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.

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.

Oncological outcome of vocal cord-only radiotherapy for cT1-T2 glottic laryngeal squamous cell carcinoma.

PURPOSE: Early-stage glottic cancer can be treated with radiotherapy only. Modern radiotherapy solutions allow for individualized dose distributions, hypofractionation and sparing of organs at risk. The target volume used to be the entire voice box. This series describe the oncological outcome and toxicity of individualized vocal cord-only hypofractionated radiotherapy for early stage (cT1a-T2 N0). METHODS: Retrospective cohort study with patients treated in a single center between 2014 and 2020. RESULTS: A total of 93 patients were included. Local control rate was 100% for cT1a, 97% for cT1b and 77% for cT2. Risk factor for local recurrence was smoking during radiotherapy. Laryngectomy-free survival was 90% at 5 years. Grade III or higher late toxicity was 3.7%. CONCLUSION: Vocal cord-only hypofractionated radiotherapy appears to be oncologically safe in early-stage glottic cancer. Modern, image-guided radiotherapy led to comparable results as historical series with very limited late toxicity.

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.

Online adaptive MR-guided radiotherapy: Conformity of contour adaptation for prostate cancer, rectal cancer and lymph node oligometastases among radiation therapists and radiation oncologists.

Background and purpose: Online adaptive MR-guided treatment planning workflows facilitate daily contour adaptation to the actual anatomy. Allocating contour adaptation to radiation therapists (RTTs) instead of radiation oncologists (ROs) might allow for increasing workflow efficiency. This study investigates conformity of adapted target contours provided by dedicated RTTs and ROs. Materials and methods: In a simulated online procedure, 6 RTTs and 6 ROs recontoured targets and organs at risk (OAR) in prostate cancer (n = 2), rectal cancer (n = 2) and lymph node-oligometastases (n = 2) cases. RTTs gained contouring competence beforehand by following a specific in-house training program. For all target contours and the reference delineations volumetric differences were determined and Dice similarity coefficient (DSC), conformity index (CI) and generalized CI were calculated. Delineation time and -confidence were registered for targets and OAR. Impact of contour adaptation on treatment plan quality was investigated. Results: Delineation conformity was generally high with DSC, CI and generalized CI values in the range of 0.81-0.94, 0.87-0.95 and 0.63-0.85 for prostate cancer, rectal cancer and LN-oligometastasis, respectively. Target volumes were comparable for both, RTTs and ROs. Time needed and confidence in contour adaptation was comparable as well. Treatment plans derived with adapted contours did not violate dose volume constrains as used in clinical routine. Conclusion: After tumor site specific training, daily contour adaptations as needed in adaptive online radiotherapy workflows can be accurately performed by RTTs. Conformity of the derived contours is high and comparable to contours as provided by ROs.

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.

Association of histological features with laryngeal squamous cell carcinoma recurrences: a population-based study of 1502 patients in the Netherlands.

BACKGROUND: Recurrences remain an important problem in laryngeal squamous cell carcinoma. Little has been described about histological characteristics of the primary laryngeal tumor that may be associated with recurrences. Identifying risk factors for recurrences might help in adapting treatment or follow-up. Using real-life population-based data, we aimed to identify histological features of the primary tumor associated with recurrences and overall survival. MATERIAL AND METHODS: Demographic, clinical and treatment information on all first primary invasive laryngeal tumors diagnosed in 2010-2014 (N = 3705) were extracted from the population-based nationwide Netherlands cancer registry (NCR) and linked to PALGA, the nationwide Dutch pathology registry, to obtain data on histological factors and recurrences. For a random 1502 patients histological information i.e., keratinization, perineural invasion (PNI+), vascular invasion (VI+), growth pattern, degree of differentiation, extracapsular spread (ECS+), cartilage- and bone invasion and extralaryngeal extension, was manually extracted from narrative pathology reports and analyzed for locoregional recurrence and overall survival using cox regression analysis. RESULTS: In total, 299 patients developed a locoregional recurrence and 555 patients died. Keratinization (HR = 0.96 (95%CI: 0.68-1.34) p = 0.79), two or three adverse characteristics (PNI+, VI+, non-cohesive growth) (HR = 1.38 (95% CI: 0.63-3.01) p = 0.42), and ECS+ (HR = 1.38 (95% CI: 0.48-4.02) p = 0.55) were not associated to recurrence. For death, also no significant association was found. CONCLUSION: In this population-based real-life dataset on laryngeal carcinoma in the Netherlands, histological factors were not associated with locoregional recurrences or overall survival, but future studies should investigate the role of these features in treatment decisions.

