Head Radiotherapy Research Articles

Normal Tissue Sparing via Adaptive Radiation Therapy for Head and Neck Cancers: Analysis with Biologically Effective Dose Distributions

Normal Tissue Sparing via Adaptive Radiation Therapy for Head and Neck Cancers: Analysis with Biologically Effective Dose Distributions

Prevalence of carotid stenosis following radiotherapy for head and neck cancer: A systematic review and meta‐analysis

Radiation to the head and neck is a well-established risk factor for the development of carotid artery stenosis. Our objective was to identify the prevalence, incidence, and degree of carotid stenosis in patients with a history of head and neck irradiation. This study was performed according to the PRISMA guidelines. A random effects model meta-analysis was conducted. Nineteen studies comprising 1479 patients were included. The prevalence of carotid stenosis >50%, >70%, and carotid occlusion was 25% (95% CI: 19%-32%), 12% (95% CI: 7%-17%), and 4% (95% CI: 2%-8%), respectively. The cumulative 12-month incidence of carotid stenosis >50% was 4% (95% CI: 2%-5%), the 24-month was 12% (95% CI: 9%-15%), and the 36-month was 21% (95% CI: 9%-36%). The yearly incidence of carotid stenosis >50% increased every year during the first 3 years following radiotherapy. We propose routine yearly Doppler ultrasound screening beginning 1 year after head and neck radiotherapy.

Ultrasound is superior to palpation for thyroid cancer detection in high-risk childhood cancer and BMT survivors

Thyroid cancer is a common subsequent malignant neoplasm in childhood cancer survivors (CCS). Patients who received radiotherapy (RT) to the head, neck, upper thorax, or total body irradiation (TBI) are considered to be at risk for subsequent thyroid cancer. Current Children's Oncology Group screening guidelines recommend annual neck palpation. Our objective was to determine if ultrasound (US) is more sensitive and specific than palpation to detect thyroid cancer in high-risk CCS and bone marrow transplant (BMT) survivors. Electronic medical records of patients followed in a longitudinal survivorship clinic from January 1, 2010 to December 31, 2017 were reviewed. Inclusion criteria included history of RT to the head, neck, upper thorax, or TBI for primary therapy or preparation for BMT prior to the age of 20years. Two hundred and twenty-five patients had documented palpation and 144 (64%) also had US evaluation. Mean radiation dose was 28.6Gy. Sixteen of 225 patients (7.1%) developed a subsequent thyroid cancer at a mean of 9.7years from the completion of RT. Sensitivity of US was 100% compared with 12.5% for palpation. US demonstrated higher accuracy, with a receiver operating characteristic (ROC) area under the curve (AUC) of 0.87 versus 0.56 for palpation (P < 0.0001). Routine screening with US was more sensitive than palpation for detection of subsequent thyroid cancer after high-risk RT in CCS and BMT survivors. Screening US may lead to earlier detection of thyroid cancer in this population. Earlier diagnosis has the potential to decrease operative complexity, and earlier definitive therapy reduces the likelihood of metastatic disease.

The effects of experimentally irradiated pituitary gland on the growth of rat’s tibia, skull, maxilla and mandible

Background/Aim. The reaction of an organism to radiation depends on the level of irradiation and the sensitivity of the affected tissue cells. The biological effects on the cells and tissues are proportional to the absorbed radiation energy. The aim of our study was to examine the effects of hypofunction of the pituitary gland, previously irradiated with x-rays, on the growth of rat?s craniofacial and stomatognathic system as well as rat?s tibia. Methods. A total dose of x-rays of 27.92 Gy was applied in eight sessions in the period from 8 to 63 days of animal age on their heads and the effects of irradiation-induced hypofunction of the pituitary gland on the growth of rat?s craniofacial and stomatognathic system and tibia were examined. In order to differentiate the effects of the irradiated pituitary gland from the direct effects of x-rays on the head, the experiment was set as a double study. One group of animals had the pituitary gland protected with a lead plate set beneath the projection of the gland, while the second group was irradiated with the same dose, but without the protection. The control group of animals were non-irradiated. Results. Growth measurements of numerous parameters of the craniofacial and stomatognathic system as well as tibia in rats with the entire locally irradiated head showed a statistically significant delay, compared to both the non-irradiated control group and the group with the protected pituitary gland. Conclusion. The damage of the stomatognathic and craniofacial system was greater in animals with irradiated head without pituitary gland protection compared to those with the gland protection whereby the growth of the craniofacial system was most affected. Irraduition-induced pituitary gland hypofunction and irradiation itself showed a stronger effect on the lower jaw growth rate impairment compared to the upper jaw. Similarly, the delay in tibia growth was more pronounced in animals without pituitary gland protection during irradiation of their heads compared to non-protected ones.

