Radiotherapy & Oncology - Articles in Press

[18F]-FDG uptake dose–response correlates with radiation pneumonitis in lung cancer patients - Corrected Proof

2012-05-11

Abstract: Purpose: To quantify the post-radiotherapy 2-[18F]-fluoro-2-deoxyglucose (FDG) pulmonary uptake dose–response in lung cancer patients and determine its relationship with radiation pneumonitis symptoms.Methods and materials: The data from 24 patients treated for lung cancer with thoracic radiotherapy who received restaging PET/CT imaging between 4 and 12weeks after radiotherapy completion were evaluated. Their radiation dose distribution was registered with the post-treatment restaging PET/CT. Using histogram analysis, the voxel average FDG-PET uptake vs. radiation dose was obtained for each case and linear regression was performed. The resulting slope, the pulmonary metabolic radiation response (PMRR), was used to characterize the dose–response. The Common Toxicity Criteria version 3 was used to score clinical pulmonary toxicity symptoms. Receiver operating characteristic (ROC) curves were used to determine the level of FDG uptake vs. dose, MLD, V5, V10, V20, and V30 that can best predict symptomatic and asymptomatic patients.Results: The median time between radiotherapy completion and FDG-PET imaging was 59days (range, 26–70days). The median of the mean SUV from lung that received 0–5Gy was 1.00 (range, 0.37–1.48), 5–10Gy was 1.01 (range, 0.37–1.77), 10–20Gy was 1.04 (0.42–1.53), and >20Gy was 1.29 (range, 0.41–8.01). Using the dose range of 0Gy to the maximum dose minus 10Gy, hierarchical linear regression model of the radiation dose and normalized FDG uptake per case found an adequate fit with the linear model. Pneumonitis scores were: Grade 0 for 13, Grade 1 for 5, Grade 2 for 6, and Grade 3, 4 or 5 for none. Using a PMRR threshold of 0.017 yields an associated true positive rate of 0.67 and false positive rate of 0.15 with average error of 30%. A V5 threshold of 57.6 gives an associated true positive rate of 0.67 and false positive rate of 0.05 with a 20% average error.Conclusion: The metabolic radiation pneumonitis dose–response was evaluated from post-treatment FDG-PET/CT imaging. Statistical modeling found a linear relationship. The FDG uptake dose–response and V5 correlated with symptomatic radiation pneumonitis.

Out-of-field dose studies with an anthropomorphic phantom: Comparison of X-rays and particle therapy treatments - Corrected Proof

2012-05-11

Abstract: Background and purpose: Characterization of the out-of-field dose profile following irradiation of the target with a 3D treatment plan delivered with modern techniques.Methods: An anthropomorphic RANDO phantom was irradiated with a treatment plan designed for a simulated tumor volume located in the center of the head. The experiment was repeated with all most common radiation treatment types (photons, protons and carbon ions) and delivery techniques (Intensity Modulated Radiation Therapy, passive modulation and spot scanning). The measurements were performed with active diamond detector and passive thermoluminescence (TLD) detectors to investigate the out-of-field dose both inside and outside the phantom.Results: The highest out-of-field dose values both on the surface and inside the phantom were measured during the treatment with 25MV photons. In the proximity of the Planned Target Volume (PTV), the lowest lateral dose profile was observed for passively modulated protons mainly because of the presence of the collimator in combination with the chosen volume shape. In the far out-of-field region (above 100mm from the PTV), passively modulated ions were characterized by a less pronounced dose fall-off in comparison with scanned beams. Overall, the treatment with scanned carbon ions delivered the lowest dose outside the target volume.Conclusions: For the selected PTV, the use of the collimator in proton therapy drastically reduced the dose deposited by ions or photons nearby the tumor. Scanning modulation represents the optimal technique for achieving the highest dose reduction far-out-of-field.

Enhanced intrinsic radiosensitivity after treatment with stereotactic radiosurgery for an acoustic neuroma - Corrected Proof

2012-05-07

Abstract: Enhanced radiosensitivity is an uncommon phenomenon attributable to deficient DNA repair after radiotherapy which can be assessed with the γ-H2AX assay. Reports of radiosensitivity after stereotactic radiosurgery (SRS) are uncommon. We describe a case where the clinical, radiological and laboratory findings suggest enhanced radiosensitivity after SRS for an acoustic neuroma.

Kinomic profiling approach identifies Trk as a novel radiation modulator - Corrected Proof

2012-05-07

Abstract: Background: Ionizing radiation treatment is used in over half of all cancer patients, thus determining the mechanisms of response or resistance is critical for the development of novel treatment approaches.Materials and methods: In this report, we utilize a high-content peptide array platform that performs multiplex kinase assays with real-time kinetic readout to investigate the mechanism of radiation response in vascular endothelial cells. We applied this technology to irradiated human umbilical vein endothelial cells (HUVEC).Results: We identified 49 specific tyrosine phosphopeptides that were differentially affected by irradiation over a time course of 1h. In one example, the Tropomyosin receptor kinase (Trk) family members, TrkA and TrkB, showed transient activation between 2 and 15min following irradiation. When we targeted TrkA and TrkB using small molecule inhibitors, HUVEC were protected from radiation damage. Conversely, stimulation of TrkA using gambogic amide promoted radiation enhancement.Conclusions: Thus, we show that our approach not only can identify rapid changes in kinase activity but also identify novel targets such as TrkA. TrkA inhibition resulted in radioprotection that correlated with enhanced repair of radiation-induced damage while TrkA stimulation by gambogic amide produced radiation sensitization.

