of volumes by radiation oncologists and 55% of volumes by radiologists. The parotid DVHs of 46% of the study contours were sufficiently different from those used clinically, such that a different IMRT plan would have been produced.
Conclusion
Interobserver variation in parotid gland delineation is significant. Further studies are required to determine ways of improving the interobserver consistency in parotid gland definition.
doi:10.1259/bjr/32038456
PMCID: PMC3587103  PMID: 22815411
13.  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
14.  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
15.  Parotid gland function after radiotherapy: the combined Michigan and Utrecht experience 
Purpose
To analyse 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 one year after radiotherapy (RT) for head and neck (HN) cancer.
Materials and methods
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 one year after RT using Lashley cups at both centers. A flow ratio <25% of pre-treatment was defined as a complication. The data were fitted to the Lyman-Kutcher-Burman (LKB) model.
Results
A total of 384 parotid glands (Michigan: 157; Utrecht: 227 glands) was available for analysis one year after RT. Combined NTCP analysis based on mean dose resulted in TD50 (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 25-30 Gy were associated with 17-26% NTCP.
Conclusions
A definite NTCP curve for parotid gland function one year after RT is presented based on mean dose. No threshold dose was observed and TD50 was equal to 40 Gy.
doi:10.1016/j.ijrobp.2009.07.1708
PMCID: PMC2889151  PMID: 20056347
Parotid gland function; xerostomia; radiotherapy; NTCP; head-and-neck cancer
16.  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
17.  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
18.  In vivo biocompatibility of the PLGA microparticles in parotid gland 
Poly(lactic-co-glycolic acid) (PLGA) microparticles are used in various disorders for the controlled or sustained release of drugs, with the management of salivary gland pathologies possible using this technology. There is no record of the response to such microparticles in the glandular parenchyma. The purpose of this study was to assess the morphological changes in the parotid gland when injected with a single dose of PLGA microparticles. We used 12 adult female Sprague Dawley rats (Rattus norvegicus) that were injected into their right parotid gland with sterile vehicle solution (G1, n=4), 0.5 mg PLGA microparticles (G2, n=4), and 0.75 mg PLGA microparticles (G3, n=4); the microparticles were dissolved in a sterile vehicle solution. The intercalar and striated ducts lumen, the thickness of the acini and the histology aspect in terms of the parenchyma organization, cell morphology of acini and duct system, the presence of polymeric residues, and inflammatory response were determined at 14 days post-injection. The administration of the compound in a single dose modified some of the morphometric parameters of parenchyma (intercalar duct lumen and thickness of the glandular acini) but did not induce tissue inflammatory response, despite the visible presence of polymer waste. This suggests that PLGA microparticles are biocompatible with the parotid tissue, making it possible to use intraglandular controlled drug administration.
PMCID: PMC3816810  PMID: 24228103
Salivary glands; parotid gland; drug delivery; microparticles; PLGA
19.  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
20.  Radiotherapy on hidradenocarcinoma 
Context:
Clear cell Hidradenocarcinoma is a rare carcinoma arising from sweat glands. It is an aggressive tumor that most metastasizes to regional lymph nodes and distant viscera; surgery with safe margins is the mainstay of treatment.
Case Report:
We report a case of 68-year-old woman who presented with an invasive clear cell hidradenocarcinoma situated in the left parotid area which recurred 5 months after surgery, this recurrence was managed successfully by high-dose irradiation of the tumor bed (66 Gy) and regional lymphatic chains (50 Gy), after a follow-up of more than 15 months, the patient is in good local control without significant toxicity.
Conclusion:
Post operative radiotherapy allows better local control and should be mandatory when histological features predictive of recurrence are present: positive margins, histology poorly differentiated, perineural invasion, vascular and lymphatic invasion, lymph node involvement, and extracapsular spread.
doi:10.4297/najms.2011.343
PMCID: PMC3336933  PMID: 22540063
Hidradenocarcinoma; sweat-gland; rare; surgery; recurrence; megavoltage external beam radiotherapy
21.  Parotid gland volumetric changes during intensity-modulated radiotherapy in head and neck cancer 
The British Journal of Radiology  2012;85(1018):1415-1419.
Objective
To evaluate volumetric changes of parotid glands (PGs) during intensity-modulated radiotherapy (IMRT) in head and neck cancer patients.
Methods
During IMRT all patients underwent kilovolt cone-beam CT (CBCT) scans to verify the set-up positioning in a protocol study. On each CBCT scan, the PGs were retrospectively contoured and evaluated with a dose–volume histogram.
Results
From February to June 2011, 10 patients were enrolled. 140 CBCT scans were registered (280 PGs): for each patient, a median of 14 CBCT scans were performed (range 14–16). At the start of radiation, the average volume for ipsilateral PGs (iPGs) was 18.77 ml (range 12.9–31.2 ml), whereas for contralateral PGs (cPGs) it was 16.63 ml (range 8.3–28.7 ml). At the last CBCT scan, the average volume loss was 43.5% and 44.0% for the iPG and cPG, respectively. When we analysed the percentage of volume loss, we observed that the volume decreased by linear regression (r2=0.92 for iPG; r2=0.91 for cPG), with an average volume loss rate of 1.5% per day for both PGs. During the third week of treatment the volume of both PGs reduced by 24–30%.