Thyroid Dose and Hypothyroidism as a Result of Radiation Therapy for Head and Neck Malignancies and Brain Tumors in Iran

Purpose: Radiation Therapy has a fundamental role in the treatment of cancer. Achieving Tumor Control Probability (TCP), while avoiding normal tissue complication is the goal of this treatment modality. The sensitivity of the thyroid gland to radiation increases the risk of developing secondary thyroid cancer and hypothyroidism. Materials and Methods: The average dose to the thyroid from head and neck irradiation was measured using in vivo dosimetry (Thermolumincsence Dosimetry). The Radiotherapy technique was given using 6 MV x-rays from an Elekta compact linear accelerator and conformal technique delivered 1.8 to 2.0 Gy over 5 sequential days per week. Results: The average absorbed dose to the thyroid from head and neck radiotherapy was 4.4% of the prescription dose and from whole brain radiotherapy was 0.7% of the prescription dose. Thyroid Stimulating Hormone (TSH) levels were determined in 30 patients before and after completion of radiation therapy. The average concentration of TSH increased from 0.88 +/- 0.55 (pre-radiotherapy) to 1.7 +/- 0.66 (post-radiotherapy), (p &lt; 0.05). Conclusion: Thyroid absorbed dose was less than the threshold dose for patients who received radiotherapy to the head and neck based on thyroid function tests

Xerostomia in the older adult population, from diagnosis to treatment

Saliva is important for the preservation and maintenance of normal physiological conditions of oral tissues, and factors influencing its decrease are associated with the risk for oral diseases. Xerostomia is the subjective sensation of oral dryness, which can be influenced by etiological factors including the use of several types of medications, Sjogren’s and metabolic syndromes, head and neck irradiation, among others. Treatment methods for xerostomia vary and can be local or systemic. The aim of this article is to present the results of a literature review addressing the correlation between xerostomia and its incidence and prevalence in the older adult population. Results of this review highlight the importance of diagnosis and appropriate management, and briefly describe treatment modalities and etiological factors such as medications, Sjogren’s syndrome, metabolic syndrome, and head and neck irradiation.

Dose cluster model parameterization of the parotid gland in irradiation of head and neck cancer.

To explore the parotid normal tissue complication probability (NTCP) modeling with percolation-based dose clusters for head-and-neck patients receiving concomitant chemotherapy and radiation therapy. Cluster models incorporating the spatial dose distribution in the parotid gland were developed to evaluate the radiation induced complication. Cluster metrics including the mean cluster size (NMCS) and the largest cluster size both normalized by the gland volume (NSLC) were evaluated and scrutinized against the benchmark NTCP. Two fitting strategies to the Lyman-Kutcher-Burman (LKB) model using the maximum likelihood method were devised: the volume parameter n fixed at 1.0 (mean dose model) and unrestricted (full LKB model). The fitted parameters TD50 and m were assessed with the LKB NTCP models with the available xerostomia data. NSLC was a better metric than NMCS with reference to the LKB model and strong correlation (r ~ 0.95) was observed between NTCP and NSLC. The mean dose model returned the parameter TD50 (39.9Gy) and m (0.4) from the NSLC of threshold dose at around 40Gy. Drastically different TD50 and m values were obtained from the fittings via the full LKB model, where the threshold dose would be near 27Gy. Bootstrapping analyses further confirmed the fitting outcomes. Strong correlation with the traditional NTCP models revealed that the cluster model could achieve what NTCP models attain and may offer additional information. Parameterization of the model indicated that the model could have different predictions from current clinical recommendations. Further investigation using toxicity data is under way to validate the cluster model.

