Purpose: To report, from a retrospective analysis of prospectively collected data, on the feasibility, outcome, toxicity, and voice-handicap index (VHI) of patients with T1a glottic cancer treated by a novel intensity modulated radiation therapy technique developed at our institution to treat only the involved vocal cord: single vocal cord irradiation (SVCI). Methods and Materials: Thirty patients with T1a glottic cancer were treated by means of SVCI. Dose prescription was set to 16 x 3.63Gy (total dose 58.08 Gy). The clinical target volume was the entire vocal cord. Setup verification was done by means of an online correction protocol using cone beamcomputed tomography. Data for voice quality assessment were collected prospectively at baseline, end of treatment, and 4, 6, and 12 weeks and 6, 12, and 18 months after treatment using VHI questionnaires.Results: After a median follow-up of 30 months (range, 7-50 months), the 2-year local control and overall survival rates were 100% and 90% because no single local recurrence was reported and 3 patients died because of comorbidity. All patients have completed the intended treatment schedule; no treatment interruptions and no grade 3 acute toxicity were reported. Grade 2 acute dermatitis or dysphagia was reported in only 5 patients (17%). No serious late toxicity was reported; only 1 patient developed temporary grade 2 laryngeal edema, and responded to a short-course of corticosteroid. The VHI improved significantly, from 33.5 at baseline to 9.5 and 10 at 6 weeks and 18 months, respectively (P < .001). The control group, treated to the whole larynx, had comparable local control rates (92.2% vs 100%, P = .24) but more acute toxicity (66% vs 17%, P < .0001) and higher VHI scores (23.8 and 16.7 at 6 weeks and 18 months, respectively, P < .0001).Conclusion: Single vocal cord irradiation is feasible and resulted in maximal local control rate at 2 years. The deterioration in VHI scores was slight and temporary and subsequently improved to normal levels. Long-term follow-up is needed to consolidate these promising results. (C) 2015 Elsevier Inc. All rights reserved.

Purpose: The purpose of this study was to verify clinical target volume-planning target volume (CTV-PTV) margins in single vocal cord irradiation (SVCI) of T1a larynx tumors and characterize inter-and intrafraction target motion.Methods and Materials: For 42 patients, a single vocal cord was irradiated using intensity modulated radiation therapy at a total dose of 58.1 Gy (16 fractions x 3.63 Gy). A daily cone beam computed tomography (CBCT) scan was performed to online correct the setup of the thyroid cartilage after patient positioning with in-room lasers (interfraction motion correction). To monitor intrafraction motion, CBCT scans were also acquired just after patient repositioning and after dose delivery. A mixed online-offline setup correction protocol ("O2 protocol") was designed to compensate for both inter-and intrafraction motion.Results: Observed interfraction, systematic (Sigma), and random (sigma) setup errors in left-right (LR), craniocaudal (CC), and anteroposterior (AP) directions were 0.9, 2.0, and 1.1 mm and 1.0, 1.6, and 1.0 mm, respectively. After correction of these errors, the following intrafraction movements derived from the CBCT acquired after dose delivery were: Sigma = 0.4, 1.3, and 0.7 mm, and sigma = 0.8, 1.4, and 0.8 mm. More than half of the patients showed a systematic non-zero intrafraction shift in target position, (ie, the mean intrafraction displacement over the treatment fractions was statistically significantly different from zero; P<.05). With the applied CTV-PTV margins (for most patients 3, 5, and 3 mm in LR, CC, and AP directions, respectively), the minimum CTV dose, estimated from the target displacements observed in the last CBCT, was at least 94% of the prescribed dose for all patients and more than 98% for most patients (37 of 42). The proposed O2 protocol could effectively reduce the systematic intrafraction errors observed after dose delivery to almost zero (Sigma = 0.1, 0.2, 0.2 mm).Conclusions: With adequate image guidance and CTV-PTV margins in LR, CC, and AP directions of 3, 5, and 3 mm, respectively, excellent target coverage in SVCI could be ensured. (C) 2015 Elsevier Inc. All rights reserved.

