Detectability and intra-fraction motion of individual elective lymph nodes in head and neck cancer patients on the Magnetic Resonance Image guided linear accelerator.

Background and purpose: Individual elective lymph node irradiation instead of elective neck irradiation is a new concept for head-and-neck cancer (HNC) patients developed for the Magnetic Resonance Image guided linear accelerator (MR-linac). To prepare this, the detectability, volume changes and intra-fraction motion of elective lymph nodes on the MR-linac was assessed. Materials and methods: A total of 15 HNC patients underwent diagnostic pre-treatment MRI. Additionally, two MR-linac scans were obtained with a 10-minute time difference in the first week of radiation treatment. Elective lymph node contours inside lymph node levels (Ib-V) were segmented on the pre-treatment MRI and the MR-linac scans and compared on number and maximal transversal diameter. Intra-fraction motion of elective lymph nodes on the MR-linac was estimated using Center of Mass (COM) distances and incremental isotropic expansion of lymph node segmentations. Results: Of all 679 detected lymph nodes on the pre-treatment MRI, eight lymph nodes were not detectable on the first MR-linac scan and 16 new lymph nodes were detected. Lymph node diameters between the pre-treatment MRI scan and the MR-linac scan varied from -0.19 to + 0.13 mm. COM distances varied from 1.2 to 1.7 mm and lymph node contours had to be expanded with 3 mm. Conclusions: Nearly all elective lymph nodes were detectable on the 1.5T MR-linac scan with no major changes in target volumes compared to the pre-treatment MRI. Simulated intra-fraction motion during the MR-linac scans was smaller than the 5-mm margin that will be used in the first elective lymph node radiation treatment.

Improved delineation with diffusion weighted imaging for laryngeal and hypopharyngeal tumors validated with pathology.

OBJECTIVE: This study aims to determine the added value of a geometrically accurate diffusion-weighted (DW-) MRI sequence on the accuracy of gross tumor volume (GTV) delineations, using pathological tumor delineations as a ground truth. METHODS: Sixteen patients with laryngeal or hypopharyngeal carcinoma were included. After total laryngectomy, the specimen was cut into slices. Photographs of these slices were stacked to create a 3D digital specimen reconstruction, which was registered to the in vivo imaging. The pathological tumor (tumorHE) was delineated on the specimen reconstruction. Six observers delineated all tumors twice: once with only anatomical MR imaging, and once (a few weeks later) when DW sequences were also provided. The majority voting delineation of session one (GTVMRI) and session two (GTVDW-MRI), as well as the clinical target volumes (CTVs), were compared to the tumorHE. RESULTS: The mean tumorHE volume was 11.1 cm3, compared to a mean GTVMRI volume of 18.5 cm3 and a mean GTVDW-MRI volume of 15.7 cm3. The median sensitivity (tumor coverage) was comparable between sessions: 0.93 (range: 0.61-0.99) for the GTVMRI and 0.91 (range: 0.53-1.00) for the GTVDW-MRI. The CTV volume also decreased when DWI was available, with a mean CTVMR of 47.1 cm3 and a mean CTVDW-MRI of 41.4 cm3. Complete tumor coverage was achieved in 15 and 14 tumors, respectively. CONCLUSION: GTV delineations based on anatomical MR imaging tend to overestimate the tumor volume. The availability of the geometrically accurate DW sequence reduces the GTV overestimation and thereby CTV volumes, while maintaining acceptable tumor coverage.

Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification.

BACKGROUND: Organoids are in vitro three-dimensional structures that can be grown from patient tissue. Head and neck cancer (HNC) is a collective term used for multiple tumor types including squamous cell carcinomas and salivary gland adenocarcinomas. METHODS: Organoids were established from HNC patient tumor tissue and characterized using immunohistochemistry and DNA sequencing. Organoids were exposed to chemo- and radiotherapy and a panel of targeted agents. Organoid response was correlated with patient clinical response. CRISPR-Cas9-based gene editing of organoids was applied for biomarker validation. FINDINGS: A HNC biobank consisting of 110 models, including 65 tumor models, was generated. Organoids retained DNA alterations found in HNC. Comparison of organoid and patient response to radiotherapy (primary [n = 6] and adjuvant [n = 15]) indicated potential for guiding treatment options in the adjuvant setting. In organoids, the radio-sensitizing potential of cisplatin and carboplatin could be validated. However, cetuximab conveyed radioprotection in most models. HNC-targeted treatments were tested on 31 models, indicating possible novel treatment options with the potential for treatment stratification in the future. Activating PIK3CA mutations did not predict alpelisib response in organoids. Protein arginine methyltransferase 5 (PRMT5) inhibitors were identified as a potential treatment option for cyclin-dependent kinase inhibitor 2A (CDKN2A) null HNC. CONCLUSIONS: Organoids hold potential as a diagnostic tool in personalized medicine for HNC. In vitro organoid response to radiotherapy (RT) showed a trend that mimics clinical response, indicating the predictive potential of patient-derived organoids. Moreover, organoids could be used for biomarker discovery and validation. FUNDING: This work was funded by Oncode PoC 2018-P0003.