Potentials of robust intensity modulated scanning proton plans for locally advanced lung cancer in comparison to intensity modulated photon plans - Corrected Proof

2012-05-07

Abstract: Background and purpose: The potentials of lung sparing, dose escalation, and the robustness of intensity modulated proton plans (IMPTrobust), obtained by minimax optimization on multiple scenarios, were studied.Materials and methods: IMPTrobust optimization as described by Fredriksson et al. was evaluated by means of comparative treatment planning using breath hold CT data from 6 non-small cell lung cancer (NSCLC) patients. IMPTrobust and single field uniform dose (SFUD) proton plans were compared to Tomotherapy and 7-field intensity modulated photon therapy (IMXT). Plan robustness against set-up errors, range uncertainties, and between field motions were analyzed as well as lung exposure quantified by the mean lung dose (MLD) and the partial lung volumes receiving at least 20, 10, and 5GyRBE (V20, V10, V5). Robustness was analyzed with regard to stability of the effective uniform dose (EUD) and the dose level reached or exceeded in 95% of the CTV (D95).Results: MLD by IMPTrobust was less than by SFUD, and Tomotherapy in each patient, on average by 14.8% and 28.5% (p<0.05, Friedman test). V20–V5 were higher with Tomotherapy compared to both proton therapy techniques, on average by a factor of >1.8. Robustness of IMPTrobust was high. EUD and D95 values were maintained above 96% and 94% of the reference plan values for all tested scenarios. With dose escalation to 86GyRBE lung tissue tolerances were maintained.Conclusions: IMPTrobust proved advantageous in terms of lung exposure and possible dose escalation while being also markedly robust. However, motion during delivery of a field remains a major problem of IMPTrobust to be mitigated by high scanning speed and variable spot size.

A radiosensitizing effect of artesunate in glioblastoma cells is associated with a diminished expression of the inhibitor of apoptosis protein survivin - Corrected Proof

2012-05-07

Abstract: Background and purpose: Novel strategies to overcome an irradiation resistant phenotype may help to increase therapeutic efficacy in glioblastoma multiforme. The present study aimed to elucidate radiation sensitizing properties of artesunate, a semi synthetic derivate of artemisinin and to assess factors involved in this effect.Materials and methods: LN229 and U87MG cells were treated with various concentrations of artesunate and radiation response was determined by a colony forming assay. Cell numbers, apoptosis induction, cell cycle distribution, and DNA repair following combined modality treatment were monitored by MTT-, caspase 3/7 assay, cytofluorometry, and γ-H2AX foci formation. Expression of survivin, survivin–GFP fusion protein, XIAP, cellular (c)IAP1 and cIAP2 was monitored by Western immunoblotting.Results: Treatment of glioma cells with artesunate and irradiation resulted in an increased apoptotic fraction, pronounced G2/M arrest and increased DNA damage as demonstrated by an elevated amount of γ-H2AX foci/nucleus. Incubation with artesunate lowers survivin expression in a time and dose-dependent manner, whereas expression of XIAP, cIAP1 and cIAP2 was not affected. In clonogenic assays, treatment with artesunate revealed a significantly reduced surviving fraction, whereas stable over expression of a survivin–GFP protein reversed artesunate-mediated radiosensitization.Conclusion: Artesunate selectively down regulates survivin that contributes to a radio-sensitization of glioma cells by an increased induction of apoptosis, cell cycle arrest, and a hampered DNA damage response.

Quality assurance in the EORTC 22033–26033/CE5 phase III randomized trial for low grade glioma: The digital individual case review - Corrected Proof

2012-05-04

Abstract: Introduction: The phase III EORTC 22033–26033/NCIC CE5 intergroup trial compares 50.4Gy radiotherapy with up-front temozolomide in previously untreated low-grade glioma. We describe the digital EORTC individual case review (ICR) performed to evaluate protocol radiotherapy (RT) compliance.Methods: Fifty-eight institutions were asked to submit 1–2 randomly selected cases. Digital ICR datasets were uploaded to the EORTC server and accessed by three central reviewers. Twenty-seven parameters were analysed including volume delineation, treatment planning, organ at risk (OAR) dosimetry and verification. Consensus reviews were collated and summary statistics calculated.Results: Fifty-seven of seventy-two requested datasets from forty-eight institutions were technically usable. 31/57 received a major deviation for at least one section. Relocation accuracy was according to protocol in 45. Just over 30% had acceptable target volumes. OAR contours were missing in an average of 25% of cases. Up to one-third of those present were incorrectly drawn while dosimetry was largely protocol compliant. Beam energy was acceptable in 97% and 48 patients had per protocol beam arrangements.Conclusions: Digital RT plan submission and review within the EORTC 22033–26033 ICR provide a solid foundation for future quality assurance procedures. Strict evaluation resulted in overall grades of minor and major deviation for 37% and 32%, respectively.

Depletion of the type 1 IGF receptor delays repair of radiation-induced DNA double strand breaks - Corrected Proof

2012-05-01

Abstract: Background and purpose: IGF-1R depletion sensitizes prostate cancer cells to ionizing radiation and DNA-damaging cytotoxic drugs. This study investigated the hypothesis that IGF-1R regulates DNA double strand break (DSB) repair.Methods: We tested effects of IGF-1R siRNA transfection on the repair of radiation-induced DSBs by immunoblotting and immunofluorescence for γH2AX, and pulsed-field gel electrophoresis. Homologous recombination (HR) was quantified by reporter assays, and cell cycle distribution by flow cytometry.Results: We confirmed that IGF-1R depletion sensitized DU145 and PC3 prostate cancer cells to ionizing radiation. DU145 control transfectants resolved radiation-induced DSBs within 24h, while IGF-1R depleted cells contained 30–40% unrepaired breaks at 24h. IGF-1R depletion induced significant reduction in DSB repair by HR, although the magnitude of the repair defect suggests additional contributory factors. Radiation-induced G2-M arrest was attenuated by IGF-1R depletion, potentially suppressing cell cycle-dependent processes required for HR. In contrast, IGF-1R depletion induced only minor radiosensitization in LNCaP cells, and did not influence repair. Cell cycle profiles were similar to DU145, so were unlikely to account for differences in repair responses.Conclusions: These data indicate a role for IGF-1R in DSB repair, at least in part via HR, and support use of IGF-1R inhibitors with DNA damaging cancer treatments.

