Non-invasive stereotactic arrhythmia radiotherapy for ventricular tachycardia: results of the prospective STARNL-1 trial.

AIMS: Stereotactic arrhythmia radiotherapy (STAR) is suggested as potentially effective and safe treatment for patients with therapy-refractory ventricular tachycardia (VT). However, the current prospective knowledge base and experience with STAR is limited. In this study we aimed to prospectively evaluate the efficacy and safety of STAR. METHODS AND RESULTS: The StereoTactic Arrhythmia Radiotherapy in the Netherlands no.1 was a pre-post intervention study to prospectively evaluate efficacy and safety of STAR. In patients with therapy-refractory VT, the pro-arrhythmic region was treated with a 25 Gy single radiotherapy fraction. The main efficacy measure was a reduction in the number of treated VT-episodes by ≥50%, comparing the 12 months before and after treatment (or end of follow-up, excluding a 6-week blanking period). The study was deemed positive when ≥50% of patients would meet this criterion. Safety evaluation included left ventricular ejection fraction, pulmonary function, and adverse events. Six male patients with an ischaemic cardiomyopathy were enrolled, and median age was 73 years (range 54-83). Median left ventricular ejection fraction was 38% (range 24-52). The median planning target volume was 187 mL (range 93-372). Four (67%) patients completed the 12-month follow-up, and two patients died (not STAR related) during follow-up. The main efficacy measure of ≥50% reduction in treated VT-episodes at the end of follow-up was achieved in four patients (67%). The median number of treated VT-episodes was reduced by 87%. No reduction in left ventricular ejection fraction or pulmonary function was observed. No treatment related serious adverse events occurred. CONCLUSIONS: STAR resulted in a ≥ 50% reduction in treated VT-episodes in 4/6 (67%) patients. No reduction in cardiac and pulmonary function nor treatment-related serious adverse events were observed during follow-up. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register-NL7510.

MR-based follow-up after brachytherapy and proton beam therapy in uveal melanoma.

PURPOSE: MRI is increasingly used in the diagnosis and therapy planning of uveal melanoma (UM). In this prospective cohort study, we assessed the radiological characteristics, in terms of anatomical and functional imaging, of UM after ruthenium-106 plaque brachytherapy or proton beam therapy (PBT) and compared them to conventional ultrasound. METHODS: Twenty-six UM patients were evaluated before and 3, 6 and 12 months after brachytherapy (n = 13) or PBT (n = 13). Tumour prominences were compared between ultrasound and MRI. On diffusion-weighted imaging, the apparent diffusion value (ADC), and on perfusion-weighted imaging (PWI), the time-intensity curves (TIC), relative peak intensity and outflow percentages were determined. Values were compared between treatments and with baseline. RESULTS: Pre-treatment prominences were comparable between MRI and ultrasound (mean absolute difference 0.51 mm, p = 0.46), but larger differences were observed post-treatment (e.g. 3 months: 0.9 mm (p = 0.02)). Pre-treatment PWI metrics were comparable between treatment groups. After treatment, brachytherapy patients showed favourable changes on PWI (e.g. 67% outflow reduction at 3 months, p < 0.01). After PBT, significant perfusion changes were observed at a later timepoint (e.g. 38% outflow reduction at 6 months, p = 0.01). No consistent ADC changes were observed after either treatment, e.g. a 0.11 × 10-3mm2/s increase 12 months after treatment (p = 0.15). CONCLUSION: MR-based follow-up is valuable for PBT-treated patients as favourable perfusion changes, including a reduction in outflow, can be detected before a reduction in size is apparent on ultrasound. For brachytherapy, a follow-up MRI is of less value as already 3 months post-treatment a significant size reduction can be measured on ultrasound.

Reduced inter-observer and intra-observer delineation variation in esophageal cancer radiotherapy by use of fiducial markers.