BACKGROUND:The purpose was to determine whether a brachytherapy boost improves outcomes in patients with advanced nasopharyngeal carcinoma treated with standard chemo-radiotherapy.METHODS:Patients with nasopharyngeal carcinoma WHO grades I-III and TNM stages III or non-metastatic stage IV were eligible for this phase III study. Patients were randomized to either arm (A) induction chemotherapy, followed by external beam radiotherapy (EBRT) with concomitant cisplatin (n = 139) or arm (B), the same schedule plus a brachytherapy boost to the nasopharynx (n = 135). The EBRT doses given were 70 Gy to the primary tumour and positive lymph nodes and 46 Gy to the negative neck. The additional brachytherapy boost in arm (B) was given by either low dose-rate (LDR - 11 Gy) or high dose-rate (HDR - 3 fractions of 3.0 Gy) brachytherapy. The primary endpoint was 3-year overall survival (OS) and secondary endpoints were: local control, regional control, distant metastasis and grade 3-4 adverse events.RESULTS:274 patients were randomized between September 2004 and December 2008. The two arms were comparable with regard to age, gender, stage and grade. 273 patients completed treatment. Median follow-up was 29 months (0.2-67 months). The effect of treatment arm, country, age, gender, WHO pathology, stage (T3-4, N2-3 versus other) and chemotherapy on overall survival (OS), disease-free survival (DFS) and local recurrence-free survival (LRFS) was studied. Stage significantly affected OS (p = 0.024) and DFS (p = 0.018) while age significantly affected OS (p = 0.014). None of the other factors studied were significant. The 3-year LRFS was 60.5% and 54.4% in arms A and B respectively (p = 0.647). The 3-year regional control rate in the neck was 59.7% and 54.3% respectively (p = 0.7). Distant metastasis developed in 59.7% of patients in arm A and 55.4% in arm B (p = 0.377). Patients with T1/T2 N + had a 3 year LRFS of 51.8% in Arm A (62 patients) versus 57.9% in Arm B (67 patients) (p = 0.343). The grade 3-4 toxicity rate was 21.6% (30/139) and 24.4% (33/135) respectively (p = 0.687).CONCLUSIONS:The addition of a brachytherapy boost to external beam radiotherapy and chemotherapy did not improve outcome in loco-regionally advanced nasopharyngeal carcinoma.

Objectives/Hypothesis: To investigate the impact of treatment modality and radiation technique on oncologic outcomes and toxicity of patients with locally advanced oropharyngeal cancer (OPC). Study Design: Retrospective analysis of outcomes and toxicity. Methods: Between 2000 and 2011, 204 consecutive patients with locally advanced OPC were treated with definitive (chemo)radiotherapy using 3-dimensional conformal (3DCRT) or intensity-modulated radiotherapy (IMRT). Endpoints were local control (LC), regional control (RC), disease-free survival (DFS), cause-specific survival (CSS), and overall survival (OS), and toxicity. Results: After a median follow-up of 44 months (range 4134), the 5-year Kaplan-Meier estimates of LC, RC, DFS, CSS, and OS were 78%, 92%, 60%, 64%, and 48%, respectively. Grade 3 mucositis and dysphagia (feeding-tube dependency) were reported in 75% and 65%, respectively. The overall incidence of grade 2 and grade 3 late toxicities were 44% and 16%, respectively. Dysphagia and xerostomia were the most frequently reported late toxicity. Chemotherapy was significantly predictive for improved outcomes and increased toxicity. IMRT was significantly correlated with reduced toxicity. Conclusions: Compared to radiation alone, chemoradiotherapy significantly improved oncologic outcomes, but with significantly increased toxicity. Compared to 3DCRT, the introduction of IMRT resulted in a significant reduction of acute and late toxicity with slightly better, or at least comparable, outcomes. Despite the improvements achieved by the implementation of chemo-IMRT, different new strategies to further improve outcome and reduce toxicity need to be thoroughly investigated in prospective, preferably, randomized trials.