A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients - Corrected Proof

2012-05-01

Abstract: Background and purpose: Significant tumor shrinkage and weight loss may occur during Intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). This study aims to evaluate the dosimetric effect of volumetric changes on target volumes and organs at risk (OARs) during IMRT, using reassessment of computed tomography (CT) and magnetic resonance imaging (MRI).Material and methods: Nineteen loco-regionally advanced NPC patients treated with IMRT were recruited prospectively. Repeat planning CT and MRI were acquired at 30 and 50Gy intervals. Recontouring of target volumes and OARs was based on the fused CT-MRI images. Hybrid plans with recontouring were generated. The assessment of volumetric and dosimetric changes was performed by comparing the hybrid plans with the original plan.Results: There was volume reduction of target volumes and parotid glands over the course of IMRT. Relative to the original plan, the hybrid plans demonstrated significantly higher dose to most of target volumes with greater dose inhomogeneity, higher maximum doses to the spinal cord and brainstem, and higher median doses to the parotid glands.Conclusions: Replanning with repeat CT and MRI scans at 30Gy is essential to keep a satisfactory dose to the target volumes and avoid overdosing the OARs.

Radiosensitization of renal cell carcinoma in vitro through the induction of autophagy - Corrected Proof

2012-05-01

Abstract: Background and purpose: For patients diagnosed with advanced renal cell carcinoma (RCC), there are few therapeutic options. Radiation therapy is predominantly used to treat metastasis and has not proven effective in the adjuvant setting for renal cancer. Furthermore, RCC is resistant to standard cytotoxic chemotherapies. Targeted anti-angiogenics are the standard of care for RCC but are not curative. Newer agents, such as mTOR inhibitors and others that induce autophagy, have shown great promise for treating RCC. Here, we investigate the potential use of the small molecule STF-62247 to modulate radiation.Materials and methods: Using RCC cell lines, we evaluate sensitivity to radiation in addition to agents that induce autophagic cell death by clonogenic survival assays. Furthermore, these were also tested under physiological oxygen levels.Results: STF-62247 specifically induces autophagic cell death in cells that have lost VHL, an essential mutation in the development of RCC. Treatment with STF-62247 did not alter cell cycle progression but when combined with radiation increased cell killing under oxic and hypoxic/physiological conditions.Conclusions: This study highlights the possibility of combining targeted therapeutics such as STF-62247 or temsirolimus with radiation to reduce the reliance on partial or full nephrectomy and improve patient prognosis.

Clinical target volumes in anal cancer: Calculating what dose was likely to have been delivered in the UK ACT II trial protocol - Corrected Proof

2012-04-23

Abstract: Purpose: Preliminary results of the UK Anal Cancer Trial (ACT) II trial in squamous cell carcinoma of the anus (SCCA) are promising, but 2-D planning with parallel–opposed fields provoked significant toxicity. We calculated likely doses delivered in the ACT II protocol to the planning target volume (PTV), nodal clinical target volumes (n-CTV) and organs at risk (OARs).Methods and Materials: Original planning CT datasets of 33 consecutive patients with SCCA, included in the ACT II trial or treated to an identical protocol, enabled dose to the primary tumour, involved nodal PTV’s, uninvolved nodal CTVs (inguino-femoral and pelvic lymph nodes) and femoral heads to be retrospectively calculated.Results: The mean dose delivered to primary PTV was 51.37±1.68Gy (95% CI), with a maximum dose (Dmax) of 54.63±2.68Gy (95% CI). Involved inguinal nodes received a mean 51.41±3.08Gy, Dmax 54.17±2.84Gy (95% CI). Clinically uninvolved nCTVs received a mean 36.53±3.38Gy (inguinal nodes) and 34.15±5.59Gy (external/internal iliac nodes). Femoral heads received a Dmax of 47.32±3.45 (95% CI). Conclusion: Calculating the likely doses delivered in ACT II from chemoradiation to PTV, n-CTV and OARs facilitates specification of nodal doses and constraints for 3D-conformal/IMRT planning and allows rational dose-escalation for T3/T4 tumours, and potential dose-reduction for T1/T2 tumours.

The dose–response of the anal sphincter region – An analysis of data from the MRC RT01 trial - Corrected Proof

2012-04-20

Abstract: Purpose: Most studies investigating the dose–response of the rectum focus on rectal bleeding. However, it has been reported that other symptoms such as urgency or sphincter control have a large impact on quality-of-life and that different symptoms are related to the dose to different parts of the anorectal wall. In this study correlations between the 3D dose distribution to the anal-sphincter region and radiation-induced side-effects were quantified.Materials and methods: Dose–surface maps of the anal canal were generated. Next, longitudinal and lateral extent and eccentricity were calculated at different dose levels; DSHs and DVHs were also determined. Correlations between these dosimetric measures and seven clinically relevant endpoints were determined by assessing dosimetric constraints. Furthermore, an LKB model was generated. The study was performed using the data of 388 prostate patients from the RT01 trial (ISRCTN 47772397).Results: Subjective sphincter control was significantly correlated with the dose to the anal surface. The strongest correlations were found for lateral extent at 53Gy (p=0.01). Outcome was also significantly correlated with the DSH and the mean dose to the anal surface.Conclusions: The dose to the anal sphincter region should be taken into account when generating treatment-plans. This could be done using shape-based tools, DSH/DVH-based tools or an NTCP model.