Objective: Delineation variation of esophageal tumors remains a large source of geometric uncertainty. In the present study, we investigated the inter- and intra-observer variation in esophageal gross tumor volume (GTV) delineation and the impact of endoscopically implanted fiducial markers on these variations. Material/Methods: Ten esophageal cancer patients with at least two markers endoscopically implanted at the cranial and caudal tumor borders and visible on the planning computed tomography (pCT) were included in this study. Five dedicated gastrointestinal radiation oncologists independently delineated GTVs on the pCT without markers and with markers. The GTV was first delineated on pCTs where markers were digitally removed and next on the original pCT with markers. Both delineation series were executed twice to determine intra-observer variation. For both the inter- and intra-observer analyses, the generalized conformity index (CIgen), and the standard deviation (SD) of the distances between delineated surfaces (i.e., overall, longitudinal, and radial SDs) were calculated. Linear mixed-effect models were used to compare the without and with markers series (α = 0.05). Results: Both the inter- and intra-observer CIgen were significantly larger in the series with markers than in the series without markers (p < .001). For the series without markers vs. with markers, the inter-observer overall SD, longitudinal SD, and radial SD was 0.63 cm vs. 0.22 cm, 1.44 cm vs. 0.42 cm, and 0.26 cm vs. 0.18 cm, respectively (p < .05); moreover, the intra-observer overall SD, longitudinal SD, and radial SD was 0.45 cm vs. 0.26 cm, 1.10 cm vs. 0.41 cm, and 0.22 cm vs. 0.15 cm, respectively (p < .05). Conclusion: The presence of markers at the cranial and caudal tumor borders significantly reduced both inter- and intra-observer GTV delineation variation, especially in the longitudinal direction. Our results endorse the use of markers in GTV delineation for esophageal cancer patients.

Temperature and thermal dose during radiotherapy and hyperthermia for recurrent breast cancer are related to clinical outcome and thermal toxicity: a systematic review.

Objective: Hyperthermia therapy (HT), heating tumors to 40-45 °C, is a known radiotherapy (RT) and chemotherapy sensitizer. The additional benefit of HT to RT for recurrent breast cancer has been proven in multiple randomized trials. However, published outcome after RT + HT varies widely. We performed a systematic review to investigate whether there is a relationship between achieved HT dose and clinical outcome and thermal toxicity for patients with recurrent breast cancer treated with RT + HT. Method: Four databases, EMBASE, PubMed, Cochrane library and clinicaltrials.gov, were searched with the terms breast, radiotherapy, hyperthermia therapy and their synonyms. Final search was performed on 3 April 2019. Twenty-two articles were included in the systematic review, reporting on 2330 patients with breast cancer treated with RT + HT. Results: Thirty-two HT parameters were tested for a relationship with clinical outcome. In studies reporting a relationship, the relationship was significant for complete response in 10/15 studies, in 10/13 studies for duration of local control, in 2/2 studies for overall survival and in 7/11 studies for thermal toxicity. Patients who received high thermal dose had on average 34% (range 27%-53%) more complete responses than patients who received low thermal dose. Patients who achieved higher HT parameters had increased odds/probability on improved clinical outcome and on thermal toxicity. Conclusion: Temperature and thermal dose during HT had significant influence on complete response, duration of local control, overall survival and thermal toxicity of patients with recurrent breast cancer treated with RT + HT. Higher temperature and thermal dose improved outcome, while higher maximum temperature increased incidence of thermal toxicity.

The effectiveness of 4DCT in children and adults: A pooled analysis.

BACKGROUND: While four-dimensional computed tomography (4DCT) is extensively used in adults, reluctance remains to use 4DCT in children. Day-to-day (interfractional) variability and irregular respiration (intrafractional variability) have shown to be limiting factors of 4DCT effectiveness in adults. In order to evaluate 4DCT applicability in children, the purpose of this study is to quantify inter- and intrafractional variability of respiratory motion in children and adults. The pooled analysis enables a solid comparison to reveal if 4DCT application for planning purposes in children could be valid. METHODS/MATERIALS: We retrospectively included 90 patients (45 children and 45 adults), for whom the diaphragm was visible on abdominal/thoracic free-breathing cone beam CTs (480 pediatric, 524 adult CBCTs). For each CBCT, the cranial-caudal position of end-exhale and end-inhale positions of the right diaphragm dome were manually selected in the projection images. The difference in position between both phases defines the amplitude. Cycle time equaled inspiratory plus expiratory time. We analyzed the variability of the inter- and intrafractional respiratory-induced diaphragm motion. RESULTS: Ranges of respiratory motion characteristics were large in both children and adults (amplitude: 4-17 vs 5-24 mm, cycle time 2.1-3.9 vs 2.7-6.5 s). The mean amplitude was slightly smaller in children than in adults (10.7 vs 12.3 mm; P = 0.06). Interfractional amplitude variability was statistically significantly smaller in children than in adults (1.4 vs 2.2 mm; P = 0.00). Mean cycle time was statistically significantly shorter in children (2.9 vs 3.6 s; P = 0.00). Additionally, intrafractional cycle time variability was statistically significantly smaller in children (0.5 vs 0.7 s; P = 0.00). CONCLUSIONS: Overall variability is smaller in children than in adults, indicating that respiratory motion is more regular in children than in adults. This implies that a single pretreatment 4DCT could be a good representation of daily respiratory motion in children and will be at least equally beneficial for planning purposes as it is in adults.