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.

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.

18F-FDG-PET/CT-based treatment planning for definitive (chemo)radiotherapy in patients with head and neck squamous cell carcinoma improves regional control and survival.

BACKGROUND AND PURPOSE: Multimodality imaging including 18F-FDG-PET has improved the detection threshold of nodal metastases in head and neck squamous cell carcinoma (HNSCC). The aim of this retrospective analysis is to investigate the impact of FDG-PET/CT-based nodal target volume definition (FDG-PET/CT-based NTV) on radiotherapy outcomes, compared to conventional CT-based nodal target volume definition (CT-based NTV). MATERIALS AND METHODS: Six-hundred-thirty-three patients treated for HNSCC with definitive (chemo)radiotherapy using IMRT/VMAT techniques between 2008 and 2017 were analyzed. FDG-PET/CT-based NTV was performed in 46% of the patients. The median follow-up was 31 months. Diagnostic imaging depicting the regional recurrence was co-registered with the initial CT-scan to reconstruct the exact site of the recurrence. Multivariate Cox regression analysis was performed to identify variables associated with radiotherapy outcome. RESULTS: FDG-PET/CT-based NTV improved control of disease in the CTVelective-nodal (HR: 0.33, p = 0.026), overall regional control (HR: 0.62, p = 0.027) and overall survival (HR: 0.71, p = 0.033) compared to CT-based NTV. The risk for recurrence in the CTVelective-nodal was increased in case of synchronous local recurrence of the primary tumor (HR: 12.4, p < 0.001). CONCLUSION: FDG-PET/CT-based NTV significantly improved control of disease in the CTVelective-nodal, overall regional control and overall survival compared to CT-based NTV. A significant proportion of CTVelective-nodal recurrences are potentially new nodal manifestations from a synchronous local recurrent primary tumor. These results support the concept of target volume transformation and give an indication of the potential of FDG-PET to guide gradual radiotherapy dose de-escalation in elective neck treatment in HNSCC.

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.

Dosimetric evaluation of synthetic CT for head and neck radiotherapy generated by a patch-based three-dimensional convolutional neural network.

PURPOSE: To develop and evaluate a patch-based convolutional neural network (CNN) to generate synthetic computed tomography (sCT) images for magnetic resonance (MR)-only workflow for radiotherapy of head and neck tumors. A patch-based deep learning method was chosen to improve robustness to abnormal anatomies caused by large tumors, surgical excisions, or dental artifacts. In this study, we evaluate whether the generated sCT images enable accurate MR-based dose calculations in the head and neck region. METHODS: We conducted a retrospective study on 34 patients with head and neck cancer who underwent both CT and MR imaging for radiotherapy treatment planning. To generate the sCTs, a large field-of-view T2-weighted Turbo Spin Echo MR sequence was used from the clinical protocol for multiple types of head and neck tumors. To align images as well as possible on a voxel-wise level, CT scans were nonrigidly registered to the MR (CTreg ). The CNN was based on a U-net architecture and consisted of 14 layers with 3 × 3 × 3 filters. Patches of 48 × 48 × 48 were randomly extracted and fed into the training. sCTs were created for all patients using threefold cross validation. For each patient, the clinical CT-based treatment plan was recalculated on sCT using Monaco TPS (Elekta). We evaluated mean absolute error (MAE) and mean error (ME) within the body contours and dice scores in air and bone mask. Also, dose differences and gamma pass rates between CT- and sCT-based plans inside the body contours were calculated. RESULTS: sCT generation took 4 min per patient. The MAE over the patient population of the sCT within the intersection of body contours was 75 ± 9 Hounsfield Units (HU) (±1 SD), and the ME was 9 ± 11 HU. Dice scores of the air and bone masks (CTreg vs sCT) were 0.79 ± 0.08 and 0.70 ± 0.07, respectively. Dosimetric analysis showed mean deviations of -0.03% ± 0.05% for dose within the body contours and -0.07% ± 0.22% inside the >90% dose volume. Dental artifacts obscuring the CT could be circumvented in the sCT by the CNN-based approach in combination with Turbo Spin Echo (TSE) magnetic resonance imaging (MRI) sequence that typically is less prone to susceptibility artifacts. CONCLUSIONS: The presented CNN generated sCTs from conventional MR images without adding scan time to the acquisition. Dosimetric evaluation suggests that dose calculations performed on the sCTs are accurate, and can therefore be used for MR-only radiotherapy treatment planning of the head and neck.