PurposeTo analyze whether local tumor control in advanced nasopharyngeal cancer (NPC) can be optimized by boosting the primary dose by endocavitary brachytherapy (EBT).Methods and MaterialsTo study the role of EBT, three data sets on NPC, that is, the “Vienna”, “Rotterdam,” and “Amsterdam” series, with a total number of 411 advanced NPC patients, were available. The Rotterdam series consisted of 72 patients (34 T1,2N+ and 38 T3,4N0,+) and were treated with neoadjuvant chemotherapy followed by external beam radiotherapy (dose 70/2 Gy). After 70/2 Gy, a boost was applied by EBT (in case of T1,2N+) or stereotactic radiation (in case of T3,4 tumors). The Amsterdam (Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute) series consisted of 76 patients (40 T1,2N+ and 36 T3,4N0,+) and were irradiated to a dose of 70/2 Gy with concomitant chemotherapy. No second boost by EBT was applied.ResultsIn the case of T1,2N+ tumors, the local relapse rate (LRR) was significantly smaller if a boost was applied, that is, 0% (0/34, EBT boost) vs. 14% (14/102, no EBT boost) (p=0.023). For the T3,4 tumors, an LRR of 10% (4/38, EBT or stereotactic radiation boost) vs. 15% (17/111, no boost) was found (p=0.463).ConclusionsIn the case of advanced NPC (T1,2N+ vs. T3,4N+,0), for early T-stages (T1,2N+), an EBT boost seems an excellent way to deliver highly conformal high doses of radiation to the nasopharynx, with high local control rates. For advanced T-stages (T3,4N+,0), the reduction in LRR (10% vs. 15%) was not significant (p=0.463).

Introducing hyperthermia in a clinical setting requires primarily the focused effort of a dedicated and highly motivated multi-disciplinary team that minimally consists of a medical/radiation oncologist, a physicist and a hyperthermia technician. In early days application of hyperthermia was mainly applied following an experience and expertise based procedure. The rapid evolutions of modern technology, like hyperthermia treatment planning and non-invasive thermometry enables new advanced methods for controlled delivery of hyperthermia. However, new advanced methods bring also new demands to the clinical staff involved. A very interesting problem is already the definition of the target for hyperthermia. A secondary challenge is to assure that what we predicted by treatment planning is also what we deliver to the patient. Solutions to these challenges are possible but come step by step. Some of these steps in the development of the HyperCollar system as used for hyperthermia treatment of head and neck tumors are reported.

The aesthetic result after brachytherapy, especially hypopigmentation, remains a significant problem. Given that brachytherapy may be carcinogenic, it is difficult to recommend this treatment in young patients. For these reasons, there is a need for alternatives to radiation.

Abstract Purpose. To investigate the robustness of single vocal cord intensity modulated radiation therapy (IMRT) treatment plans for set-up errors, respiration, and deformation. Material and methods. Four-dimensional computed tomography (4D-CT) scans of 10 early glottic carcinoma patients, previously treated with conventional techniques, were used in this simulation study. For each patient a pre-treatment 4D-CT was used for IMRT planning, generating a reference dose distribution. Prescribed PTV dose was 66 Gy. The impact of systematic set-up errors was simulated by applying shifts of ± 2 mm to the planning CT scans, followed by dose re-calculation with original beam segments, MUs, etc. Effects of respiration and deformation were determined utilizing extreme inhale and exhale CT scans, and repeat scans acquired after 22 Gy, 44 Gy, and 66 Gy, respectively. All doses were calculated using Monte Carlo dose simulations. Results. Considering all investigated geometrical perturbations, reductions in the clinical target volume (CTV) V95%, D98%, D2%, and generalized equivalent uniform dose (gEUD) were limited to 1.2 ± 2.2%, 2.4 ± 2.9%, 0.2 ± 1.8%, and 0.6 ± 1.1 Gy, respectively. The near minimum dose, D98%, was always higher than 89%, and gEUD always remained higher than 66 Gy. Planned contra-lateral (CL) vocal cord DMean, gEUD, and V40 Gy were 38.2 ± 6.0 Gy, 43.4 ± 5.6 Gy, and 42.7 ± 14.9%. With perturbations these values changed by −0.1 ± 4.3 Gy, 0.1 ± 4.0 Gy, and −1.0 ± 9.6%, respectively. Conclusions. On average, CTV dose reductions due to geometrical perturbations were very low, and sparing of the CL vocal cord was maintained. In a few observations (6 of 103 simulated situations), the near-minimum CTV-dose was around 90%, requiring attention in deciding on a future clinical protocol.