Individual elective lymph node irradiation for the reduction of complications in head and neck cancer patients (iNode): A phase-I feasibility trial protocol.

Introduction: The long-term complication rate in head-and-neck squamous cell carcinoma (HNSCC) patients caused by radiotherapy (RT) can be decreased by restricting elective neck irradiation (ENI) from large adjacent lymph node levels to only individual elective lymph nodes. The primary objective of this study is to treat the first HNSCC patients with individual elective lymph node irradiation by means of a Magnetic Resonance-linac (MR-linac) in order to assess the feasibility. Methods and analysis: In this phase I feasibility study, 20 patients will be included with histologically proven cT2-4N0-1M0 HNSCC originating from the oropharynx, hypopharynx or larynx, planned for treatment with primary radiotherapy and bilateral elective neck irradiation (ENI). Patients will be treated with 35 fractions in six weeks, according to the DAHANCA schedule. Individual lymph nodes inside the conventional lymph node levels will be categorized in low-risk, intermediate-risk and high-risk based on cytology, histology and imaging parameters. Low-risk and intermediate-risk lymph nodes will irradiated in 20 and 23 fractions respectively, with a fraction dose of 2 Gy (=40/46 Gy EQD2). The high-risk lymph nodes and the primary tumor will be irradiated in 35 fractions of 2 Gy (=70 Gy equivalent dose in 2 Gy fractions (EQD2)). To limit treatment burden, 20 fractions will be applied on the MR-linac. The last 15 fractions (sequential boost at the primary tumor, intermediate-risk and high-risk lymph nodes) will be applied on a conventional linear accelerator. The main study endpoint is the percentage of fractions that are successfully completed on the MR-linac. Ethics and dissemination: With individual elective lymph node irradiation we expect less toxicity and a better quality of life for HNSCC patients. However, as the treatment time on the MR-linac will be longer (30-45 vs 15 min per fraction) we need to examine if patients can endure this new treatment concept.

Factors associated with swallowing dysfunction in patients with head and neck cancer.

BACKGROUND: The aim of this prospective cohort study was to investigate swallowing function in relation to personal and clinical factors among patients with head and neck cancer (HNC) from diagnosis up to 2 years after treatment. METHODS: The 100 ml water swallow test was measured before treatment, and 3, 6, 12, and 24 months after treatment. Linear mixed-effects model analysis was conducted to investigate changes over time and the association with personal (sex and age) and clinical (tumor site, tumor stage, and treatment modality) factors. RESULTS: Among 128 included patients, number of swallows increased from baseline to 3 months after treatment and decreased to baseline again at 6 months after treatment. The number of swallows was associated with age and treatment modality. CONCLUSIONS: In patients with HNC, swallowing (dys)function changes over time with the worst score 3 months after treatment. A higher age and being treated with surgery are factors associated with swallowing dysfunction over time.

The course of swallowing problems in the first 2 years after diagnosis of head and neck cancer.