Fractionated head and neck irradiation impacts taste progenitors, differentiated taste cells, and Wnt/\u03b2-catenin signaling in adult mice

Head and neck cancer patients receiving conventional repeated, low dose radiotherapy (fractionated IR) suffer from taste dysfunction that can persist for months and often years after treatment. To understand the mechanisms underlying functional taste loss, we established a fractionated IR mouse model to characterize how taste buds are affected. Following fractionated IR, we found as in our previous study using single dose IR, taste progenitor proliferation was reduced and progenitor cell number declined, leading to interruption in the supply of new taste receptor cells to taste buds. However, in contrast to a single dose of IR, we did not encounter increased progenitor cell death in response to fractionated IR. Instead, fractionated IR induced death of cells within taste buds. Overall, taste buds were smaller and fewer following fractionated IR, and contained fewer differentiated cells. In response to fractionated IR, expression of Wnt pathway genes, Ctnnb1, Tcf7, Lef1 and Lgr5 were reduced concomitantly with reduced progenitor proliferation. However, recovery of Wnt signaling post-IR lagged behind proliferative recovery. Overall, our data suggest carefully timed, local activation of Wnt/β-catenin signaling may mitigate radiation injury and/or speed recovery of taste cell renewal following fractionated IR.

Nigella sativa oil and thymoquinone reduce oxidative stress in the brain tissue of rats exposed to total head irradiation

Purpose: To evaluate the antioxidant and radio-protective effects of Nigella sativa oil (NSO) and thymoquinone (TQ) on radiation-induced oxidative stress in brain tissue.Materials and methods: Fifty-four Sprague-Dawley rats were divided into six groups to test the radio-protective effectiveness of Nigella sativa oil and thymoquine administered by either orogastric tube or intraperitoneal injection. Appropriate control groups were also studied.Results: Brain antioxidant capacity, as measured by the levels of total superoxide scavenger activity (TSSA), non-enzymatic superoxide scavenger activity (NSSA), superoxide dismutase, paraoxonase (PON) activities, total antioxidant status and total sulfhydryl (-SH) group, were lower in the irradiation (IR) only group while xanthine oxidase (XO) activity, total oxidant status (TOS), oxidative stress index (OSI) and lipid hydroperoxide (LOOH) levels were higher in the group compared with all other groups. Brain glutathione-S-transferase (GST) activity significantly decreased in the IR only group when compared with the control groups. Glutathione peroxidase (GSH-Px) activity was lower in the IR only, NSO plus IR, TQ plus IR groups when compared with the control group of TQ. Arylesterase (ARYL) activity was not statistically significant in the IR only group compared with all other groups.Conclusions: The results suggest that Nigella sativa oil (NSO) and its active component, TQ, clearly protect brain tissue from radiation-induced oxidative stress.

Anti-inflammatory and vasculogenic conditioning of peripheral blood mononuclear cells reinforces their therapeutic potential for radiation-injured salivary glands

BackgroundThere are currently no effective treatments available for patients with irreversible loss of salivary gland (SG) function caused by radiation therapy for head and neck cancer. In this study, we have developed an effective culture method to enhance the anti-inflammatory and vasculogenic phenotypes of peripheral blood mononuclear cells (PBMNCs) and investigated whether such effectively conditioned PBMNCs (E-MNCs) could regenerate radiation-injured SGs and ameliorate salivary secretory function in mice.MethodsMouse PBMNCs were expanded in primary serum-free culture with five vasculogenic proteins for 5 days, and then the resulting cells (E-MNCs) were analyzed for their characteristics. Subsequently, 5 × 104 E-MNCs (labeled with EGFP in some experiments) were injected intra-glandularly into a mouse model of radiation-injured atrophic submandibular glands. After 2–3 weeks, the submandibular glands were harvested, and then the injected E-MNCs were tracked. Four, 8, and 12 weeks after irradiation (IR), salivary outputs were measured to evaluate the recovery of secretory function, and the gland tissues were harvested for histological and gene expression analyses to clarify the effects of cell transplantation.ResultsThe resulting E-MNCs contained an enriched population of definitive CD11b/CD206-positive (M2 macrophage-like) cells and showed anti-inflammatory and vasculogenic characteristics. Salivary secretory function in E-MNC-transplanted mice gradually recovered after 4 weeks post-irradiation (post-IR) and reached 3.8-fold higher than that of non-transplanted mice at 12 weeks. EGFP-expressing E-MNCs were detected in a portion of the vascular endothelium and perivascular gland tissues at 2 weeks post-IR, but mainly in some microvessels at 3 weeks. Between 4 and 12 weeks post-IR, mRNA expression and histological analyses revealed that E-MNC transplantation reduced the expression of inflammatory genes and increased the level of tissue-regenerative activities such as stem cell markers, cell proliferation, and blood vessel formation. At 12 weeks post-IR, the areas of acinar and ductal cells regenerated, and the glands had less fibrosis.ConclusionsThis effective conditioning of PBMNCs is a simple, rapid, and efficient method that provides a non-invasive source of therapeutic cells for regenerating radiation-injured atrophic SGs.