Purpose: To investigate interfraction setup variations of the primary tumor, elective nodes, and vertebrae in laryngeal cancer patients and to validate protocols for cone beam computed tomography (CBCT)-guided correction.Methods and Materials: For 30 patients, CBCT-measured displacements in fractionated treatments were used to investigate population setup errors and to simulate residual setup errors for the no action level (NAL) offline protocol, the extended NAL (eNAL) protocol, and daily CBCT acquisition with online analysis and repositioning.Results: Without corrections, 12 of 26 patients treated with radical radiation therapy would have experienced a gradual change (time trend) in primary tumor setup >= 4 mm in the cranio-caudal (CC) direction during the fractionated treatment (11/12 in caudal direction, maximum 11 mm). Due to these trends, correction of primary tumor displacements with NAL resulted in large residual CC errors (required margin 6.7 mm). With the weekly correction vector adjustments in eNAL, the trends could be largely compensated (CC margin 3.5 mm). Correlation between movements of the primary and nodal clinical target volumes (CTVs) in the CC direction was poor (r(2) = 0.15). Therefore, even with online setup corrections of the primary CTV, the required CC margin for the nodal CTV was as large as 6.8 mm. Also for the vertebrae, large time trends were observed for some patients. Because of poor CC correlation (r(2) = 0.19) between displacements of the primary CTV and the vertebrae, even with daily online repositioning of the vertebrae, the required CC margin around the primary CTV was 6.9 mm.Conclusions: Laryngeal cancer patients showed substantial interfraction setup variations, including large time trends, and poor CC correlation between primary tumor displacements and motion of the nodes and vertebrae (internal tumor motion). These trends and nonrigid anatomy variations have to be considered in the choice of setup verification protocol and planning target volume margins. eNAL could largely compensate time trends with minor prolongation of fraction time. (c) 2013 Elsevier Inc.

BACKGROUND AND PURPOSE:In Rotterdam, patient-specific hyperthermia (HT) treatment planning (HTP) is applied for all deep head and neck (H&N) HT treatments. In this paper we introduce VEDO (the Visualisation Tool for Electromagnetic Dosimetry and Optimisation), the software tool required, and demonstrate its value for HTP-guided online complaint-adaptive (CA) steering based on specific absorption rate (SAR) optimisation during a H&N HT treatment.MATERIALS AND METHODS:VEDO integrates CA steering, visualisation of the SAR patterns and mean tumour SAR (SAR(target)) optimisation in a single screen. The pre-calculated electromagnetic fields are loaded into VEDO. During treatment, VEDO shows the SAR pattern, overlaid on the patients' CT-scan, corresponding to the actually applied power settings and it can (re-)optimise the SAR pattern to minimise SAR at regions where the patient senses discomfort while maintaining a high SAR(target).RESULTS:The potential of the quantitative SAR steering approach using VEDO is demonstrated by analysis of the first treatment in which VEDO was used for two patients using the HYPERcollar. These cases show that VEDO allows response to power-related complaints of the patient and to quantify the change in absolute SAR: increasing either SAR(target) from 96 to 178 W/kg (case 1); or show that the first SAR distribution was already optimum (case 2).CONCLUSION:This analysis shows that VEDO facilitates a quantitative treatment strategy allowing standardised application of HT by technicians of different HT centres, which will potentially lead to improved treatment quality and the possibility of tracking the effectiveness of different treatment strategies.