INTRODUCTION: Head and neck cancer (HNC) and its treatment often negatively impact swallowing function. The aim was to investigate the course of patient-reported swallowing problems from diagnosis to 3, 6, 12, and 24 months after treatment, in relation to demographic, clinical, and lifestyle factors. METHODS: Data were used of the Netherlands Quality of Life and Biomedical Cohort Study in head and neck cancer research (NET-QUBIC). The primary outcome measures were the subscales of the Swallowing Quality of Life Questionnaire (SWAL-QOL). Linear mixed-effects models (LMM) were conducted to investigate changes over time and associations with patient, clinical, and lifestyle parameters as assessed at baseline. RESULTS: Data were available of 603 patients. There was a significant change over time on all subscales. Before treatment, 53% of patients reported swallowing problems. This number increased to 70% at M3 and decreased to 59% at M6, 50% at M12, and 48% at M24. Swallowing problems (i.e., longer eating duration) were more pronounced in the case of female, current smoking, weight loss prior to treatment, and stage III or IV tumor, and were more prevalent at 3 to 6 months after treatment. Especially patients with an oropharynx and oral cavity tumor, and patients receiving (C)RT following surgery or CRT only showed a longer eating duration after treatment, which did not return to baseline levels. CONCLUSION: Half of the patients with HNC report swallowing problems before treatment. Eating duration was associated with sex, smoking, weight loss, tumor site and stage, and treatment modality, and was more pronounced 3 to 6 months after treatment.

Target Definition in MR-Guided Adaptive Radiotherapy for Head and Neck Cancer.

In recent years, MRI-guided radiotherapy (MRgRT) has taken an increasingly important position in image-guided radiotherapy (IGRT). Magnetic resonance imaging (MRI) offers superior soft tissue contrast in anatomical imaging compared to computed tomography (CT), but also provides functional and dynamic information with selected sequences. Due to these benefits, in current clinical practice, MRI is already used for target delineation and response assessment in patients with head and neck squamous cell carcinoma (HNSCC). Because of the close proximity of target areas and radiosensitive organs at risk (OARs) during HNSCC treatment, MRgRT could provide a more accurate treatment in which OARs receive less radiation dose. With the introduction of several new radiotherapy techniques (i.e., adaptive MRgRT, proton therapy, adaptive cone beam computed tomography (CBCT) RT, (daily) adaptive radiotherapy ensures radiation dose is accurately delivered to the target areas. With the integration of a daily adaptive workflow, interfraction changes have become visible, which allows regular and fast adaptation of target areas. In proton therapy, adaptation is even more important in order to obtain high quality dosimetry, due to its susceptibility for density differences in relation to the range uncertainty of the protons. The question is which adaptations during radiotherapy treatment are oncology safe and at the same time provide better sparing of OARs. For an optimal use of all these new tools there is an urgent need for an update of the target definitions in case of adaptive treatment for HNSCC. This review will provide current state of evidence regarding adaptive target definition using MR during radiotherapy for HNSCC. Additionally, future perspectives for adaptive MR-guided radiotherapy will be discussed.

Factors associated with masticatory function as measured with the Mixing Ability Test in patients with head and neck cancer before and after treatment: a prospective cohort study.

PURPOSE: After treatment for head and neck cancer (HNC), patients often experience major problems in masticatory function. The aim of this prospective cohort study among patients with HNC was to investigate which personal and clinical factors are associated with masticatory function from diagnosis up to 2 years after treatment with curative intent. METHODS: Masticatory function was measured using the Mixing Ability Test (MAT) before treatment (baseline), and 3, 6, 12, and 24 months after treatment. A linear mixed-effects model with a random intercept and slope was conducted to investigate changes over time and the association with personal (sex, age) and clinical (tumor site, tumor stage, treatment modality) factors as measured at baseline. RESULT: One-hundred-twenty-five patients were included. The prevalence of masticatory dysfunction was estimated at 29% at M0, 38% at M3, 28% at M6, 26% at M12, and 36% at M24. A higher (worse) MAT score was associated with age, tumor stage, tumor site, timing of assessment, and the interaction between assessment moment and tumor site. CONCLUSION: In patients with HNC, masticatory function changed over time and dysfunction was associated with a higher age, a tumor in the oral cavity, a higher tumor stage, and a shorter time since treatment. The prevalence of masticatory dysfunction ranged from 26 to 38%.

Comprehensive Quantitative Evaluation of Variability in Magnetic Resonance-Guided Delineation of Oropharyngeal Gross Tumor Volumes and High-Risk Clinical Target Volumes: An R-IDEAL Stage 0 Prospective Study.