NTCP models for patient-rated xerostomia and sticky saliva after treatment with intensity modulated radiotherapy for head and neck cancer: The role of dosimetric and clinical factors - Corrected Proof

2012-04-20

Abstract: Purpose: The purpose of this multicentre prospective study was to develop multivariable logistic regression models to make valid predictions about the risk of moderate-to-severe patient-rated xerostomia (XERM6) and sticky saliva 6months (STICM6) after primary treatment with intensity modulated radiotherapy (IMRT) with or without chemotherapy for head and neck cancer (HNC).Methods and materials: The study population was composed of 178 consecutive HNC patients treated with IMRT. All patients were included in a standard follow up programme in which acute and late side effects and quality of life were prospectively assessed, prior to, during and after treatment.The primary endpoints were XERM6 and STICM6 as assessed by the EORTC QLQ-H&N35 after completing IMRT. Organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate-to-severe xerostomia or sticky saliva, respectively, at baseline were excluded.The optimal number of variables for a multivariate logistic regression model was determined using a bootstrapping method.Results: Eventually, 51.6% of the cases suffered from XERM6. The multivariate analysis showed that the mean contralateral parotid gland dose and baseline xerostomia (none vs. a bit) were the most important predictors for XERM6. For the multivariate NTCP model, the area under the receiver operating curve (AUC) was 0.68 (95% CI 0.60–0.76) and the discrimination slope was 0.10, respectively. Calibration was good with a calibration slope of 1.0.At 6months after IMRT, 35.6% of the cases reported STICM6. The mean contralateral submandibular gland dose, the mean sublingual dose and the mean dose to the minor salivary glands located in the soft palate were most predictive for STICM6. For this model, the AUC was 0.70 (95% CI 0.61–0.78) and the discrimination slope was 0.12. Calibration was good with a calibration slope of 1.0.Conclusions: The multivariable NTCP models presented in this paper can be used to predict patient-rated xerostomia and sticky saliva. The dose volume parameters included in the models can be used to further optimise IMRT treatment.

EGFR-mediated stimulation of sodium/glucose cotransport promotes survival of irradiated human A549 lung adenocarcinoma cells - Corrected Proof

2012-04-19

Abstract: Background and purpose: Solid tumor cells may adapt to an ischemic microenvironment by upregulation of sodium/glucose cotransport (SGLT) in the plasma membrane which supplies the tumor cell with glucose even at very low extracellular glucose concentration. Since SGLT activity has been shown to depend on the epithelial growth factor receptor (EGFR) and EGFR reportedly is activated by ionizing radiation, we tested for irradiation-induced SGLT activity.Materials and methods: A549 lung adenocarcinoma and FaDu head and neck squamous cancer cells were irradiated with 0 and 4Gy X-ray and electrogenic SGLT transport activity was recorded by patch clamp current clamp in the presence and absence of extracellular glucose (5mM), the SGLT inhibitor phlorizin (500μM), and the inhibitor of the EGFR tyrosine kinase activity erlotinib (1μM). In addition, the effect of phlorizin and erlotinib on glucose uptake and clonogenic survival was tested in irradiated and control cells by tracer flux and colony formation assays, respectively.Results: Irradiated A549 cells exhibited a significantly lower membrane potential 3h after irradiation than the control cells. Phlorizin, erlotinib or removal of extracellular glucose, hyperpolarized the irradiated A549 cells to a significantly higher extent than the control cells. Similarly, but less pronounced, glucose removal hyperpolarized irradiated FaDu cells. In addition, irradiated A549 cells exhibited a highly increased 3H-glucose uptake which was sensitive to phlorizin. Finally, phlorizin radiosensitized the A549 and FaDu cells as evident from the colony formation assays.Conclusions: Taken together, these data suggest an irradiation-stimulated and EGFR-mediated increase in SGLT-generated glucose uptake which is required for the survival of the genotoxically stressed tumor cells.

Credentialing of radiotherapy centres for a clinical trial of adaptive radiotherapy for bladder cancer (TROG 10.01) - Corrected Proof

Tomas Kron, Daniel Pham, Paul Roxby, Aldo Rolfo, Farshad Foroudi — 2012-04-09

Abstract: Background: Daily variations in bladder filling make conformal treatment of bladder cancer challenging. On-line adaptive radiotherapy with a choice of plans has been demonstrated to reduce small bowel irradiation in single institution trials. In order to support a multicentre feasibility clinical trial on adaptive radiotherapy for bladder cancer (TROG 10.01) a credentialing programme was developed for centres wishing to participate.Methods: The credentialing programme entails three components: a facility questionnaire; a planning exercise which tests the ability of centres to create three adaptive plans based on a planning and five cone beam CTs; and a site visit during which image quality, imaging dose and image guidance procedures are assessed. Image quality and decision making were tested using customised inserts for a Perspex phantom (Modus QUASAR) that mimic different bladder sizes. Dose was assessed in the same phantom using thermoluminescence dosimetry (TLD).Results: All 12 centres participating in the full credentialing programme were able to generate appropriate target volumes in the planning exercise and identify the correct target volume and position the bladder phantom in the phantom within 3mm accuracy. None of the imaging doses exceeded the limit of 5cGy with a CT on rails system having the lowest overall dose.Conclusion: A phantom mimicking the decision making process for adaptive radiotherapy was found to be well suited during site visits for credentialing of centres participating in a clinical trial of adaptive radiotherapy for bladder cancer. Combined with a planning exercise the site visit allowed testing the ability of centres to create adaptive treatment plans and make appropriate decisions based on the volumetric images acquired at treatment.

