Comparative study of setup errors between new and reused thermoplastic masks in irradiated head and neck cancer patients

Aim:In radiation therapy, accurate dose distribution in target volume requires accurate treatment setup. The set-up errors are unwanted and inherent in the treatment process. By achieving these errors, a set-up margin (SM) of clinical target volume (CTV) to planning target volume (PTV) can be determined. In the current study, systematic and random set-up errors that occurred during prostate cancer radiotherapy were measured by an electronic portal imaging device (EPID). The obtained values were used to propose the optimum CTV-to-PTV margin in prostate cancer radiotherapy.Materials and methods:A total of 21 patients with prostate cancer treated with external beam radiation therapy (EBRT) participated in this study. A total of 280 portal images were acquired during 12 months. Gross, population systematic (Σ) and random (σ) errors were obtained based on the portal images in Anterior–Posterior (AP), Medio-Lateral (ML) and Superior–Inferior (SI) directions. The SM of CTV to PTV were then calculated and compared by using the formulas presented by the International Commission on Radiation Units and Measurements (ICRU) 62, Stroom and Heijmen and Van Herk et al.Results:The findings showed that the population systematic errors during prostate cancer radiotherapy in AP, ML and SI directions were 1·40, 1·95 and 1·94 mm, respectively. The population random errors in AP, ML and SI directions were 2·09, 1·85 and 2·29 mm, respectively. The SM of CTV to PTV calculated in accordance with the formula of ICRU 62 in AP, ML and SI directions were 2·51, 2·68 and 3·00 mm, respectively. And according to Stroom and Heijmen, formula were 4·23, 5·19 and 5·48 mm, respectively. And Van Herk et al. formula were 4·96, 6·17 and 6·45 mm, respectively.Findings:The SM of CTV to PTV in all directions, based on the formulas of ICRU 62, Stroom and Heijmen and van Herk et al., were equal to 2·73, 4·98 and 5·86 mm, respectively; these values were obtained by averaging the margins in all directions.

To quantify systematic and random patient set-up errors in breast and head and neck conventional irradiation and to evaluate a no-action level (NAL) protocol for systematic set-up error off-line correction in head and neck cancer and breast cancer patients. Verification electronic portal images of orthogonal set-up fields were obtained daily for the initial four consecutive fractions for 20 patients treated for breast cancer and for 20 head and neck cancer patients. The calculated systematic error was used to shift the isocentre accordingly on the fifth treatment day. From then until the end of the treatment course, pair orthogonal portal images of set-up fields were obtained weekly. To assess the impact of the protocol, pre- and post-correction systematic errors were compared and PTV margins were estimated before and after correction using published margin recipes. Population systematic set-up error decreased in the breast cancer patient group after the implementation of NAL protocol from 4.0 to 1.7 mm on the x-axis, from 4.7 to 2.1 mm on the y-axis and from 2.8 to 0.9 mm on the z axis. The percentage of patients with individual systematic set-up error reduction was 80%, 90% and 80% on the x-, y and z-axes respectively. Population systematic set-up error decreased also in the head and neck cancer patient group from 2.3 to 1.1 mm on the x-axis, from 1.6 to 1.4 mm on the y-axis and from 1.7 to 0.7 mm on the z-axis. The percentage of patients with individual systematic set-up error reduction was 70%, 65% and 85% on the x-, y- and z-axes respectively. Margin reduction achievable with NAL protocol implementation on the x-, y- and z-axes was 6.3, 7.2 and 4.8 mm for breast cancer patients and 3.3, 0.6 and 2.8 mm for head and neck cancer patients. NAL off-line protocol is useful for systematic set-up error correction and PTV margin reduction in conventional breast and head and neck irradiation.