Radiotherapy-Compatible Robotic System for Multi-Landmark Positioning in Head and Neck Cancer Treatments

The spine flexibility creates one of the most significant challenges to proper positioning in radiation therapy of head and neck cancers. Even though existing immobilization techniques can reduce the positioning uncertainty, residual errors (2–3 mm along the cervical spine) cannot be mitigated by single translation-based approaches. Here, we introduce a fully radiotherapy-compatible electro-mechanical robotic system, capable of positioning a patient’s head with submillimeter accuracy in clinically acceptable spatial constraints. Key mechanical components, designed by finite element analysis, are fabricated with 3D printing and a cyclic loading test of the printed materials captures a great mechanical robustness. Measured attenuation of most printed components is lower than analytic estimations and radiographic imaging shows no visible artifacts, implying full radio-compatibility. The new system evaluates the positioning accuracy with an anthropomorphic skeletal phantom and optical tracking system, which shows a minimal residual error (0.7 ± 0.3 mm). This device also offers an accurate assessment of the post correction error of aligning individual regions when the head and body are individually positioned. Collectively, the radiotherapy-compatible robotic system enables multi-landmark setup to align the head and body independently and accurately for radiation treatment, which will significantly reduce the need for large margins in the lower neck.

Diameter of External Carotid Arteries in Patients With Mandibular Osteoradionecrosis.

To evaluate the association between osteoradionecrosis (ORN) of the mandible and stenosis of the external carotid artery after radiation therapy (RT) for head and neck cancer. The computed tomography images of 42 patients (36 men, six women; median age, 64.5 years) treated with RT for head and neck cancer between January 2011 and December 2015 were reviewed. The cross-sectional diameters of the bilateral external carotid arteries were measured on contrast-enhanced images taken after completion of RT. Nine of the 42 included patients (21.4%) developed ORN after a median interval of 34 months from completion of RT. Univariate analysis revealed that external carotid artery diameter ≤ the median diameter was significantly associated with ORN development (p=0.008 and 0.013). In multivariate analysis, left external carotid artery diameter ≤ the median was significantly associated with ORN development (p=0.023). External carotid artery stenosis was significantly associated with ORN development.

Effective Volume of Parotid Glands for Assessing Radiation Injury during Radiation Therapy for Head and Neck Cancer

Effective Volume of Parotid Glands for Assessing Radiation Injury during Radiation Therapy for Head and Neck Cancer

Low Peripheral Blood Leukocyte Counts during Radiation Therapy for Head and Neck Cancer Predict Distant Relapse and Dysphagia

Low Peripheral Blood Leukocyte Counts during Radiation Therapy for Head and Neck Cancer Predict Distant Relapse and Dysphagia

Evaluation of Patient vs. Provider Based Assessments of Xerostomia and Dysphagia Compared Against Weight Loss in the Irradiated Head and Neck Cancer Patient