The PET-boost randomised phase II dose-escalation trial in non-small cell lung cancer - Corrected Proof

2012-04-09

Abstract: Purpose: The local site of relapse in non-small cell lung cancer (NSCLC) is primarily located in the high FDG uptake region of the primary tumour prior to treatment. A phase II PET-boost trial (NCT01024829) randomises patients between dose-escalation of the entire primary tumour (arm A) or to the high FDG uptake region inside the primary tumour (>50% SUVmax) (arm B), whilst giving 66Gy in 24 fractions to involved lymph nodes. We analysed the planning results of the first 20 patients for which both arms A and B were planned.Methods: Boost dose levels were escalated up to predefined normal tissue constraints with an equal mean lung dose in both arms. This also forces an equal mean PTV dose in both arms, hence testing pure dose-redistribution. Actual delivered treatment plans from the ongoing clinical trial were analysed. Patients were randomised between arms A and B if dose-escalation to the primary tumour in arm A of at least 72Gy in 24 fractions could be safely planned.Results: 15/20 patients could be escalated to at least 72Gy. Average prescribed fraction dose was 3.27±0.31Gy [3.01–4.28Gy] and 3.63±0.54Gy [3.20–5.40Gy] for arms A and B, respectively. Average mean total dose inside the PTV of the primary tumour was comparable: 77.3±7.9Gy vs. 77.5±10.1Gy. For the boost region dose levels of on average 86.9±14.9Gy were reached. No significant dose differences between both arms were observed for the organs at risk. Most frequent observed dose-limiting constraints were the mediastinal structures (13/15 and 14/15 for arms A and B, respectively), and the brachial plexus (3/15 for both arms).Conclusion: Dose-escalation using an integrated boost could be achieved to the primary tumour or high FDG uptake regions whilst keeping the pre-defined dose constraints.

Tumour microenvironment heterogeneity affects the perceived spatial concordance between the intratumoural patterns of cell proliferation and 18F-fluorothymidine uptake - Corrected Proof

2012-03-23

Abstract: Background and purpose: PET imaging with 18F-fluorothymidine (18F-FLT) can potentially be used to identify tumour subvolumes for selective dose escalation in radiation therapy. The purpose of this study is to analyse the co-localization of intratumoural patterns of cell proliferation with 18F-FLT tracer uptake.Materials and methods: Mice bearing FaDu or SQ20B xenograft tumours were injected with 18F-FLT, and bromodeoxyuridine (proliferation marker). Ex vivo images of the spatial pattern of intratumoural 18F-FLT uptake and that of bromodeoxyuridine DNA incorporation were obtained from thin tumour tissue sections. These images were segmented by thresholding and Relative Operating Characteristic (ROC) curves and Dice similarity indices were evaluated.Results: The thresholds at which maximum overlap occurred between FLT-segmented areas and areas of active cell proliferation were significantly different for the two xenograft tumour models, whereas the median Dice values were not. However, ROC analysis indicated that segmented FLT images were more specific at detecting the proliferation pattern in FaDu tumours than in SQ20B tumours.Conclusion: Highly dispersed patterns of cell proliferation observed in certain tumours can affect the perceived spatial concordance between the spatial pattern of 18F-FLT uptake and that of cell proliferation even when high-resolution ex vivo autoradiography imaging is used for 18F-FLT imaging.

Adaptive radiotherapy for long course neo-adjuvant treatment of rectal cancer - Corrected Proof

2012-03-23

Abstract: Purpose: To quantify the potential margin reduction with adaptive radiotherapy (ART) during neo-adjuvant treatment of locally-advanced rectal cancer.Methods and materials: Repeat CT scans were acquired for 28 patients treated with 25×2Gy, daily during the first week, and followed by weekly scans. The CTV was delineated on all scans, and shape variation was estimated. Five ART strategies were tested, consisting of an average CTV over the planning CT and one to five repeat CTs. Required PTV margins were calculated for adapted and non-adapted treatment. The strategy with the least PTV volume over the whole treatment was selected and bowel area dose reduction was estimated.Results: Substantial systematic and random shape variation demanded for a PTV margin up to 2.4cm at the upper-anterior part of the CTV. Plan adaptation after fraction 4 resulted in a maximum 0.7cm margin reduction and a significant PTV reduction from 1185 to 1023cc (p<0.0001). The bowel area volume receiving 15, 45, and 50Gy was reduced from 436 to 402cc, 111 to 81cc, and 49 to 29cc, respectively (p<0.0001).Conclusions: With adaptive radiotherapy, maximum required PTV margins can be reduced from 2.4 to 1.7cm, resulting in significantly less dose to the bowel area.

Programmable segmented volumetric modulated arc therapy for respiratory coordination in pancreatic cancer - Corrected Proof

Jian-Kuen Wu, Chien-Jang Wu, Jason Chia-Hsien Cheng — 2012-03-14

Abstract: We programmably divided long-arc volumetric modulated arc therapy (VMAT) into split short arcs, each taking less than 30s for respiratory coordination. The VMAT plans of five pancreatic cancer patients were modified; the short-arc plans had negligible dose differences and satisfied the 3%/3-mm gamma index on a MapCHECK-2 device.

Quantifying motion for pancreatic radiotherapy margin calculation - Corrected Proof

2012-03-14

Abstract: Background and purpose: Pancreatic radiotherapy (RT) is limited by uncertain target motion. We quantified 3D patient/organ motion during pancreatic RT and calculated required treatment margins.Materials and methods: Cone-beam computed tomography (CBCT) and orthogonal fluoroscopy images were acquired post-RT delivery from 13 patients with locally advanced pancreatic cancer. Bony setup errors were calculated from CBCT. Inter- and intra-fraction fiducial (clip/seed/stent) motion was determined from CBCT projections and orthogonal fluoroscopy.Results: Using an off-line CBCT correction protocol, systematic (random) setup errors were 2.4 (3.2), 2.0 (1.7) and 3.2 (3.6)mm laterally (left–right), vertically (anterior–posterior) and longitudinally (cranio-caudal), respectively. Fiducial motion varied substantially. Random inter-fractional changes in mean fiducial position were 2.0, 1.6 and 2.6mm; 95% of intra-fractional peak-to-peak fiducial motion was up to 6.7, 10.1 and 20.6mm, respectively. Calculated clinical to planning target volume (CTV–PTV) margins were 1.4cm laterally, 1.4cm vertically and 3.0cm longitudinally for 3D conformal RT, reduced to 0.9, 1.0 and 1.8cm, respectively, if using 4D planning and online setup correction.Conclusions: Commonly used CTV–PTV margins may inadequately account for target motion during pancreatic RT. Our results indicate better immobilisation, individualised allowance for respiratory motion, online setup error correction and 4D planning would improve targeting.