Set-up errors are an undesirable part of the radiation treatment process. The goal of online imaging is to increase treatment accuracy by reducing the set-up errors. This study aimed to determine the daily variation of patient set-up uncertainties and planning target volume (PTV) margins for head and neck cancer patients using pre-treatment verification by mega voltage cone-beam computed tomography (MV-CBCT). This retrospective study was internal record base of head and neck (H&N) cancer patients treated with definitive radiotherapy, adjuvant radiotherapy, and hypo-fractionated radiotherapy at our institution since the implementation of HalcyonTM 2.0 machine (Varian, US). Errors collected from each patient setup were recorded and evaluated for each direction [medio-lateral (ML), supero-inferior (SI), antero-posterior (AP)] discretely. For each patient, the systematic error (∑) and random error (σ) were collected. Clinical target volume (CTV) to planning target volume (PTV) margin was calculated using International Commission on Radiation Units and Measurements (ICRU) 62 ( ), Stroom's (PTV margin = 2∑ + 0.7σ), and Van Herk's (PTV margin = 2.5∑ + 0.7σ) formula. A total of 7900 pre-treatment CBCT scans of 301 patients were analyzed and a total of 23,000 error measurements in the ML, SI, and AP directions were recorded. For all of our H&N cancer patients, the CTV to PTV margin, calculated from the van Herk formula for the head and neck patients was 0.49 mm in the anteroposterior axis. An isometric PTV margin of 5 mm may be considered safe if daily imaging is not being done. In case daily online pretreatment imaging is being utilized, further reduction of PTV margin is possible.

The risk of carotid stenosis in head and neck cancer patients after radiation therapy

Simple SummaryFollowing radiotherapy for head and neck cancer, patients are at risk for developing a recurrent or second tumor. Often reirradiation is required in these patients, which is hampered in dose by the previous irradiation. Besides chemotherapy, hyperthermia can potentially increase the effectivity of the radiotherapy. In this study we have used a new hyperthermia applicator in order to increase the effectivity of the radiotherapy in patients requiring reirradiation. We show that the added hyperthermia treatment is tolerated by patients and that we reach a higher hyperthermia dose to the tumor compared to the previous applicator. In addition, we show that the tumor control and survival as well as toxicity are similar compared to what has been reported in literature using chemotherapy as an additive to reirradiation in head and neck cancer patients.(1) Background: Head and neck cancer (HNC) patients with recurrent or second primary (SP) tumors in previously irradiated areas represent a clinical challenge. Definitive or postoperative reirradiation with or without sensitizing therapy, like chemotherapy, should be considered. As an alternative to chemotherapy, hyperthermia has shown to be a potent sensitizer of radiotherapy in clinical studies in the primary treatment of HNC. At our institution, we developed the Hypercollar3D, as the successor to the Hypercollar, to enable improved application of hyperthermia for deeply located HNC. In this study, we report on the feasibility and clinical outcome of patients treated with the Hypercollar3D as an adjuvant to reirradiation in recurrent or SP HNC patients; (2) Methods: We retrospectively analyzed all patients with a recurrent or SP HNC treated with reirradiation combined with hyperthermia using the Hypercollar3D between 2014 and 2018. Data on patients, tumors, and treatments were collected. Follow-up data on disease specific outcomes as well as acute and late toxicity were collected. Data were analyzed using Kaplan Meier analyses; (3) Results: Twenty-two patients with recurrent or SP HNC were included. The average mean estimated applied cfSAR to the tumor volume for the last 17 patients was 80.5 W/kg. Therefore, the novel Hypercollar3D deposits 55% more energy at the target than our previous Hypercollar applicator. In patients treated with definitive thermoradiotherapy a complete response rate of 81.8% (9/11) was observed at 12 weeks following radiotherapy. Two-year local control (LC) and overall survival (OS) were 36.4% (95% CI 17.4–55.7%) and 54.6% (95% CI 32.1–72.4%), respectively. Patients with an interval longer than 24 months from their previous radiotherapy course had an LC of 66.7% (95% CI 37.5–84.6%), whereas patients with a time interval shorter than 24 months had an LC of 14.3% (95% CI 0.7–46.5%) at 18 months (p = 0.01). Cumulative grade 3 or higher toxicity was 39.2% (95% CI 16.0–61.9%); (4) Conclusions: Reirradiation combined with deep hyperthermia in HNC patients using the novel Hypercollar3D is feasible and deposits an average cfSAR of 80.5 W/kg in the tumor volume. The treatment results in high complete response rates at 12 weeks post-treatment. Local control and local toxicity rates were comparable to those reported for recurrent or SP HNC. To further optimize the hyperthermia treatment in the future, temperature feedback is warranted to apply heat at the maximum tolerable dose without toxicity. These data support further research in hyperthermia as an adjuvant to radiotherapy, both in the recurrent as well as in the primary treatment of HNC patients.