Uniform FDG-PET guided GRAdient Dose prEscription to reduce late Radiation Toxicity (UPGRADE-RT): study protocol for a randomized clinical trial with dose reduction to the elective neck in head and neck squamous cell carcinoma.

BACKGROUND: In definitive radiation therapy for head and neck cancer, clinically uninvolved cervical lymph nodes are irradiated with a so-called 'elective dose' in order to achieve control of clinically occult metastases. As a consequence of high-resolution diagnostic imaging, occult tumor volume has significantly decreased in the last decades. Since the elective dose is dependent on occult tumor volume, the currently used elective dose may be higher than necessary. Because bilateral irradiation of the neck contributes to dysphagia, xerostomia and hypothyroidism in a dose dependent way, dose de-escalation to these regions can open a window of opportunity to reduce toxicity and improve quality of life after treatment. METHODS: UPGRADE-RT is a multicenter, phase III, single-blinded, randomized controlled trial. Patients to be treated with definitive radiation therapy for a newly diagnosed stage T2-4 N0-2 M0 squamous cell carcinoma of the oropharynx, hypopharynx or larynx are eligible. Exclusion criteria are recurrent disease, oncologic surgery to the head and neck area, concomitant chemotherapy or epidermal growth factor receptor inhibitors. In total, 300 patients will be randomized in a 2:1 ratio to a treatment arm with or without de-escalation of the elective radiation dose and introduction of an intermediate dose-level for selected lymph nodes. Radiation therapy planning FDG-PET/CT-scans will be acquired to guide risk assessment of borderline-sized cervical nodes that can be treated with the intermediate dose level. Treatment will be given with intensity-modulated radiation therapy or volumetric arc therapy with simultaneous-integrated boost using an accelerated fractionation schedule, 33 fractions in 5 weeks. The primary endpoint is 'normalcy of diet' at 1 year after treatment (toxicity). The secondary endpoint is the actuarial rate of recurrence in electively irradiated lymph nodes at 2 years after treatment (safety). DISCUSSION: The objective of the UPGRADE-RT trial is to investigate whether de-escalation of elective radiation dose and the introduction of an intermediate dose-level for borderline sized lymph nodes in the treatment of head and neck cancer will result in less radiation sequelae and improved quality of life after treatment without compromising the recurrence rate in the electively treated neck. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02442375 .

Quality-of-life after radiotherapy for advanced laryngeal cancer: Results of a phase III trial of the Dutch Head and Neck Society.

BACKGROUND/PURPOSE: To report on health-related quality-of-life (HRQoL) of patients with laryngeal cancer, treated in a randomized trial comparing accelerated radiotherapy with carbogen and nicotinamide (ARCON) against accelerated radiotherapy alone (AR). MATERIAL/METHODS: HRQoL was assessed using the HRQoL Questionnaire-C30 (QLQ-C30) and the Head & Neck cancer module (QLQ-H&N35) at baseline, at completion of radiotherapy and at 6, 12, and 24months post-baseline. RESULTS: From 269/345 patients (AR: 136/174; ARCON: 133/171) data on HRQoL were available for analysis. Moderate to severe clinical impact of the treatment was observed for nearly all items of the QLQ-C30 and QLQ-H&N35 between baseline and end-of-treatment. At 6months, scores returned to baseline level with exception of dry mouth, sticky saliva, and taste/smell. No difference between AR and ARCON was observed. At 2years from baseline, the percentage of patients reporting moderate to severe complaints of dry mouth, sticky saliva, or changes in taste/smell was 30%, 22% and 18%, respectively, while the majority of patients had no or few complaints of swallowing (79%) or speech (64%). CONCLUSIONS: With accelerated radiotherapy, high local tumor control was obtained while maintaining good speech and swallowing function. Long-term dry mouth, sticky saliva and changes in taste/smell are limited to one quarter of patients. (ClinicalTrials.gov number, NCT00147732).