Involved field radiation therapy following high dose chemotherapy and autologous stem cell transplant benefits local control and survival in refractory or recurrent Hodgkin lymphoma - Corrected Proof

2012-03-07

Abstract: Background and purpose: Patients with recurrent or primary refractory Hodgkin lymphoma (HL) treated with high dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) commonly relapse post-ASCT in previous disease sites. We sought to evaluate involved field radiation therapy (IFRT) following ASCT and patterns of recurrence, overall survival (OS), and disease specific survival (DSS).Methods and materials: Between May 1993 and October 2003, 62 (n=66) evaluable patients with refractory/relapsed HL underwent HDT followed by ASCT. Thirty-two (52%) patients received IFRT following transplant. Survival was calculated from the day of hematopoietic stem cell infusion.Results: Median follow-up was 2.3years (range 0.03–11.56). Estimated 3-year OS (p=0.05) and DSS (p=0.08) were 69.6% and 82.1% with IFRT and 40% and 57.6% without IFRT on univariate analysis. B-symptoms were adverse on univariate (p=0.007) and multivariate (p=0.01) analysis. HL patients who received IFRT following ASCT had improved local control in areas of previously recurrent disease (p=0.03).Conclusion: OS and DSS showed marginal benefit at 3years. Given the retrospective nature of our study and attendant selection bias that can be both positive and negative, a future prospective study is warranted to better understand the value of IFRT in the transplant setting.

Salvage stereotactic reirradiation using the CyberKnife for the local recurrence of nasal or paranasal carcinoma - Corrected Proof

2012-03-07

Abstract: Purpose: To evaluate the clinical outcome of stereotactic reirradiation using the CyberKnife system for recurrent nasal or paranasal carcinoma.Materials and methods: From May 2005 to February 2010, 51 patients with local recurrence of nasal or paranasal carcinoma were reirradiated using CyberKnife. Tumor volume ranged from 3.1 to 204.9ml (median, 33.8). The previous conventional radiotherapy dose ranged from 40 to 70Gy (median, 60). The median follow-up period for surviving patients was 21months (range, 12–52). The marginal doses were 20–41.5Gy in 1–5 fractions (35Gy). Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 4.0.Results: The median overall survival and local control periods after reirradiation were 14.5 and 9.5months, respectively. The 1-year survival and local control rates were 67% and 62%, respectively. Grade 3 or higher adverse events were observed in 23%. Grade 4 dermatitis and soft tissue necrosis were observed in 2 and 1 patients who had received trimodality combination therapy as their previous treatment, respectively.Conclusions: Salvage stereotactic reirradiation using CyberKnife is feasible and effective for the local recurrence of nasal and paranasal carcinomas. To further improve treatment outcomes, exploration of better planning and dose fractionation, as well as combination chemotherapy would be worthwhile.

Dosimetric predictors of chest wall pain after lung stereotactic body radiotherapy - Corrected Proof

2012-03-02

Abstract: Purpose: To identify risk factors for the development of chest wall (CW) pain after thoracic stereotactic body radiotherapy (SBRT).Methods and materials: A registry of patients with lung lesions treated with lung SBRT was explored to identify patients treated with 54Gy in three fractions or 50Gy in five fractions. One hundred and forty-six lesions in 140 patients were identified; complete electronic treatment plans were available on 86 CWs. The CW was contoured as a 3cm outward expansion from the involved lung. Univariate and multivariate analyses were used to correlate patient, tumor, and dosimetric factors to the development of CW toxicity.Results: CW pain occurred in 22 patients (15.7%). The Kaplan–Meier estimated risk of CW pain at 2years was 20.1% (95% C.I., 13.2–28.8%). On univariate analysis of patient factors, elevated BMI (p=0.026) and connective tissue disease (p=0.036) correlated with CW pain. The percent of CW receiving 30, 35, or 40Gy was most predictive of CW pain on multivariate analysis using logistic regression, while V40 alone was predictive using Cox regression. A V30 threshold of 0.7% and V40 threshold of 0.19% was correlated with a 15% risk of CW pain.Conclusions: We have described patient and dosimetric parameters that correlate with CW pain after lung SBRT. The risk of CW pain may be mitigated by attempting to reduce the relative proportion of CW receiving 30–40Gy during treatment planning.

Ensuring the integrity of treatment parameters throughout the radiotherapy process - Corrected Proof

Fredrik Nordström, Crister Ceberg, Sven Å.J. Bäck — 2012-02-20

Abstract: Background and purpose: Ensuring data integrity in radiotherapy is of major importance and a complex task. The aim of this study was to compare three different combinations of treatment planning and record and verify systems with respect to data integrity.Materials and methods: A software for comparison of treatment parameters in DICOM-RT files was developed using the MATLAB R2010a (MathWorks Inc.) environment. One hundred treatment plans were analyzed for each system combination. In the first step of the analysis, all parameters were compared and a normal condition for each system combination was identified. The second step focused on the discovery of potential special cause deviations, e.g. by applying tolerance levels.Results: In total, 15% and 0.37% of all comparisons failed to meet the defined integrity demands in step 1 and step 2 of the analysis, respectively. Differences in the data integrity level between the systems were observed, ranging on average from 3.1 to 11.9 discrepancies per beam for the different RV-TPS combinations.Conclusions: The proposed method can be used to increase the safety for individual patients by ensuring that the intended treatment is delivered. The system combination with the highest level of data integrity was found to be the one which shares a single database.