Target tailoring and proton beam therapy to reduce small bowel dose in cervical cancer radiotherapy : A comparison of benefits.

PURPOSE: The aim of the study was to investigate the potential clinical benefit from both target tailoring by excluding the tumour-free proximal part of the uterus during image-guided adaptive radiotherapy (IGART) and improved dose conformity based on intensity-modulated proton therapy (IMPT). METHODS: The study included planning CTs from 11 previously treated patients with cervical cancer with a >4-cm tumour-free part of the proximal uterus on diagnostic magnetic resonance imaging (MRI). IGART and robustly optimised IMPT plans were generated for both conventional target volumes and for MRI-based target tailoring (where the non-invaded proximal part of the uterus was excluded), yielding four treatment plans per patient. For each plan, the V15Gy, V30Gy, V45Gy and Dmean for bladder, sigmoid, rectum and bowel bag were compared, and the normal tissue complication probability (NTCP) for ≥grade 2 acute small bowel toxicity was calculated. RESULTS: Both IMPT and MRI-based target tailoring resulted in significant reductions in V15Gy, V30Gy, V45Gy and Dmean for bladder and small bowel. IMPT reduced the NTCP for small bowel toxicity from 25% to 18%; this was further reduced to 9% when combined with MRI-based target tailoring. In four of the 11 patients (36%), NTCP reductions of >10% were estimated by IMPT, and in six of the 11 patients (55%) when combined with MRI-based target tailoring. This >10% NTCP reduction was expected if the V45Gy for bowel bag was >275 cm3 and >200 cm3, respectively, during standard IGART alone. CONCLUSIONS: In patients with cervical cancer, both proton therapy and MRI-based target tailoring lead to a significant reduction in the dose to surrounding organs at risk and small bowel toxicity.

Reirradiation + hyperthermia for recurrent breast cancer en cuirasse.

BACKGROUND AND PURPOSE: Patients with irresectable locoregional recurrent breast cancer en cuirasse (BCEC) do not have effective curative treatment options. Hyperthermia, the elevation of tumor temperature to 40-45 °C, is a well-established radio- and chemotherapy sensitizer. A total of 196 patients were treated with reirradiation and hyperthermia (reRT+HT) at two Dutch institutes from 1982-2005. The palliative effect was evaluated in terms of clinical outcome and toxicity. PATIENTS AND METHODS: All patients received previous irradiation to a median dose of 50 Gy. In all, 75% of patients received 1-6 treatment modalities for previous tumor recurrences. ReRT consisted of 8 × 4 Gy given twice a week or 12 × 3 Gy given four times a week. Superficial hyperthermia was added once or twice a week. Tumor area comprised ≥½ of the ipsilateral chest wall. RESULTS: Overall clinical response rate was 72% (complete response [CR] 30%, partial response [PR] 42%, stable disease [SD] 22%, progressive disease [PD] 6%). The local progression-free rate at 1 year was 24%. Median survival was 6.9 months. Forty-three percent of our patients with CR, PR, SD after treatment remained infield progression-free until death or last follow-up. Acute ≥grade 3 toxicity occurred in 33% of patients, while late ≥grade 3 toxicity was recorded in 14% of patients. Tumor ulceration prior to treatment had a negative impact on both clinical outcome and toxicity. CONCLUSION: ReRT+HT provides sustainable palliative tumor control, despite refractory, extensive tumor growth. Compared to currently available systemic treatment options, reRT+HT is more effective with less toxicity.

Analysis of clinical data to determine the minimum number of sensors required for adequate skin temperature monitoring of superficial hyperthermia treatments.