PURPOSE: Tumor and target volume manual delineation remains a challenging task in head and neck cancer radiation therapy. The purpose of this study was to conduct a multi-institutional evaluation of manual delineations of gross tumor volume (GTV), high-risk clinical target volume (CTV), parotids, and submandibular glands on treatment simulation magnetic resonance scans of patients with oropharyngeal cancer. METHODS AND MATERIALS: We retrospectively collected pretreatment T1-weighted, T1-weighted with gadolinium contrast, and T2-weighted magnetic resonance imaging scans for 4 patients with oropharyngeal cancer under an institution review board-approved protocol. We provided the scans to 26 radiation oncologists from 7 international cancer centers that participated in this delineation study. We also provide the patients' clinical history and physical examination findings, along with a medical photographic image and radiologic results. We used both the Simultaneous Truth and Performance Level Estimation algorithm and pair-wise comparisons of the contours, using overlap/distance metrics. Lastly, to assess experience and CTV delineation institutional practices, we had participants complete a brief questionnaire. RESULTS: Large variability was measured between observers' delineations for GTVs and CTVs. The mean Dice similarity coefficient values across all physicians' delineations for GTVp, GTVn, CTVp, and CTVn were 0.77, 0.67, 0.77, and 0.69, respectively, for Simultaneous Truth and Performance Level Estimation algorithm comparison, and 0.67, 0.60, 0.67, and 0.58, respectively, for pair-wise analysis. Normal tissue contours were defined more consistently when considering overlap/distance metrics. The median radiation oncology clinical experience was 7 years. The median experience delineating on magnetic resonance imaging was 3.5 years. The GTV-to-CTV margin used was 10 mm for 6 of 7 participant institutions. One institution used 8 mm, and 3 participants (from 3 different institutions) used a margin of 5 mm. CONCLUSIONS: The data from this study suggests that appropriate guidelines, contouring quality assurance sessions, and training are still needed for the adoption of magnetic resonance-based treatment planning for head and neck cancers. Such efforts should play a critical role in reducing delineation variation and ensure standardization of target design across clinical practices.

MRI visibility and displacement of elective lymph nodes during radiotherapy in head and neck cancer patients.

Background and purpose: To decrease the impact of radiotherapy to healthy tissues in the head and neck region, we propose to restrict the elective neck irradiation to elective lymph nodes at risk of containing micro metastases instead of the larger lymph node volumes. To assess whether this new concept is achievable in the clinic, we determined the number, volume changes and displacement of elective lymph nodes during the course of radiotherapy. Materials and methods: MRI scans of 10 head and neck cancer (HNC) patients were acquired before radiotherapy and in week 2, 3, 4 and 5 during radiotherapy. The weekly delineations of elective lymph nodes inside the lymph node levels (Ib/II/III/IVa/V) were rigidly registered and analyzed regarding number and volume. The displacement of elective lymph nodes was determined by center of mass (COM) distances, vector-based analysis and the isotropic contour expansion of the lymph nodes of the pre-treatment scan or the scan of the previous week in order to geographically cover 95% of the lymph nodes in the scans of the other weeks. Results: On average, 31 elective lymph nodes in levels Ib-V on each side of the neck were determined. This number remained constant throughout radiotherapy in most lymph node levels. The volume of the elective lymph nodes reduced significantly in all weeks, up to 50% in week 5, compared to the pre-treatment scan. The largest median COM displacements were seen in level V, for example 5.2 mm in week 5 compared to the pre-treatment scan. The displacement of elective lymph nodes was mainly in cranial direction. Geographical coverage was obtained when the lymph node volumes were expanded with 7 mm in case the pre-treatment scan was used and 6.5 mm in case the scan of the previous week was used. Conclusion: Elective lymph nodes of HNC patients remained visible on MRI and decreased in size during radiotherapy. The displacement of elective lymph nodes differ per lymph node level and were mainly directed cranially. Weekly adaptation does not seem to improve coverage of elective lymph nodes. Based on our findings we expect elective lymph node irradiation is achievable in the clinic.

Mastication, swallowing, and salivary flow in patients with head and neck cancer: objective tests versus patient-reported outcomes.