Prognostic significance of the total dose of cisplatin administered during concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma - Corrected Proof

2012-02-02

Abstract: Background and purpose: Concurrent chemoradiotherapy (CRT) confers survival benefit over radiotherapy (RT) alone in the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC). This study explored the prognostic significance of the total dose of cisplatin delivered during CRT.Materials and methods: A retrospective analysis was performed in patients with stage II to IVB NPC (AJCC 6th edition) who participated in 3 prospective studies. All patients received cisplatin at a fixed dose of 40mg/m2/week during a 6–7-weeks course of CRT. Chi-square test was used in the univariate analysis. Relationship between prognostic factors, the total dose of cisplatin administered and time-to-event endpoints were analyzed with the Cox Hazards model.Results: Two hundred and forty-one patients were identified with the following stage distribution: Stage II=13.7%, III=45.2%, IV=41.1%. The median total number of cycles of cisplatin administered per patient was 5 cycles (range 1–8 cycles). At a median follow-up of 56.5months (range 4.2–200.2months), 93 patients (38.6%) had relapsed and 85 patients (35.2%) died. For all patients, the total number of cycles of cisplatin delivered was significantly associated with survival in the univariate but not the multivariate analysis. In a sub-group analysis of 142 patients with stage II and III NPC, patients who received more than 5 cycles of cisplatin had significantly better overall survival than those who did not (hazard ratio 0.44; 95% confidence interval, 0.23–0.85; p=0.02).Conclusion: Number of cycles of cisplatin delivered is an independent prognostic factor in patients with stage II–III NPC undergoing CRT with weekly cisplatin.

Out-of-field contributions for IMRT and volumetric modulated arc therapy measured using gafchromic films and compared to calculations using a superposition/convolution based treatment planning system - Corrected Proof

Frank Van den Heuvel, Gilles Defraene, Wouter Crijns, Ria Bogaerts — 2012-02-02

Abstract: Purpose: To quantify the whole-body-dose delivered during the application of new techniques and compare them to the results obtained by treatment planning systems. The ultimate goal being the use of planning data in combination with complication data to assess the impact of low doses of ionizing radiation.Methods: A film technique using gafchromic films to assess low doses was used on simplified phantoms and compared to data from treatment planning systems as well as a simplified whole body dose calculation system (Peridose). The types of treatment include open fields, intensity modulated radiation therapy (IMRT) and volumetric arc treatments. The film measurements were confirmed using TLDs in Alderson phantoms. In addition neutron contributions were measured as these are not taken into account in the current modern treatment planning systems, but can add significantly to the patient’s whole body dose.Results: Dose outside of the treatment plane diminished to 1% of the prescribed dose, this for open fields, IMRT and rotational treatments alike. Noteworthy was an increase at about 20cm from the central plane in IMRT, and in a more limited fashion for volumetric modulated arc treatment. In open fields this was not observed. Treatment planning systems were good at determining the out-of-field doses of single field treatments. In complex plans the TPS underestimated the dose to the patient. At distances greater than 20cm from the field edge, these systems did not predict any dose. The Peridose program performed well in the case of classical treatments. In the case of IMRT treatments, the overall evolution of the dose as a function of the distance to the field was well-modeled. However, an over estimation of the order of 60–80% was observed, leaving the possibility for a corrective factor based on a point measurement. Dose levels over the whole body were of the order 100mGy or higher over a complete treatment for the more complex treatments. Neutron dose levels were of the order single digit mSv for 10MV treatments. For 18MV the level of neutron contribution was in agreement with recent publications, corroborating reports that the dose from neutrons is lower than previously reported.

Late toxicities after conventional radiation therapy alone for nasopharyngeal carcinoma - Corrected Proof

2012-01-27

Abstract: Background and purpose: We sought to evaluate the nature and frequency of late toxicities in a cohort of nasopharyngeal cancer (NPC) patients treated with conventional radiotherapy alone.Methods and materials: Seven-hundred and ninety-six consecutive NPC patients treated using conventional radiotherapy at a single center from 1992 to 1995 were retrospectively analyzed. Patients with histology proven, completely staged, Stage I–IVB World Health Organization Type I–III NPC and completed radical radiotherapy were included. Patients with incomplete staging investigations, distant metastases at diagnosis, previous treatment, and incomplete radiotherapy were excluded. Radiotherapy-related complications were categorized using the RTOG Late Radiation Morbidity Scoring Criteria.Results: Median follow-up was 7.2years. The 5-year overall survival and disease free survival were 69% and 56%, respectively, and the corresponding 10-year rates were 52% and 44%. Among 771 patients with at least 3months of follow-up post treatment, 565 (73%) developed RT-related complications. Diagnosed neurological complications were cranial nerve palsies (n=70; 9%), temporal lobe necrosis (n=37; 5%), Lhermitte’s syndrome (n=7; 1%), and brachial plexopathy (n=2; 0.3%). Non-neurological complications included xerostomia (n=353; 46%), neck fibrosis (n=169; 22%), hypo-pituitarism (n=48; 6%), hearing loss (n=120; 16%), dysphagia (n=116; 15%), otorrhea (n=101; 13%), tinnitus (n=94; 12%), permanent tube feeding (n=61; 8%), trismus (n=45; 6%), second malignancies within treatment field (n=17; 2%), and osteo-radionecrosis (n=13; 2%).Conclusions: While radiotherapy is curative in NPC, many patients suffer significant late treatment morbidities with conventional radiotherapy techniques.

Multivariate modeling of complications with data driven variable selection: Guarding against overfitting and effects of data set size - Corrected Proof