Evaluation of set-up errors in head and neck radiotherapy using electronic portal imaging

Purpose The purpose of this study is to evaluate a novel, bimodal strategy to implement smoking cessation treatment prior to oncologic therapy in newly-diagnosed head and neck cancer (HNC) patients. Background Among the 65,000 people who develop HNC in the United States (US) annually, 20-30% smoke cigarettes and 50-80% will continue smoking throughout survivorship. Quitting smoking before oncologic therapy correlates with improved health outcomes. However, the window of opportunity to quit smoking is narrow since cancer treatment often begins 4-5 weeks after the first oncology visit. The failure to rapidly implement evidence-based smoking cessation treatment is a major cause of this problem. Offering both behavioral therapy and pharmacotherapy increases abstinence rates by 2-3-fold. Despite this, only 4-17% of cancer patients receive both therapies at any time. Methods We conducted a pragmatic, quasi-experimental, pilot study using a pre-post design to evaluate a strategy to rapidly implement behavioral therapy and pharmacotherapy. The pre-test period was from 1/21-3/22 and the strategy was deployed from 4/22-10/22. The population included newly-diagnosed patients with mucosal HNC or salivary gland cancer. The setting was an academic medical center with an established tobacco treatment program (TTP). The implementation strategy involved bimodal administration of the evidence-based Ask, Advise, Connect (AAC) approach before and at the first surgical oncology visit. First, a dedicated medical assistant (MA) used an electronic health record (EHR)-based tool to identify, ask, advise, and connect (i.e. refer) smokers to the TTP at the time of clinic referral, or ~1-2 weeks before the first surgical oncology visit. Second, the AAC strategy was delivered by the triage MA and nurse at the time of the first surgical oncology visit. Some surgeons opportunistically offered patients pharmacotherapy. Results Among the 383 eligible, newly-diagnosed HNC patients, and 48 (12.5%) were current smokers. Twelve smokers were diagnosed between 4/22-10/22 and were eligible for the bimodal AAC strategy. However, only six of 12 patients received the AAC strategy before the first oncology visit. Among the 48 smokers, 75% were male, the median age was 65.5-years, and cancer treatment was started a median 34 days after the first oncology visit. Within 30 days of the first surgical oncology visit, 67% were advised to quit, 25% were referred to the TTP, 6% completed a comprehensive TTP visit, 21% had pharmacotherapy ordered, and 17% received both behavioral therapy and pharmacotherapy. While there were otherwise no differences in outcomes between pre- and post-strategy groups, more bimodal AAC strategy-eligible patients received pharmacotherapy (42%) compared to pre-strategy patients (14%, p=0.040). Conclusions Our bimodal AAC strategy correlated with increased use of pharmacotherapy, despite suboptimal fidelity to the approach. Additional strategies to improve delivery of timely behavioral therapy and pharmacotherapy for smoking cessation are needed. Citation Format: Sahajveer Mann, Julia Casazza, Dalia Mitchell, Quynh-Chi Dang, Dequan Weston, Brette Harding, Baran D. Sumer, Brittny Tillman, Heather Kitzman, George Jackson, Robert Schnoll, Amit Singal, Andrew T. Day. Piloting a novel strategy to rapidly implement smoking cessation treatment for newly-diagnosed head and neck cancer patients [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-058.