PURPOSE: Before and after treatment for head and neck cancer (HNC), many patients have problems with mastication, swallowing, and salivary flow. The aim of this study was to investigate the association between objective test outcomes of mastication, swallowing, and salivary flow versus patient-reported outcomes (PROs) measuring mastication-, swallowing-, and salivary flow-related quality of life. METHODS: Data of the prospective cohort "Netherlands Quality of Life and Biomedical Cohort Study" was used as collected before treatment, and 3 and 6 months after treatment. Spearman's rho was used to test the association between objective test outcomes of the mixing ability test (MAT) for masticatory performance, the water-swallowing test (WST) for swallowing performance, and the salivary flow test versus PROs (subscales of the EORTC QLQ-H&N35, Swallow Quality of Life questionnaire (SWAL-QoL-NL) and Groningen Radiation-Induced Xerostomia (GRIX)). RESULTS: Data of 142 patients were used, and in total, 285 measurements were performed. No significant correlations were found between the MAT or WST and subscales of the EORTC QLQ-H&N35. Significant but weak correlations were found between the MAT or WST and 4 subscales of the SWAL-QoL-NL. Weak to moderate correlations were found between the salivary flow test and GRIX at 3 and 6 months after treatment, with the highest correlation between salivary flow and xerostomia during the day (Spearman's rho = - 0.441, p = 0.001). CONCLUSION: The association between objective test outcomes and PROs is weak, indicating that these outcome measures provide different information about masticatory performance, swallowing, and salivary flow in patients with HNC.

Reliability of the 100 mL water swallow test in patients with head and neck cancer and healthy subjects.

BACKGROUND: Dysphagia may occur in up to 44% of patients with head and neck cancer (HNC) treated with radiation therapy and up to 84% of patients treated with surgery. To test the extent of dysphagia, the 100 mL water swallow test (WST) was developed. In this study, reliability of the 100 mL WST was determined in patients with HNC and healthy subjects. METHODS: Thirty-three patients and 40 healthy subjects performed the WST twice on the same day. To assess reliability, the intraclass correlation coefficient (ICC2,1 ), standard error of measurement, smallest detectable change, and limits of agreement were calculated. RESULTS: Good to excellent correlations were found for patients with HNC (number of swallows; ICC = 0.923, duration; ICC = 0.893), and excellent correlations for healthy subjects (number of swallows; ICC = 0.950, duration; ICC = 0.916). CONCLUSION: The 100 mL WST has a good to excellent reliability in patients with HNC and healthy subjects.

Magnetic resonance guided elective neck irradiation targeting individual lymph nodes: A new concept.

BACKGROUND AND PURPOSE: Conventional elective neck irradiation (ENI) in head and neck cancer consists of radiotherapy (RT) to the regional lymph node (LN) levels contoured on computed tomography. Hybrid Magnetic Resonance (MR) - RT modalities, such as combined magnetic resonance imaging - linear accelerators (MRLs), might enable new ENI strategies in which individual non-suspect lymph nodes (i-LNs) are targeted. In this treatment planning study, new MR-based strategies targeting i-LNs (i-ENI) were compared to conventional treatment. MATERIALS AND METHODS: All i-LNs were delineated on MR images of ten retrospectively selected patients with T2-4aN0M0 laryngeal cancer. Three strategies were considered. Strategy A: Conventional ENI delivered with a conventional linear accelerator (35x 1.55 Gy). Strategy B: MRL-based i-ENI (35x 1.55 Gy) to the individual lymph nodes including a background dose to the conventional elective neck volumes (35x 1.03 Gy). Strategy C: Same as Strategy B, but without background dose. In all plans the dose prescription to the primary tumor was 35x 2 Gy. Mean dose (D mean) reductions in the organs at risk (OAR) were compared using the Wilcoxon signed rank test. RESULTS: Compared to conventional ENI (strategy A), significant D mean reductions of 6.0 Gy and 8.0 Gy were observed in the submandibular glands, of 9.4 Gy and 13 Gy in the carotid arteries and of 9.9 Gy and 19.4 Gy in the thyroid for strategy B and C, respectively. Large inter-patient variations of D mean reductions were observed in all OARs. CONCLUSION: MRL-based i-ENI is a new promising concept that could reduce the mean dose to OARs in the neck significantly for patients with laryngeal cancer.

Reliability of the mixing ability test testing masticatory performance in patients with head and neck cancer and healthy controls.

BACKGROUND: Treatment of patients with head and neck cancer can result in disrupted mastication. To measure masticatory performance in people with compromised mastication, the mixing ability test (MAT) was developed. OBJECTIVE: In this study, the reliability of the MAT was evaluated in patients with head and neck cancer and healthy controls. METHODS: Thirty-four patients with head and neck cancer and 42 healthy controls performed the MAT twice on the same day. To assess reliability, the intra-class correlation coefficient (ICC2,1 ), standard error of measurement (SEM), smallest detectable change (SDC) and limits of agreement (LoA) were calculated. RESULTS: A good (ICC = 0.886) and moderate correlation (ICC = 0.525) were found for patients and healthy controls, respectively. Patients had a worse mixing ability (mean = 19.12, SD = 4.56) in comparison with healthy controls (mean = 16.42, SD = 2.04). The SEM was 0.76 in patients and 1.45 in healthy controls, with a SDC of 2.12 and 4.02, respectively. The LoA was -4.46 to 4.42 in patients and -3.65 to 4.59 in healthy controls. CONCLUSION: The MAT has a good reliability in patients with head and neck cancer and a moderate reliability in healthy controls.