Interaction of quantitative (18)F-FDG-PET-CT imaging parameters and human papillomavirus status in oropharyngeal squamous cell carcinoma.

BACKGROUND: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) have a better survival than with HPV-negative oropharyngeal SCC. An (18) F-fluorodeoxyglucose positron emission tomography-CT ((18) F-FDG-PET-CT) may also provide prognostic information. We evaluated glycolytic characteristics in HPV-negative and HPV-positive oropharyngeal SCC. METHODS: Forty-four patients underwent pretreatment (18) F-FDG-PET-CT. Standardized uptake values (SUVs) and metabolic active tumor volumes (MATVs) were determined for primary tumors. HPV status was determined with p16 immunostaining, followed by high-risk HPV DNA detection on the positive cases. RESULTS: Twenty-seven patients were HPV-positive (61.4%). Median MATV was 2.8 mL (range = 1.6-5.1 mL) for HPV-positive and 6.0 mL (range = 4.4-18.7 mL) for HPV-negative tumors (p < .001). SUV values are volume dependent (partial volume effect), therefore, MATV was included as covariate in multivariate analysis. In this multivariate analysis, the maximum SUV in HPV-positive tumors was 3.9 units lower than in HPV-negative tumors (p = .01). CONCLUSION: The (18) F-FDG-PET-CT parameters are lower in HPV-positive than in HPV-negative patients. Low pretreatment SUV values in HPV-positive oropharyngeal SCC may be at least partly explained by HPV-induced tumor changes.

Prognostic value of the proliferation marker Ki-67 in laryngeal carcinoma: results of the accelerated radiotherapy with carbogen breathing and nicotinamide phase III randomized trial.

BACKGROUND: The prognostic and predictive value of the proliferation marker Ki-67 was investigated in a randomized trial comparing accelerated radiotherapy with carbogen breathing and nicotinamide (ARCON) to accelerated radiotherapy in laryngeal carcinoma. METHODS: Labeling index of Ki-67 (Li Ki-67) in immunohistochemically stained biopsies and the colocalization with carbonic anhydrase IX (CAIX) were related to tumor control and patient survival. RESULTS: On average, node-positive patients had a higher Li Ki-67 (median 14% vs 8%; p < .01). In patients with a high Li Ki-67, the 5-year regional control and metastases-free survival were 79% versus 96% (p < .01) and 71% versus 88% (p = .05) for accelerated radiotherapy and ARCON, respectively. The 5-year local control and disease-specific survival were not significantly different. Patients with low Ki-67 expression had an excellent outcome with accelerated radiotherapy alone. CONCLUSION: Patients with laryngeal carcinomas with high proliferative activity are at increased risk of regional and distant metastases formation. This risk can be reduced by treatment with ARCON.

Diffusion-weighted EPI- and HASTE-MRI and 18F-FDG-PET-CT early during chemoradiotherapy in advanced head and neck cancer.

MAIN PROBLEM: Diffusion-weighted MRI (DW-MRI) has potential to predict chemoradiotherapy (CRT) response in head and neck squamous cell carcinoma (HNSCC) and is generally performed using echo-planar imaging (EPI). However, EPI-DWI is susceptible to geometric distortions. Half-fourier acquisition single-shot turbo spin-echo (HASTE)-DWI may be an alternative. This prospective pilot study evaluates the potential predictive value of EPI- and HASTE-DWI and 18F-fluorodeoxyglucose PET-CT (18F-FDG-PET-CT) early during CRT for locoregional outcome in HNSCC. METHODS: Eight patients with advanced HNSCC (7 primary tumors and 25 nodal metastases) scheduled for CRT, underwent DW-MRI (using both EPI- and HASTE-DWI) and 18F-FDG-PET(-CT) pretreatment, early during treatment and three months after treatment. Median follow-up time was 38 months. RESULTS: No local recurrences were detected during follow-up. Median Apparent Diffusion Coefficient (ADC)EPI-values in primary tumors increased from 77×10(-5) mm(2)/s pretreatment, to 113×10(-5) mm(2)/s during treatment (P=0.02), whereas ADCHASTE did not increase (74 and 74 mm(2)/s, respectively). Two regional recurrences were diagnosed. During treatment, ADCEPI tended to be higher for patients with regional control [(117.3±12.1)×10(-5) mm(2)/s] than for patients with a recurrence [(98.0±4.2)×10(-5) mm(2)/s]. This difference was not seen with ADCHASTE. No correlations between ΔADCEPI and ΔSUV (Standardized Uptake Value) were found in the primary tumor or nodal metastases. CONCLUSIONS: HASTE-DWI seems to be inadequate in early CRT response prediction, compared to EPI-DWI which has potential to predict locoregional outcome. EPI-DWI and 18F-FDG-PET-CT potentially provide independent information in the early response to treatment, since no correlations were found between ΔADCEPI and ΔSUV.