Simple SummaryUnderstanding the patients’ problems is essential to improve their quality of life. Through interviews and observations with patients, caregivers, and medical staff, we aimed to identify the various issues experienced by head and neck cancer patients during the treatment process and suggest improvement directions. As a result, the patients wanted to obtain comprehensive and reliable information during the treatment process. The patient also wished the medical staff could explain things easily so they could understand. For continuing long-term treatment, it was important for medical staff to encourage the patients and build a relationship with them. To successfully treat head and neck cancer patients, we need to consider what information should be delivered, how we should provide it, and how we can encourage them to support their emotions.Based on the treatment journey, this study aimed to present insights into improving the patient-centered service experience for head and neck cancer (HNC) patients. We interviewed and observed patients, caregivers, and doctors. We conducted a qualitative content analysis and service clue analysis to identify barriers and enablers to patient care and to derive insights into the patient experience (PE). We received feedback from doctors considering the priority, importance, and feasibility of improvements and classified the insights into three service experience aspects, to suggest improvement directions. As a result, the ‘functional’ aspect of service experience stressed the importance of a comprehensive guide to the treatment process, delivery of reliable information, use of easy-to-understand terms, repeated summary explanations, the establishment of close and flexible linkages between departments, and the provision of educational programs. Regarding the ‘mechanic’ aspect, the use of large and clear visuals for patients, to easily understand the care information provided by medical staff was distinguished. In the ‘humanic’ aspect, patients’ psychological stability, trust in doctors, and doctor’s encouragement and support through maintaining a positive attitude were prioritized. This qualitative study provided integrative insights into the HNC patient experience, through the application of service design methodologies, such as a patient journey map, participatory research methods, and service experience clues.

Purpose: 1. To understand practice patterns among head and neck surgeons and radiation oncologists in the assessment and management of malnutrition in head and neck cancer patients. 2. To identify barriers that prevent the identification of and intervention upon malnutrition. Background: Among patients who undergo surgery for head and neck cancer, there is a strong association between severe malnutrition and increased postoperative complications, length of stay, and cost of care. We aim to evaluate the association between the type of head and neck cancer provider and their comfort with the diagnosis and management of malnutrition in this patient population. Methods: A 17-question survey was distributed to 1,392 members of the American Head and Neck Society (AHNS) between 04/01/2018 and 04/18/2018. Chi squared testing was used to perform subgroup analysis by hospital type, fellowship training, clinical experience, and specialty. Results: The response rate among AHNS members was 9%, with 124 total respondents, including both otolaryngologists and radiation oncologists. There was strong agreement among respondents that malnutrition is important to identify and negatively impacts the quality of life, cost of care, length of hospital stay, mortality, and postoperative complications. The majority of respondents stated that although they were comfortable with screening for malnutrition, they were not familiar with the National Comprehensive Cancer Network (NCCN) guidelines on nutrition screening and intervention. Respondents reported use of various screening tools including serum markers, body mass index (BMI), and weight loss. Subgroup analysis demonstrated that otolaryngologists and academic hospitals were significantly more likely to screen by lab markers compared to radiation oncologists and community hospitals (p<0.05). Furthermore, although familiarity with NCCN guidelines was poor, fellowship-trained head and neck surgeons felt significantly more comfortable in their knowledge of NCCN guidelines than those without additional training (p<0.05). Barriers to screening for malnutrition included lack of training or familiarity with screening tools and guidelines, as well as lack of access to ancillary staff, such as nutritionists and speech therapists. Conclusion: There was a strong consensus among respondents that identification and management of malnutrition among head and neck cancer patients is important. However, familiarity with guidelines on screening and treating malnutrition was lacking, occasionally leading to practice patterns that deviated from the best available evidence. Citation Format: Amarbir S. Gill, Michael Kinzinger, Michael G. Moore. Malnutrition evaluation in head and neck cancer patients: Practice patterns among otolaryngologists and radiation oncologists [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B19.