Advances in cancer imaging require renewed radiotherapy dose and target volume concepts.

Advances in diagnostic imaging create opportunities for improved therapeutic targeting of cancer but conceptual thinking about radiotherapy target volume definition and dose-prescription is not keeping up. In this opinion paper we discuss how modern imaging can contribute to new concepts for radiotherapy dose-prescription and target volume definition illustrated by the example of head and neck cancer. These new insights have the potential to significantly reduce radiation associated toxicity and may have important impact on the combination of radiotherapy with systemic cancer therapies.

Brain and Head-and-Neck MRI in Immobilization Mask: A Practical Solution for MR-Only Radiotherapy.

In brain/head-and-neck radiotherapy (RT), thermoplastic immobilization masks guarantee reproducible patient positioning in treatment position between MRI, CT, and irradiation. Since immobilization masks do not fit in the diagnostic MR head/head-and-neck coils, flexible surface coils are used for MRI imaging in clinical practice. These coils are placed around the head/neck, in contact with the immobilization masks. However, the positioning of these flexible coils is technician dependent, thus leading to poor image reproducibility. Additionally, flexible surface coils have an inferior signal-to-noise-ratio (SNR) compared to diagnostic coils. The aim of this work was to create a new immobilization setup which fits into the diagnostic MR coils in order to enhance MR image quality and reproducibility. For this purpose, a practical immobilization setup was constructed. The performances of the standard clinical and the proposed setups were compared with four tests: SNR, image quality, motion restriction, and reproducibility of inter-fraction subject positioning. The new immobilization setup resulted in 3.4 times higher SNR values on average than the standard setup, except directly below the flexible surface coils where similar SNR was observed. Overall, the image quality was superior for brain/head-and-neck images acquired with the proposed RT setup. Comparable motion restriction in feet-head/left-right directions (maximum motion ≈1 mm) and comparable inter-fraction repositioning accuracy (mean inter-fraction movement 1 ± 0.5 mm) were observed for the standard and the new setup.

Targeted Intervention to Improve the Quality of Head and Neck Radiation Therapy Treatment Planning in the Netherlands: Short and Long-Term Impact.

PURPOSE: To benchmark and improve, through means of a targeted intervention, the quality of intensity modulated radiation therapy treatment planning for locally advanced head and neck cancer (HNC) in the Netherlands. The short and long-term impact of this intervention was assessed. METHODS AND MATERIALS: A delineated computed tomography-scan of an oropharynx HNC case was sent to all 15 Dutch radiation therapy centers treating HNC. Aims for planning target volume and organ-at-risk (OAR) dosimetry were established by consensus. Each center generated a treatment plan. In a targeted intervention, OAR sparing of all plans was discussed, and centers with the best OAR sparing shared their planning strategies. Impact of the intervention was assessed by (1) short-term (half a year after intervention) replanning of the original case and (2) long-term (1 and 3 years after intervention) planning of new cases. RESULTS: Benchmarking revealed substantial difference in OAR doses. Initial mean doses were 22 Gy (range, 15-31 Gy), 35 Gy (18-49 Gy), and 37 Gy (20-46 Gy) for the contralateral parotid gland, contralateral submandibular gland, and combined swallowing structures, respectively. Replanning after targeted intervention significantly reduced mean doses and variation, but clinically relevant differences still remained: 18 Gy (14-22 Gy), 28 Gy (17-45 Gy), and 29 Gy (18-39 Gy), respectively. One and 3 years later the variation remained stable. CONCLUSIONS: Despite many years of HNC intensity modulated radiation therapy experience, initial treatment plans showed surprisingly large variations. The simple targeted intervention used in this analysis improved OAR sparing, and its impact was durable; however, fairly large dose differences still continue to exist. Additional work is needed to understand these variations and to minimize them. A national radiation oncology platform can be instrumental for developing and maintaining high-quality planning protocols.