PURPOSE: Tumor response and treatment toxicity are related to minimum and maximum tissue temperatures during hyperthermia, respectively. Using a large set of clinical data, we analyzed the number of sensors required to adequately monitor skin temperature during superficial hyperthermia treatment of breast cancer patients. METHODS: Hyperthermia treatments monitored with >60 stationary temperature sensors were selected from a database of patients with recurrent breast cancer treated with re-irradiation (23 × 2 Gy) and hyperthermia using single 434 MHz applicators (effective field size 351-396 cm2). Reduced temperature monitoring schemes involved randomly selected subsets of stationary skin sensors, and another subset simulating continuous thermal mapping of the skin. Temperature differences (ΔT) between subsets and complete sets of sensors were evaluated in terms of overall minimum (Tmin) and maximum (Tmax) temperature, as well as T90 and T10. RESULTS: Eighty patients were included yielding a total of 400 hyperthermia sessions. Median ΔT was <0.01 °C for T90, its 95% confidence interval (95%CI) decreased to ≤0.5 °C when >50 sensors were used. Subsets of <10 sensors result in underestimation of Tmax up to -2.1 °C (ΔT 95%CI), which decreased to -0.5 °C when >50 sensors were used. Thermal profiles (8-21 probes) yielded a median ΔT < 0.01 °C for T90 and Tmax, with a 95%CI of -0.2 °C and 0.4 °C, respectively. The detection rate of Tmax ≥43 °C is ≥85% while using >50 stationary sensors or thermal profiles. CONCLUSIONS: Adequate coverage of the skin temperature distribution during superficial hyperthermia treatment requires the use of >50 stationary sensors per 400 cm2 applicator. Thermal mapping is a valid alternative.

Clinical validation of a novel thermophysical bladder model designed to improve the accuracy of hyperthermia treatment planning in the pelvic region.

PURPOSE: Hyperthermia treatment planning for deep locoregional hyperthermia treatment may assist in phase and amplitude steering to optimize the temperature distribution. This study aims to incorporate a physically correct description of bladder properties in treatment planning, notably the presence of convection and absence of perfusion within the bladder lumen, and to assess accuracy and clinical implications for non muscle invasive bladder cancer patients treated with locoregional hyperthermia. METHODS: We implemented a convective thermophysical fluid model based on the Boussinesq approximation to the Navier-Stokes equations using the (finite element) OpenFOAM toolkit. A clinician delineated the bladder on CT scans obtained from 14 bladder cancer patients. We performed (1) conventional treatment planning with a perfused muscle-like solid bladder, (2) with bladder content properties without and (3) with flow dynamics. Finally, we compared temperature distributions predicted by the three models with temperature measurements obtained during treatment. RESULTS: Much higher and more uniform bladder temperatures are predicted with physically accurate fluid modeling compared to previously employed muscle-like models. The differences reflect the homogenizing effect of convection, and the absence of perfusion. Median steady state temperatures simulated with the novel convective model (3) deviated on average -0.6 °C (-12%) from values measured during treatment, compared to -3.7 °C (-71%) and +1.5 °C (+29%) deviation for the muscle-like (1) and static (2) models, respectively. The Grashof number was 3.2 ± 1.5 × 105 (mean ± SD). CONCLUSIONS: Incorporating fluid modeling in hyperthermia treatment planning yields significantly improved predictions of the temperature distribution in the bladder lumen during hyperthermia treatment.

Dosimetric advantages of a clinical daily adaptive plan selection strategy compared with a non-adaptive strategy in cervical cancer radiation therapy.

BACKGROUND: Radiation therapy (RT) using a daily plan selection adaptive strategy can be applied to account for interfraction organ motion while limiting organ at risk dose. The aim of this study was to quantify the dosimetric consequences of daily plan selection compared with non-adaptive RT in cervical cancer. MATERIAL AND METHODS: Ten consecutive patients who received pelvic irradiation, planning CTs (full and empty bladder), weekly post-fraction CTs and pre-fraction CBCTs were included. Non-adaptive plans were generated based on the PTV defined using the full bladder planning CT. For the adaptive strategy, multiple PTVs were created based on both planning CTs by ITVs of the primary CTVs (i.e., GTV, cervix, corpus-uterus and upper part of the vagina) and corresponding library plans were generated. Daily CBCTs were rigidly aligned to the full bladder planning CT for plan selection. For daily plan recalculation, selected CTs based on initial similarity were deformably registered to CBCTs. Differences in daily target coverage (D98% > 95%) and in V0.5Gy, V1.5Gy, V2Gy, D50% and D2% for rectum, bladder and bowel were assessed. RESULTS: Non-adaptive RT showed inadequate primary CTV coverage in 17% of the daily fractions. Plan selection compensated for anatomical changes and improved primary CTV coverage significantly (p < 0.01) to 98%. Compared with non-adaptive RT, plan selection decreased the fraction dose to rectum and bowel indicated by significant (p < 0.01) improvements for daily V0.5Gy, V1.5Gy, V2Gy, D50% and D2%. However, daily plan selection significantly increased the bladder V1.5Gy, V2Gy, D50% and D2%. CONCLUSIONS: In cervical cancer RT, a non-adaptive strategy led to inadequate target coverage for individual patients. Daily plan selection corrected for day-to-day anatomical variations and resulted in adequate target coverage in all fractions. The dose to bowel and rectum was decreased significantly when applying adaptive RT.