Conclusion
Our data show that, during IMRT, the shrinkage of PGs should be taken into account. A replan could be indicated in the third week of radiotherapy.
doi:10.1259/bjr/30678306
PMCID: PMC3474039  PMID: 22573295
22.  Rab3D Is Not Required for Exocrine Exocytosis but for Maintenance of Normally Sized Secretory Granules 
Molecular and Cellular Biology  2002;22(18):6487-6497.
Rab3D, a member of the Rab3 subfamily of the Rab/ypt GTPases, is expressed on zymogen granules in the pancreas as well as on secretory vesicles in mast cells and in the parotid gland. To shed light on the function of Rab3D, we have generated Rab3D-deficient mice. These mice are viable and have no obvious phenotypic changes. Secretion of mast cells is normal as revealed by capacitance patch clamping. Furthermore, enzyme content and overall morphology are unchanged in pancreatic and parotid acinar cells of knockout mice. Both the exocrine pancreas and the parotid gland show normal release kinetics in response to secretagogue stimulation, suggesting that Rab3D is not involved in exocytosis. However, the size of secretory granules in both the exocrine pancreas and the parotid gland is significantly increased, with the volume being doubled. We conclude that Rab3D exerts its function during granule maturation, possibly by preventing homotypic fusion of secretory granules.
doi:10.1128/MCB.22.18.6487-6497.2002
PMCID: PMC135623  PMID: 12192047
23.  Adenoid cystic carcinoma of the parotid gland: Anastamosis of the facial nerve with the great auricular nerve after radical parotidectomy 
Adenoid cystic carcinoma of the parotid gland is a rare and slowly growing, but highly malignant tumor. Surgical resection of a malignant parotid tumor should include resection of the facial nerve when the nerve is involved in the tumor. Facial nerve reconstruction is required after nerve resection. A 14 year-old female presented with complaints of painless enlargement of the right parotid gland and facial asymmetry. Physical examination revealed a firm mass in the region of the parotid gland as well as right facial paralysis. Biopsy obtained from the mass showed an adenoid cystic carcinoma of the parotid gland. A radical parotidectomy with a modified radical neck dissection was carried out. Grafting material for the facial reconstruction was harvested from the great auricular nerve. The proximal main trunk and each distal branch of the facial nerve were coapted with the greater auricular nerve. The patient received radiotherapy after surgery and was seen to achieve grade IV facial function one year after surgery. Thus, the great auricular nerve is appropriate grafting material for coaptation of each distal branch of the facial nerve.
doi:10.4103/0970-0358.44948
PMCID: PMC2740500  PMID: 19753265
Adenoid cystic carcinoma; facial nerve reconstruction; parotid gland; radiotherapy
24.  Radiotherapy of abdomen with precise renal assessment with SPECT/CT imaging (RAPRASI): design and methodology of a prospective trial to improve the understanding of kidney radiation dose response 
BMC Cancer  2013;13:381.
Background
The kidneys are a principal dose-limiting organ in radiotherapy for upper abdominal cancers. The current understanding of kidney radiation dose response is rudimentary. More precise dose-volume response models that allow direct correlation of delivered radiation dose with spatio-temporal changes in kidney function may improve radiotherapy treatment planning for upper-abdominal tumours.
Our current understanding of kidney dose response and tolerance is limited and this is hindering efforts to introduce advanced radiotherapy techniques for upper-abdominal cancers, such as intensity-modulated radiotherapy (IMRT). The aim of this study is to utilise radiotherapy and combined anatomical/functional imaging data to allow direct correlation of radiation dose with spatio-temporal changes in kidney function. The data can then be used to develop a more precise dose-volume response model which has the potential to optimise and individualise upper abdominal radiotherapy plans.
Methods/design
The Radiotherapy of Abdomen with Precise Renal Assessment with SPECT/CT Imaging (RAPRASI) is an observational clinical research study with participating sites at Sir Charles Gairdner Hospital (SCGH) in Perth, Australia and the Peter MacCallum Cancer Centre (PMCC) in Melbourne, Australia. Eligible patients are those with upper gastrointestinal cancer, without metastatic disease, undergoing conformal radiotherapy that will involve incidental radiation to one or both kidneys. For each patient, total kidney function is being assessed before commencement of radiotherapy treatment and then at 4, 12, 26, 52 and 78 weeks after the first radiotherapy fraction, using two procedures: a Glomerular Filtration Rate (GFR) measurement using the 51Cr-ethylenediamine tetra-acetic acid (EDTA) clearance; and a regional kidney perfusion measurement assessing renal uptake of 99mTc-dimercaptosuccinic acid (DMSA), imaged with a Single Photon Emission Computed Tomography / Computed Tomography (SPECT/CT) system. The CT component of the SPECT/CT provides the anatomical reference of the kidney’s position. The data is intended to reveal changes in regional kidney function over the study period after the radiotherapy. These SPECT/CT scans, co-registered with the radiotherapy treatment plan, will provide spatial correlation between the radiation dose and regional renal function as assessed by SPECT/CT. From this correlation, renal response patterns will likely be identified with the purpose of developing a predictive model.
Trial registration
Australian New Zealand Clinical Trials Registry: ACTRN12609000322235
doi:10.1186/1471-2407-13-381
PMCID: PMC3751853  PMID: 23937668
Radiotherapy; Kidney; Functional imaging
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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