Computed tomography-based tumour volume as a predictor of outcome in laryngeal cancer: results of the phase 3 ARCON trial.

PURPOSE: Retrospective studies indicate that larger tumour volume is a strong prognostic indicator for poor tumour control after (chemo)radiotherapy for laryngeal cancer. The impact of tumour volume on the outcome of patients treated within a prospective study comparing accelerated radiotherapy (AR)±carbogen breathing and nicotinamide (ARCON) was investigated. METHODS AND MATERIALS: Of 345 patients with cT2-4 laryngeal cancer, pre-treatment computed tomography (CT) scans of 270 patients were available for tumour volume calculation. Contouring of the primary tumour and involved lymph nodes was reviewed by one experienced head and neck radiation oncologist. Kaplan-Meier plots were used for analysis of outcome. RESULTS: Of 137 AR and 133 ARCON patients, 57 and 80 versus 56 and 77 patients had glottic and supraglottic tumours, respectively. A correlation between primary tumour volume and T-stage was observed (Rs=.51, P<.01). In both treatment arms no correlation was detected between the primary tumour volume and local control (LC), regional control (RC) and metastasis-free survival (MFS). A strong correlation between total nodal volume and N-stage was found (Rs=.93, P<.01). Both in the AR and ARCON groups total nodal volume was not associated with poorer RC rate. However, based on individual lymph node analyses, nodal control was in favour of ARCON, irrespective of volume (P<.01). CONCLUSION: Neither primary tumour volume, nor total nodal volume is a prognostic factor for patients with cT2-4 laryngeal cancer treated with accelerated radiotherapy±carbogen breathing and nicotinamide. Additional analyses based on individual nodal volumes demonstrate an excellent regional control rate and a significant benefit of ARCON.

Improved recurrence-free survival with ARCON for anemic patients with laryngeal cancer.

PURPOSE: Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial. EXPERIMENTAL DESIGN: Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient. RESULTS: Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P = 0.44) and disease-free survival (DFS, 75% vs. 70%; P = 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P = 0.03) and DFS (68% vs. 45%; P = 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed. CONCLUSION: Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732).

Epidermal growth factor receptor expression in laryngeal cancer predicts the effect of hypoxia modification as an additive to accelerated radiotherapy in a randomised controlled trial.

Accelerated radiotherapy (AR) improves the poor prognosis associated with epidermal growth factor receptor (EGFR) overexpression frequently seen in head and neck carcinomas. Combining AR with carbogen and nicotinamide (ARCON) counteracts enhanced tumour cell proliferation- and hypoxia-related radioresistance. The purpose of this study was to investigate if EGFR expression levels are associated with response to ARCON in patients with carcinoma of the larynx. Patients (N=272) with advanced stage larynx carcinoma were randomised between AR alone and ARCON. Paraffin-embedded biopsies from these patients were processed for immunohistochemical staining of EGFR. EGFR fraction was quantitated by automated image analysis and related to clinical outcome. A large variation was observed in EGFR fraction between tumours with expression levels ranging from 0 to 0.93 (median fraction 0.4). No difference in 5-year locoregional control was found between low and high EGFR expressing tumours in the AR arm (69% versus 75%), which is in line with the established effect of AR in EGFR overexpressing tumours. There was, however, a significant association in the ARCON arm: patients with low EGFR levels had a better 5-year locoregional control (88% versus 72% p=0.02) and disease-specific survival (92% versus 77% p=0.01). ARCON improved locoregional control relative to AR only in patients with low EGFR expression (hazard ratio (HR) 0.34 p=0.009). In conclusion, only in tumours with a low EGFR fraction, adding hypoxia modification to AR has an additive beneficial effect on outcome. EGFR expression is a predictive biomarker for the selection of patients that will or will not respond to ARCON.