Interfractional renal and diaphragmatic position variation during radiotherapy in children and adults: is there a difference?

BACKGROUND: Pediatric safety margins are generally based on data from adult studies; however, adult-based margins might be too large for children. The aim of this study was to quantify and compare interfractional organ position variation in children and adults. MATERIAL AND METHODS: For 35 children and 35 adults treated with thoracic/abdominal irradiation, 850 (range 5-30 per patient) retrospectively collected cone beam CT images were registered to the reference CT that was used for radiation treatment planning purposes. Renal position variation was assessed in three orthogonal directions and summarized as 3D vector lengths. Diaphragmatic position variation was assessed in the cranio-caudal (CC) direction only. We calculated means and SDs to estimate group systematic (Σ) and random errors (σ) of organ position variation. Finally, we investigated possible correlations between organ position variation and patients' height. RESULTS: Interfractional organ position variation was different in children and adults. Median 3D right and left kidney vector lengths were significantly smaller in children than in adults (2.8, 2.9 mm vs. 5.6, 5.2 mm, respectively; p < .05). Generally, the pediatric Σ and σ were significantly smaller than in adults (p < .007). Overall and within both subgroups, organ position variation and patients' height were only negligibly correlated. CONCLUSIONS: Interfractional renal and diaphragmatic position variation in children is smaller than in adults indicating that pediatric margins should be defined differently from adult margins. Underlying mechanisms and other components of geometrical uncertainties need further investigation to explain differences and to appropriately define pediatric safety margins.

Addition of MRI for CT-based pancreatic tumor delineation: a feasibility study.

PURPOSE: To assess the effect of additional magnetic resonance imaging (MRI) alongside the planning computed tomography (CT) scan on target volume delineation in pancreatic cancer patients. MATERIAL AND METHODS: Eight observers (radiation oncologists) from six institutions delineated the gross tumor volume (GTV) on 3DCT, and internal GTV (iGTV) on 4DCT of four pancreatic cancer patients, while MRI was available in a second window (CT + MRI). Variations in volume, generalized conformity index (CIgen), and overall observer variation, expressed as standard deviation (SD) of the distances between delineated surfaces, were analyzed. CIgen is a measure of overlap of the delineated iGTVs (1 = full overlap, 0 = no overlap). Results were compared with those from an earlier study that assessed the interobserver variation by the same observers on the same patients on CT without MRI (CT-only). RESULTS: The maximum ratios between delineated volumes within a patient were 6.1 and 22.4 for the GTV (3DCT) and iGTV (4DCT), respectively. The average (root-mean-square) overall observer variations were SD = 0.41 cm (GTV) and SD = 0.73 cm (iGTV). The mean CIgen was 0.36 for GTV and 0.37 for iGTV. When compared to the iGTV delineated on CT-only, the mean volumes of the iGTV on CT + MRI were significantly smaller (32%, Wilcoxon signed-rank, p < .0005). The median volumes of the iGTV on CT + MRI were included for 97% and 92% in the median volumes of the iGTV on CT. Furthermore, CT + MRI showed smaller overall observer variations (root-mean-square SD = 0.59 cm) in six out of eight delineated structures compared to CT-only (root-mean-square SD = 0.72 cm). However, large local observer variations remained close to biliary stents and pathological lymph nodes, indicating issues with instructions and instruction compliance. CONCLUSIONS: The availability of MRI images during target delineation of pancreatic cancer on 3DCT and 4DCT resulted in smaller target volumes and reduced the interobserver variation in six out of eight delineated structures.

A flexible 70 MHz phase-controlled double waveguide system for hyperthermia treatment of superficial tumours with deep infiltration.