To investigate the impact of up‐front neck dissection on the outcome of patients with node‐positive hypopharyngeal cancer (HPC) treated with (chemo)radiation.

Background and purposeTo investigate the impact of unilateral neck irradiation (UNI) of well-lateralized oropharyngeal cancer (OPC) on outcome and toxicity.Materials and methodsUnilateral neck IMRT was applied to 185 consecutive patients with well-lateralized OPC (restricted to tonsillar fossa, soft palate with at least 1cm from midline or lateral pharyngeal wall). Endpoints were regional control (RC), local control (LC), disease-free survival (DFS), overall survival (OS), and toxicity.ResultsSix regional failures were reported (3.2%); 2 were contralateral (1.1%). The 5-year Kaplan–Meier estimates of RC, LC, DFS, and OS were 96%, 91%, 84%, and 70%, respectively. Feeding tube was given to 11.3%. Chemotherapy was significantly predictive for toxicity. However, no patient was still feeding tube dependent 6weeks after treatment. Overall grade 3 late toxicity was 2.2%. Grade 3 xerostomia was reported in only 1 patient while no patient developed grade 3 dysphagia.ConclusionThis largest study on unilateral neck IMRT for well-lateralized OPC showed excellent outcome and favorable toxicity profile. Given the increasing incidence of OPC, especially among younger patients, and the favorable results reported in the current study and by other investigators, expanding the indications for UNI still needs to be further investigated in prospective, preferably, randomized trials.

In our randomized trial on hyperbaric oxygen (HBO), it was shown that HBO could reduce dysphagia and xerostomia, which are frequently encountered after (chemo-) radiotherapy (RT) and/or surgery for head and neck cancer (HNC). A risk model and nomogram are developed to select those patients who most likely will respond to HBO treatment. A total of 434 HNC patients treated from 2000 to 2008 were analyzed and filled out the EORTC QLQC-30 and H&N35 questionnaires. Age, gender, chemotherapy, T and N stages, site, radiotherapy technique, RT boost, surgery of the primary tumor and neck, bilateral RT, and dose were analyzed in a statistical model. The discriminative value of the model was evaluated based on receiver operating characteristics (ROC), the area under the curve (AUC), sensitivity, specificity, and proportion of correctly classified measures. Significant factors in predicting swallowing problems are age, follow-up duration, tumor site, chemotherapy, surgery of the primary tumor and neck, and dose. For dry mouth, the significant factors are age, gender, tumor site, N stage, chemotherapy, and bilateral irradiation. For dysphagia and xerostomia, the area under the ROC curve is 0.7034 and 0.7224, respectively, with a specificity of 89/77 %, sensitivity of 27/58 %, and a positive predictive value of 83/67 % for dysphagia and xerostomia, respectively. The developed predictive risk model could be used to select patients for costly hyperbaric oxygen treatment to prevent or reduce severe late side effects of HNC treatment. Our model serves as a guideline for the Department of Radiation Oncology to reduce costs by excluding patients not amenable to hyperbaric oxygen protocols. The nomogram presented is a useful tool for clinicians in assessing patient risks when deciding on follow-up strategies (e.g., hyperbaric oxygen treatment) after RT or surgery for HNC.

BackgroundThe purpose of this study was to reduce the incidence of radiation-induced toxicity in patients with early-stage oropharyngeal cancer, using highly conformal radiation techniques.MethodsBetween 2000 and 2011, 167 patients with T1-3N0-3 oropharyngeal cancer were treated with 46-Gy intensity-modulated radiation therapy (IMRT) followed by 22-Gy brachytherapy boost. In patients with node-positive disease, neck dissection was performed.ResultsThe 5-year Kaplan-Meier estimates of local control, regional control, disease-free survival (DFS), and overall survival (OS) were 94%, 97%, 84%, and 72%, respectively. Feeding tubes were required in 26% of the patients. Grade 2 late xerostomia and dysphagia were 11% and 8%, respectively. Chemotherapy, tumor subsite, and bilateral neck irradiation correlate significantly with toxicity. Quality of life (QOL) scores deteriorate during and shortly after treatment but returned in all scales to baseline scores within 6 to 12 months, with the exception of xerostomia.ConclusionBrachytherapy boost and neck dissection (in node-positive oropharyngeal cancer) after 46-Gy of IMRT resulted in excellent outcomes with low incidence of late toxicity and good QOL scores. (c) 2013 Wiley Periodicals, Inc. Head Neck 35: 1689-1697, 2012