The purpose of this study was to determine the phenotyping of Peripheral Blood Lymphocytes (PBL) in Head and Neck Cancers (HNCA) patients and to relate this with the level of Cell-Mediated Immunity (CMI) measured by in vitro lymphoproliferative assay, in order to evaluate immune suppression in HNCA patients and its possible mechanisms. Accordingly, one hundred twenty two HNCA patients and 100 control subjects were enrolled in this study. HNCA patients were classified into 42 nasopharyngeal carcinoma, 66 carcinoma of larynx and 14 Hypo Pharyngeal Carcinoma (HPC). For measuring CMI, Microculture Tetrazolium assay (MTT) was applied on the freshly isolated lymphocytes of HNCA patients and control group. Immunophenotyping of PBL was carried out for monitoring the blood level of CD3+, CD4+, CD8+, CD21+ cells in HNCA patients in comparison with controls. The results of both assays have been integrated, revealed the presence of remarked immune suppression in HNCA patients in comparison with the controls, especially for NasoPharyngeal Carcinoma (NPC) patients who were immunosuppressed more than other studied HNCA types. Surprisingly, NPC group showed the lowest CMI level along with the highest level of PBL subsets, particularly NPC patients expressed the highest level of CD8+ cells among HNCA. It was inferred that CD8+ cells were more likely immune suppressor rather than cytotoxic cells and this is the principal factor for inducing sustained immunosuppression in HNCA and in NPC in particular. Furthermore CD4/CD8 ratio proved to be a reliable index for assessing the immunological status of HNCA patients and more dependable index than other immunity-evaluating factors.

BackgroundCirculating interleukin-6 (IL-6) improves outcome prediction for second primary cancer (SPC) in head and neck cancer (HNC) patients. This study aimed to identify factors associated with IL-6 serum levels in HNC patients.MethodsThis study was conducted as part of a phase III chemoprevention trial. IL-6 was measured using chemiluminescent immunometric assay on pretreatment serum sample obtained from 527 stage I-II HNC patients. Patients’ lifestyle habits, sociodemographic, medical and tumor characteristics were evaluated before radiation therapy (RT). Factors independently associated with IL-6 levels before RT were identified using multiple linear regression.ResultsThe median IL-6 serum level was 3.1 ng/L. In the multivariate analysis, eight factors were significantly associated (p < 0.05) with IL-6: age, gender, marital status, body mass index, tobacco consumption, comorbidities, Karnofsky Performance Status and HNC site. Smoking duration and lifetime pack-years were positively associated with IL-6 serum levels in a dose-response relationship (p-value for trend ≤0.03).ConclusionsCirculating IL-6 is a strong predictor of the occurrence of SPC in HNC patients. We identified eight factors independently associated with serum IL-6 levels in 527 stage I-II HNC patients.The dose-response relationship between lifetime smoking and IL-6 serum levels suggested a causal role of tobacco exposure on IL-6 production. Further studies are needed to establish whether the effect of tobacco exposure on SPC could be partly mediated by IL-6, a pro-inflammatory cytokine.

Simple SummaryMany head and neck cancer patients report sexual problems. A deterioration in sexuality and sexual dysfunction from baseline to 3 months after treatment was observed especially in patients treated with chemoradiation. This effect seems to differ between men and women. Men reported change in erectile function, orgasm, satisfaction with intercourse, and overall satisfaction, while women reported change in desire, arousal, and orgasm. These findings are helpful to improve information on sexuality and sexual care in head and neck cancer patients. The aim of this study was to investigate changes in sexuality and sexual dysfunction in head and neck cancer (HNC) patients in the first two years after treatment, in relation to the type of treatment. Data were used of 588 HNC patients participating in the prospective NETherlands Quality of life and Biomedical Cohort Study (NET-QUBIC) from diagnosis to 3, 6, 12 and 24 months after treatment. Primary outcome measures were the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI). The total scores of the IIEF and FSFI were dichotomized into sexual (dys)function. In men, type of treatment was significantly associated with change in erectile function, orgasm, satisfaction with intercourse, and overall satisfaction. In women, type of treatment was significantly associated with change in desire, arousal, and orgasm. There were significant differences between treatment groups in change in dysfunctional sexuality. A deterioration in sexuality and sexual dysfunction from baseline to 3 months after treatment was observed especially in patients treated with chemoradiation. Changes in sexuality and sexual dysfunction in HNC patients were related to treatment, with an acute negative effect of chemoradiation. This effect on the various domains of sexuality seems to differ between men and women.