PURPOSE: Superficial tumours with deep infiltration in the upper 15 cm of the trunk cannot be treated adequately with existing hyperthermia systems. The aim of this study was to develop, characterise and evaluate a new flexible two-channel hyperthermia system (AMC-2) for tumours in this region. MATERIALS AND METHODS: The two-channel AMC-2 system has two horizontally revolving and height adjustable 70 MHz waveguides. Three different interchangeable antennas with sizes 20 × 34, 15 × 34 and 8.5 × 34 cm were developed and their electrical properties were determined. The performance of the AMC-2 system was tested by measurements of the electric field distribution in a saline water filled elliptical phantom, using an electric field vector probe. Clinical feasibility was demonstrated by treatment of a melanoma in the axillary region. RESULTS: Phantom measurements showed a good performance for all waveguides. The large reflection of the smallest antenna has to be compensated by increased forward power. Field patterns become asymmetrical when using smaller top antennas, necessitating phase corrections. The clinical application showed that tumours deeper than 4 cm can be heated adequately. A median tumour temperature of 42 °C can be reached up to 12 cm depth with adequate antenna positioning and phase-amplitude steering. CONCLUSIONS: This 70 MHz AMC-2 waveguide system is a useful addition to existing loco-regional hyperthermia equipment as it is capable of heating axillary tumours and other tumours deeper than 4 cm.

Dosimetric advantages of proton therapy compared with photon therapy using an adaptive strategy in cervical cancer.

Background Image-guided adaptive proton therapy (IGAPT) can potentially be applied to take into account interfraction motion while limiting organ at risk (OAR) dose in cervical cancer radiation therapy (RT). In this study, the potential dosimetric advantages of IGAPT compared with photon-based image-guided adaptive RT (IGART) were investigated. Material and methods For 13 cervical cancer patients, full and empty bladder planning computed tomography (CT) images and weekly CTs were acquired. Based on both primary clinical target volumes (pCTVs) [i.e. gross tumor volume (GTV), cervix, corpus-uterus and upper part of the vagina] on planning CTs, the pretreatment observed full range primary internal target volume (pITV) was interpolated to derive pITV subranges. Given corresponding ITVs (i.e. pITVs including lymph nodes), patient-specific photon and proton plan libraries were generated. Using all weekly CTs, IGART and IGAPT treatments were simulated by selecting library plans and recalculating the dose. For each recalculated IGART and IGAPT fraction, CTV (i.e. pCTV including lymph nodes) coverage was assessed and differences in fractionated substitutes of dose-volume histogram (DVH) parameters (V15Gy, V30Gy, V45Gy, Dmean, D2cc) for bladder, bowel and rectum were tested for significance (Wilcoxon signed-rank test). Also, differences in toxicity-related DVH parameters (rectum V30Gy, bowel V45Gy) were approximated based on accumulated dose distributions. Results In 92% (96%) of all recalculated IGAPT (IGART) fractions adequate CTV coverage (V95% >98%) was obtained. All dose parameters for bladder, bowel and rectum, except the fractionated substitute for rectum V45Gy, were improved using IGAPT. Also, IGAPT reduced the mean dose to bowel, bladder and rectum significantly (p < 0.01). In addition, an average decrease of rectum V30Gy and bowel V45Gy indicated reductions in toxicity probabilities when using IGAPT. Conclusion This study demonstrates the feasibility of IGAPT in cervical cancer using a plan-library based plan-of-the-day approach. Compared to photon-based IGART, IGAPT maintains target coverage while significant dose reductions for the bladder, bowel and rectum can be achieved.

Quantification of delineation errors of the gross tumor volume on magnetic resonance imaging in uterine cervical cancer using pathology data and deformation correction.