In addition to provider based assessment, e.g. Common Terminology Criteria for Adverse Events (CTCAE) grades, there is an increasing use of patient-reported outcome (PRO) questionnaires, such as the University of Michigan Xerostomia Questionnaire (XQ), the Sydney Swallow Questionnaire (SSQ), and the MD Anderson Dysphagia Inventory (MDADI). The aim of this study was to evaluate the performance of different measurements for xerostomia and dysphagia compared against an objective value, in this case, weight loss (WL) at 6 months after RT. We hypothesized that PROs would have a higher correlation to WL than provider-based assessments with the CTCAE scale. Eligible cases included patients treated from January 2014 to February 2019 with completed XQ, SSQ, MDADI, CTCAE xerostomia, and CTCAE dysphagia scores at 6 months post-treatment. Patients were also required to have their weight recorded at baseline (before or within the first week of the start of treatment) and at 6 months after completion of RT. Patients’ demographic and clinical features were also included in the model, including age at start of treatment, gender, race, smoking status, attending physician, tumor stage, tumor site, chemotherapy, human papillomavirus association, and use of enteral support. WL was calculated by the percent change at 6 months compared to baseline and then binarized into high (WL>5%) and low (WL≤5%). Logistic regression was performed to assess the association between WL and variables. Six classification models that adjusted patients’ demographics, clinical features, xerostomia (XQ and CTCAE xerostomia), and dysphagia (SSQ, MDADI, and CTCAE dysphagia) were developed. The area under the receiver operating curve (AUC) was used to evaluate the performance of xerostomia and dysphagia measurements (Table). All data analysis was performed using STATA v.15. Of 103 patients who met the inclusion criteria, 78 (76%) were in the high WL group. Median XQ score was 31/80; median SSQ and MDADI were 348.9/1700 and 89/100, respectively. 40 (38.9%) patients had CTCAE xerostomia grade≥2, and 17 (16.5%) were classified as CTCAE dysphagia grade≥2. Among the six models predicting WL at 6 months after RT (Table), the model using XQ and SSQ yielded the best performance (AUC = 0.60). The prediction of WL at 6 months post RT was improved using patient-reported xerostomia and dysphagia as measured by XQ and SSQ scores. Future healthcare providers may consider PROs to not only better measure and monitor symptoms, but to direct therapeutic interventions and predict for treatment effects.Abstract 3379; Table 1Model performance with different xerostomia and dysphagia measurementsXerostomiaDysphagiaAUCXQSSQ0.60XQMDADI0.56XQCTCAE dysphagia0.55CTCAE xerostomiaSSQ0.59CTCAE xerostomiaMDADI0.53CTCAE xerostomiaCTCAE dysphagia0.52 Open table in a new tab

Routine Preoperative Laryngoscopy for Thyroid Surgery Is Not Necessary Without Risk Factors.

Background: Routine preoperative vocal cord (VC) assessment with laryngoscopy in patients undergoing thyroidectomy allows clear documentation of baseline VC function, aids in surgical planning in patients with palsies, and facilitates interpretation of intraoperative neuromonitoring (IONM) findings. We aimed to determine the incidence of preoperative vocal cord palsy (VCP); to evaluate the associated risk factors for preoperative VCP; and to calculate the cost-savings potential of implementing a selective approach. Methods: Patients with a pre-thyroidectomy VC assessment by fiberoptic laryngoscopy were retrospectively recruited from the Monash University Endocrine Surgery Unit database from 2000 to 2018. Cases with preoperative VCP were reviewed for potential contributing factors and compared with a non-palsy cohort. Results: Of the 5987 patients who had preoperative laryngoscopy, VCP was documented in 41 (0.68%) patients. Four clinical parameters were found to be potential indicators of VCP, including: age (p < 0.001), nodule ≥3.5 cm recorded on ultrasound imaging (p = 0.01), presence of voice symptoms (p < 0.001), and previous neck surgery (p < 0.001). Malignant cytology (p = 0.5) and exposure to head and neck irradiation were not different between the groups. Utilizing these risk factors, 2354 (39%) patients had at least one feature that may raise suspicion for preoperative VCP. By performing preoperative laryngoscopy only on this subset of patients, the potential cost savings exceeds 400 Australian Dollars per patient. Conclusions: Using this large dataset, we have established that a VCP is rare in the absence of a large nodule, hoarseness, or previous neck surgery. Therefore, in the era of IONM, we support a selective approach to preoperative laryngoscopy by using the aforementioned criteria.