Background: Globally, head and neck cancer (HNC) considered the sixth most severe cancer associated with multiple risk factors. Due to lack of personalized therapies and undefined biomarkers, HNC shows low overall survival rate. Long non-coding RNA (LncRNA) helps to regulate multiple gene expressions in multiple biological responses. LncRNA tumor biomarkers stimulated tumor aggressiveness, cellular proliferation and inhibit apoptosis with poor prognosis. BLACAT-1, NEAT-1, HIF-1α, Caspase-3, Caspase-9 and Telomerase were associated with metastasis, tumor staging (TNM stage) activated proliferation, invasion and migration. Objective: The presented study aims to analyze tumorigenic biomarkers, (BLACAT-1, NEAT-1 and HIF-1α, Caspase-3, Caspase-9 and Telomerase) in development and progression of head and neck cancer. Meanwhile, to observe the correlation between these biomarkers in promoting head and neck cancer. Methods: In this comprehensive study, EDTA blood samples (5ml each) were collected from a cohort comprising 50 head and neck cancer (HNC) patients and an additional 30 healthy controls. The primary objective was to extract RNA from these samples for a detailed analysis. The study focused on evaluating the correlation between various tumor biomarkers across different HNC tumor subtypes. This correlation was meticulously analyzed using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), a method known for its precision in quantifying gene expression levels. Results: BLACAT-1 shows a significant increase expression in squamous cell carcinoma. NEAT-1, Caspase-3 and Caspase-9 are non-significant in HNC tumor types whereas, inverse correlation was observed between NEAT-1 with Caspase-9 and direct proportion between NEAT-1 with Caspase-3. However, HIF-1α represented an insignificant data among all tumor subtypes under hypoxic microenvironment. Conclusion: Higher expression levels are suggesting potential biomarkers, therefore a gene signature can be developed for determining the severity of breast tumor; therefore, can be exploited as novel therapeutic approaches to block tumor metastasis and angiogenesis.

Our goal is to determine an optimized image-guided setup by comparing setup errors determined by two-dimensional (2D) and three-dimensional (3D) image guidance for head and neck cancer (HNC) patients immobilized by customized thermoplastic masks. Nine patients received weekly imaging sessions, for a total of 54, throughout treatment. Patients were first set up by matching lasers to surface marks (initial) and then translationally corrected using manual registration of orthogonal kilovoltage (kV) radiographs with DRRs (2D-2D) on bony anatomy. A kV cone beam CT (kVCBCT) was acquired and manually registered to the simulation CT using only translations (3D-3D) on the same bony anatomy to determine further translational corrections. After treatment, a second set of kVCBCT was acquired to assess intrafractional motion. Averaged over all sessions, 2D-2D registration led to translational corrections from initial setup of 3.5 ± 2.2 (range 0–8) mm. The addition of 3D-3D registration resulted in only small incremental adjustment (0.8 ± 1.5 mm). We retrospectively calculated patient setup rotation errors using an automatic rigid-body algorithm with 6 degrees of freedom (DoF) on regions of interest (ROI) of in-field bony anatomy (mainly the C2 vertebral body). Small rotations were determined for most of the imaging sessions; however, occasionally rotations > 3° were observed. The calculated intrafractional motion with automatic registration was < 3.5 mm for eight patients, and < 2° for all patients. We conclude that daily manual 2D-2D registration on radiographs reduces positioning errors for mask-immobilized HNC patients in most cases, and is easily implemented. 3D-3D registration adds little improvement over 2D-2D registration without correcting rotational errors. We also conclude that thermoplastic masks are effective for patient immobilization.

Salivary DNA methylation derived estimates of biological aging, cellular frequency and protein expression as predictors of oral mucositis severity and survival in head and neck cancer patients