BACKGROUND: To safely optimize target volumes using magnetic resonance imaging (MRI) for uterine cervical cancer radiation therapy, MRI findings need to be validated. The aim of this study was to correlate pre-operatively acquired MRI and surgical specimen imaging for uterine cervical cancer patients using deformable image registration and quantify gross tumor volume (GTV) delineation discrepancies. MATERIAL AND METHODS: For 16 retrospectively selected early-stage uterine cervical cancer patients, the cervix-uterus structure, uterine cavity and the GTV were delineated on 2D pathology photos after macroscopic intersection and corresponding pre-operatively acquired T2-weighted 2D sagittal MR images. Segmentations of pathology photos and MR images were simultaneously registered using a three-step multi-image registration strategy. The registration outcome was evaluated by the Dice similarity coefficient (DSC) and the surface distance error (SDE). In addition, GTV expansions within the cervix-uterus structure needed to obtain 95% GTV coverage were determined. RESULTS: After three-step multi-image registration, the median DSC and median SDE were 0.98 and 0.4 mm (cervix-uterus) and 0.90 and 0.4 mm (uterine cavity), respectively. The average SDE around the GTV was 0.7 mm (range, 0.1 mm - 2.6 mm). An underestimation of MRI-based GTV delineations was found when no margin was applied, indicated by a mean GTV coverage of 61%. To obtain 95% GTV coverage for 90% of the patients, a minimum 12.0 mm margin around MRI-based GTVs was needed. CONCLUSION: The presented three-step multi-image registration strategy was suitable and accurate to correlate MRI and pathology data for uterine cervical cancer patients. To cover the pathology-based GTV, a margin of at least 12.0 mm around GTV delineations on T2-weighted MRI is needed.

Post-operative radiotherapy in patients with early stage cervical cancer.

OBJECTIVE: The aim of this study is to investigate the impact of treatment policy changes in cervical cancer patients treated with adjuvant (chemo) radiotherapy. METHODS: Between 1970 and 2007, 292 patients received adjuvant radiotherapy after a radical hysterectomy with pelvic lymphadenectomy for early stage cervical carcinoma. All patients received pelvic radiotherapy (40 Gy-46 Gy in 1.8 Gy-2 Gy/fraction). Vaginal vault brachytherapy boost (10-14 Gy) was increasingly used for patients with high-risk factors, and since 1993 systematically applied in patients with at least 2 of the 3 risk factors: adenocarcinoma, nodal involvement and parametrial invasion. Cisplatin-based chemotherapy was introduced in this group of patients from 2000. RESULTS: The 5-year cumulative risk of local recurrence (CRLR) was 13% (95%CI 9%-17%), resulting in an overall 5-year survival (OS) of 78% (95%CI 83%-73%). Since 1970, the OR for the 5-year locoregional recurrence risk (LRR) decreased from 2.5 to 1.15 (linear-OR=-0.02/year). The OR for the 5-year mortality risk reduced from 2.2 in 1970 to 1.0 in 2007 (linear-OR=-0.03/year). The largest risk reductions were observed before 1990 with a minor rise after 2002. The risk of severe late toxicity reduced from 1.8% to 1.5% (linear-OR=-0.03/year). The addition of concomitant adjuvant chemotherapy since 2000 may have benefited a subgroup of patients with squamous cell carcinoma, but not the patients with adenocarcinoma, and after introduction of chemotherapy the risk of severe late toxicity tripled from 2% to 7%. CONCLUSION: Since 1970, tumour recurrence risk and mortality have decreased, as radiation dose increased. The potential benefit of concomitant adjuvant chemotherapy could not be demonstrated in this nonrandomized study.

A new grading system for ototoxicity in adults.

OBJECTIVE: This study aimed to propose an ototoxicity grading system sensitive to the effect of ototoxicity on specific daily life situations like speech intelligibility and the perception of ultra-high sounds and to test its feasibility compared to current criteria. METHODS: Pure tone averages (PTAs) for speech perception (1-2-4 kHz) and ultra-high frequencies (8-10-12.5 kHz) were incorporated. Threshold shift and hearing level posttreatment were taken into account. Criteria were tested on head and neck cancer patients treated with (chemo-)radiotherapy ([C]RT) and compared with the Common Terminology Criteria for Adverse Events version 4 (CTCAEv4) and the American Speech-Language-Hearing Association criteria (ASHA). RESULTS: Grades 1 and 2 were based on threshold shifts from baseline (in dB) and subjective complaints. Grades 3 and 4 were defined as treatment-induced hearing loss of ≥ 35 dB at PTA 1-2-4 kHz and ≥ 70 dB at PTA 1-2-4 kHz, respectively. In high-dose cisplatin CRT incidences by the new criteria, CTCAEv4 and ASHA were comparable (78%-88%). In RT and low-dose cisplatin CRT, incidences were 36% to 39% in the new criteria versus 22% to 53% in CTCAEv4 and ASHA. CONCLUSION: The new criteria show an increased sensitivity to ototoxicity compared to CTCAEv4 and ASHA and provide insight into the effect of hearing loss on certain daily life situations. The new grading system seems feasible for clinic and research purposes.