Combination of chemotherapy and radiotherapy: A thirty years evolution

Chemoradiotherapy is now considered the standard of care for many locally advanced diseases. Cytotoxic drugs have been largely evaluated in this setting, with cisplatin and 5FU the most often used drugs. A large amount of pre-clinical studies has demonstrated the synergy between both modalities. Concomitant administration seems the more beneficial in many diseases. Emergence of new approaches, combining targeted therapies and radiotherapy (RT) is now a reality. The main example is the association of cetuximab and RT in head and neck carcinomas, even if, 14 years after the initial publication, the best way to use it is still unknown. New compounds as inhibitors of DNA-repair or immune checkpoints are under investigation and showed early promising results.

Establishment of a Murine Pro-acinar Cell Line to Characterize Roles for FGF2 and \u03b13\u03b21 Integrins in Regulating Pro-acinar Characteristics

Radiation therapy for head and neck cancers results in permanent damage to the saliva producing acinar compartment of the salivary gland. To date, a pure pro-acinar cell line to study underlying mechanisms of acinar cell differentiation in culture has not been described. Here, we report the establishment of a pro-acinar (mSG-PAC1) and ductal (mSG-DUC1) cell line, from the murine submandibular salivary gland (SMG), which recapitulate developmental milestones in differentiation. mSG-DUC1 cells express the ductal markers, keratin-7 and keratin-19, and form lumenized spheroids. mSG-PAC1 cells express the pro-acinar markers SOX10 and aquaporin-5. Using the mSG-PAC1 cell line, we demonstrate that FGF2 regulates specific steps during acinar cell maturation. FGF2 up-regulates aquaporin-5 and the expression of the α3 and α6 subunits of the α3β1 and α6β1 integrins that are known to promote SMG morphogenesis and differentiation. mSG-DUC1 and mSG-PAC1 cells were derived from genetically modified mice, homozygous for floxed alleles of the integrin α3 subunit. Similar to SMGs from α3-null mice, deletion of α3 alleles in mSG-PAC1 cells results in the up-regulation of E-cadherin and the down-regulation of CDC42. Our data indicate that mSG-DUC1 and mSG-PAC1 cells will serve as important tools to gain mechanistic insight into salivary gland morphogenesis and differentiation.

Long-term recurrences of jaw osteoradionecrosis after apparent healing with the PENTOCLO protocol

Osteoradionecrosis of the jaws (ORNJ) is a late complication of head and neck irradiation estimated at around 3% of irradiated patients. The PENTO protocol (Pentoxyfilline and Tocopherol), with the eventual adjunction of Clodronate (PENTOCLO), showed interesting results even in advanced ORNJ. The current literature does not describe the long-term outcomes and particularly after the completion of the protocol. The PENTO or PENTOCLO protocol should be prescribed as a life-long treatment or the outcome should be monitored at least as long as the duration of the protocol after its end.

Long-term Pilocarpine Treatment Improves Salivary Flow in Irradiated Mice.

Radiation therapy for head and neck cancer frequently causes salivary gland dysfunction. Pilocarpine is a clinically approved and effective drug that induces saliva secretion, thereby keeping the oral mucosa moist and reducing discomfort in patients, but the effect is transient. We expected that this drug also has beneficial long-term effects that maintain the integrity of salivary glands by reducing, for instance, apoptosis. Here, we examined the effects of long-term pilocarpine administration in irradiated mice. The results indicated that long-term pilocarpine administration significantly improved salivary flow in irradiated mice, suggesting the potential beneficial effects of long-term administration. To elucidate the underlying mechanism, we analyzed the histology, apoptosis, and proliferation of acinar cells, and the expression of functional membrane proteins such as transmembrane member 16A, aquaporin-5, and Na-K-Cl cotransporter. Long-term pilocarpine treatment seemed to decrease irradiation-induced apoptosis, although the change was not statistically significant. The present results indicated that long-term administration of pilocarpine has beneficial effects on salivary flow in irradiated mice, and suggested that long-term administration possibly decreases apoptosis in irradiated salivary glands.