The main goal of the current study was to comprehensively address the impact of chemoradiation and radiation techniques on toxicity, quality of life (QoL), and functional outcome.

OBJECTIVES:To report oncologic outcomes of patients with paranasal sinus cancer (PNSC) treated by surgery and radiotherapy or (chemo)radiation and to investigate the impact of improving the radiation technique on outcomes and toxicity. MATERIALS AND METHODS:Between 1999 and 2010, 82 consecutive patients with PNSC were treated by surgery and radiotherapy or by definitive (chemo)radiation. Three-dimensional conformal (3DCRT) or highly-conformal intensity-modulated RT (IMRT) was used. Endpoints were local control (LC), regional control (RC), disease-free (DFS), cause-specific (CSS), and overall survival (OS), late toxicity, and quality-of-life (QoL). RESULTS:After median follow-up of 51 months, the 5-year actuarial rates of LC, RC, DFS, CSS, and OS were 74%, 94%, 56%, 64%, and 54%, respectively. Grade ≥ 2 late toxicity at 5-years was 28%. High T-stage and perineural invasion were significantly associated with poor LC and RT-technique with late toxicity. Late toxicity was significantly lowered using IMRT, compared to 3DCRT (17% vs. 52%, p<0.0001). Visual preservation were significantly improved using IMRT (88% and 65%, respectively, p=0.01). LC-rate was also improved by IMRT (80% vs. 64%, respectively, p=0.2). QoL-scores deteriorated during and shortly after treatment but returned in almost all scales to baseline levels within 3-12 months. CONCLUSIONS:Surgery and radiotherapy or definitive (chemo)radiation resulted in good LC rates but with high rate of late side-effects. However, late toxicity and permanent visual impairment were significantly decreased by using highly-conformal IMRT without jeopardizing outcome. The improvements in the therapeutic ratio achieved by using IMRT would allow dose escalation of RT to further improve outcomes.

To prospectively assess the outcome and toxicity of frameless stereotactic body radiotherapy (SBRT) as a treatment option for boosting primary oropharyngeal cancers (OPC) in patients who not suitable for the standard brachytherapy boost (BTB).Between 2005 and 2010, 51 patients with Stage I to IV biopsy-proven OPC who were not suitable for BTB received boosts by means of SBRT (3 times 5.5 Gy, prescribed to the 80% isodose line), after 46 Gy of IMRT to the primary tumor and neck (when indicated). Endpoints of the study were local control (LC), disease-free survival (DFS), overall survival (OS), and acute and late toxicity.After a median follow-up of 18 months (range, 6-65 months), the 2-year actuarial rates of LC, DFS, and OS were 86%, 80%, and 82%, respectively, and the 3-year rates were 70%, 66%, and 54%, respectively. The treatment was well tolerated, as there were no treatment breaks and no Grade 4 or 5 toxicity reported, either acute or chronic. The overall 2-year cumulative incidence of Grade ≥2 late toxicity was 28%. Of the patients with 2 years with no evidence of disease (n = 20), only 1 patient was still feeding tube dependent and 2 patients had Grade 3 xerostomia.According to our knowledge, this study is the first report of patients with primary OPC who received boosts by means of SBRT. Patients with OPC who are not suitable for the standard BTB can safely and effectively receive boosts by SBRT. With this radiation technique, an excellent outcome was achieved. Furthermore, the SBRT boost did not have a negative impact regarding acute and late side effects.