Two-year results of a prospective preventive swallowing rehabilitation trial in patients treated with chemoradiation for advanced head and neck cancer.

The objective of the study was the assessment of the results of a prospective clinical trial with two preventive swallowing rehabilitation programs on the long-term side effects of chemoradiotherapy (CCRT) in advanced head and neck cancer patients. The study cohort consisted of 29 patients, randomized in two exercise groups: a standard (S) group receiving routine swallowing exercises (N = 14), and an experimental (E) group receiving swallowing exercises based on the TheraBite® Jaw Motion Rehabilitation System™ (N = 15). Assessment of functional changes was carried out with multidimensional outcome measures (e.g., videofluoroscopy, study-specific questionnaires) at four time points (pre-treatment, at 10 weeks, 1 year, and 2 years post-treatment). Overall, in the first year post-treatment many initial tumor- and treatment-related problems diminished significantly, except xerostomia (59%). The only additional improvement at 2 years was that the overall weight significantly further increased (p = 0.000), however, without regaining baseline value. In the subgroup analysis according to exercise group, this difference was significant in the E-group only (p = 0.002). The same was the case for the subgroup analysis according to site of disease, with a significant weight gain in the 'below the hyoid bone' group only. This study shows that the overall functional problems at 1 and 2 years post-CCRT are limited. Both rehabilitation programs produce similar results, with a slight but significant benefit for the E-group in weight gain at 2 years, as also seen in the 'below the hyoid bone' group. Both rehabilitation programs applied are feasible and show good compliance despite the burdensome CCRT.

Development of a software for quantitative evaluation radiotherapy target and organ-at-risk segmentation comparison.

Modern radiotherapy requires accurate region of interest (ROI) inputs for plan optimization and delivery. Target delineation, however, remains operator-dependent and potentially serves as a major source of treatment delivery error. In order to optimize this critical, yet observer-driven process, a flexible web-based platform for individual and cooperative target delineation analysis and instruction was developed in order to meet the following unmet needs: (1) an open-source/open-access platform for automated/semiautomated quantitative interobserver and intraobserver ROI analysis and comparison, (2) a real-time interface for radiation oncology trainee online self-education in ROI definition, and (3) a source for pilot data to develop and validate quality metrics for institutional and cooperative group quality assurance efforts. The resultant software, Target Contour Testing/Instructional Computer Software (TaCTICS), developed using Ruby on Rails, has since been implemented and proven flexible, feasible, and useful in several distinct analytical and research applications.

Quantitative Perfusion-Weighted Magnetic Resonance Imaging in Uveal Melanoma.

Purpose: Perfusion-weighted imaging (PWI; magnetic resonance imaging [MRI]) has been shown to provide valuable biological tumor information in uveal melanoma (UM). Clinically used semiquantitative methods do not account for tumor pigmentation and eye movement. We hypothesize that a quantitative PWI method that incorporates these, provides a more accurate description of tumor perfusion than the current clinical method. The aim of this study was to test this in patients with UM before and after radiotherapy. Methods: Perfusion-weighted 3T MRIs were retrospectively analyzed in 47 patients with UM before and after radiotherapy. Tofts pharmacokinetic modeling was performed to determine vascular permeability (Ktrans), extracellular extravascular space (ve), and reflux rate (kep). These were compared with semiquantitative clinical parameters including peak intensity and outflow percentage. Results: The effect of tumor pigmentation on peak intensity and outflow percentage was statistically significant (P < 0.01) and relative peak intensity was significantly different between melanotic and amelanotic tumors (1.5 vs. 1.9, P < 0.01). Before radiotherapy, median tumor Ktrans was 0.63 min-1 (range = 0.06-1.42 min-1), median ve was 0.23 (range = 0.09-0.63), and median kep was 2.3 min-1 (range = 0.6-5.0 min-1). After radiotherapy, 85% showed a decrease in Ktrans and kep (P < 0.01). Changes in tumor pigmentation before and after radiotherapy were small and not significant (median increase in T1 of 33 ms, P = 0.55). Conclusions: Quantitative PWI parameters decreased significantly after radiotherapy and can therefore can serve as an early biomarker for treatment response assessment. However, due to the nonsignificant changes in tumor pigmentation before and after radiotherapy, the current semiquantitative method appears to be sufficiently sensitive for detection of changes in tumor perfusion.