2012-01-24

Abstract: Purpose: Multivariate modeling of complications after radiotherapy is frequently used in conjunction with data driven variable selection. This study quantifies the risk of overfitting in a data driven modeling method using bootstrapping for data with typical clinical characteristics, and estimates the minimum amount of data needed to obtain models with relatively high predictive power.Materials and methods: To facilitate repeated modeling and cross-validation with independent datasets for the assessment of true predictive power, a method was developed to generate simulated data with statistical properties similar to real clinical data sets. Characteristics of three clinical data sets from radiotherapy treatment of head and neck cancer patients were used to simulate data with set sizes between 50 and 1000 patients. A logistic regression method using bootstrapping and forward variable selection was used for complication modeling, resulting for each simulated data set in a selected number of variables and an estimated predictive power. The true optimal number of variables and true predictive power were calculated using cross-validation with very large independent data sets.Results: For all simulated data set sizes the number of variables selected by the bootstrapping method was on average close to the true optimal number of variables, but showed considerable spread. Bootstrapping is more accurate in selecting the optimal number of variables than the AIC and BIC alternatives, but this did not translate into a significant difference of the true predictive power. The true predictive power asymptotically converged toward a maximum predictive power for large data sets, and the estimated predictive power converged toward the true predictive power. More than half of the potential predictive power is gained after approximately 200 samples. Our simulations demonstrated severe overfitting (a predicative power lower than that of predicting 50% probability) in a number of small data sets, in particular in data sets with a low number of events (median: 7, 95th percentile: 32). Recognizing overfitting from an inverted sign of the estimated model coefficients has a limited discriminative value.Conclusions: Despite considerable spread around the optimal number of selected variables, the bootstrapping method is efficient and accurate for sufficiently large data sets, and guards against overfitting for all simulated cases with the exception of some data sets with a particularly low number of events. An appropriate minimum data set size to obtain a model with high predictive power is approximately 200 patients and more than 32 events. With fewer data samples the true predictive power decreases rapidly, and for larger data set sizes the benefit levels off toward an asymptotic maximum predictive power.

Hypofraction radiotherapy of liver tumor using cone beam computed tomography guidance combined with active breath control by long breath-holding - Corrected Proof

2012-01-20

Abstract: Background and purpose: To evaluate the feasibility and validity of cone beam computed tomography (CBCT) and active breath control (ABC) by long breath-holding in hypofraction radiotherapy of liver tumor.Methods and materials: Twenty-four patients received hypofraction radiotherapy of liver tumor with long breath-holding at end-inhale; four prescriptions were used: 6Gy×7 (n=8), 10Gy×4 (n=7), 5Gy×9 (n=6), 4Gy×10 (n=3). For each fraction, all patients received pre-correction CBCT scans with ABC, some patients received post-correction and post-treatment CBCT. The interfraction and intrafraction liver positioning errors on medial–lateral (ML), cranial–caudal (CC) and anterior–posterior (AP) directions were obtained. The theoretic margin from clinical target volume (CTV) to planning target volume (PTV) was calculated based on post-treatment error. The dosimetric parameters of PTV and normal tissue were compared between ABC and free breathing (FB).Results: The interfraction error in liver positioning showed system errors (Σ) of 3.18mm (ML), 6.80mm (CC) and 3.05mm (AP); random error (σ) of 3.03mm (ML), 6.78mm (CC) and 3.62mm (AP). These errors were significantly reduced with CBCT guided online correction. The intrafraction systematic error was 0.72mm (ML), 2.21mm (CC), 1.49mm (AP), and random error was 2.30mm (ML), 3.58mm (CC), 2.49mm (AP). Dosimetric parameters such as PTV, the liver’s volume included by 23, 30Gy isodose curve (V23, V30), mean dose to normal liver (MDTNL) and mean dose to cord were significantly larger for FB (P<0.05).Conclusion: Liver radiotherapy with long time breath-holding at end-inhale is an effective method to reduce liver motion, PTV and dose to normal tissue. Interfraction and intrafraction liver positioning errors were substantial. CBCT guided online correction of positioning error is recommended for liver radiotherapy with end-inhale ABC.

Bone marrow transplantation enhances trafficking of host-derived myelomonocytic cells that rescue intestinal mucosa after whole body radiation - Corrected Proof

2012-01-19

Abstract: Background: Bone marrow (BM)-derived cells were demonstrated within intestines after radiation damage and were reported to be responsible for intestine repair. However, there was a discrepancy between intestine epithelial clonogenic regeneration, and mouse survival after BM transplantation (BMT) and radiation. The contribution of BM to acute intestine repair after radiation needed further investigation.Methods: Mouse survival, intestine microcolony assay, immunohistochemical studies of both intestine and BM were evaluated in mice after whole body irradiation (WBI) and BMT. Immunoblotting, flowcytometry, and double immunostaining were used to evaluate the amount and the character of stroma cells within intestines of recipient mice after receiving gender-mismatched BMT or BMT from green fluorescence donors.Results: Stromal cell proliferation within the lamina propria correlated with the beneficial effect of BMT to intestine recovery and day-8 survival of mice. Few donor-derived cells were found before the completion of intestine repair. The number of host but not donor-derived myelomonocytic and stromal cells increased dramatically within one week after radiation and BMT. Depletion of myelomonocytic cells of recipient mice abolished the mitigating effect of BMT.Conclusions: Besides rescuing injured BM from aplasia, BMT triggers trafficking of host CD11b(+) myelomonocytic cells from the host marrow to the radiation-injured intestinal mucosa, enhancing the proliferation of intestinal stroma cells, leading secondarily to epithelial regeneration.

Stereotactic body radiation therapy in the treatment of multiple primary lung cancers - Corrected Proof

2012-01-16

Abstract: Background and purpose: Patients with multiple primary lung cancers (MPLC) present a therapeutic dilemma, particularly when they are at high risk for surgical resection. We evaluated the role of stereotactic body radiation therapy (SBRT) in the treatment of MPLC.Materials and methods: A prospective thoracic SBRT registry was explored for patients with either synchronous or metachronous MPLC treated with SBRT for one or both of their tumors. Sixty-three patients were identified and clinical data were analyzed.Results: Fifteen patients had synchronous lesions and 48 patients had metachronous lesions. Seventy-six lesions were treated with SBRT. Median follow-up was 24months for living patients. Median progression-free survival (PFS) and overall survival (OS) for the entire cohort was 15.5 and 20months, respectively. Patients with metachronous MPLC had a significantly higher 2year PFS (53.3% vs. 0%, p=0.0466) compared to patients with synchronous MPLC. Likewise, 2year OS was also superior for patients with metachronous versus synchronous MPLC (68.1% vs. 27.5%, p=0.0014). Six tumors (7.9%) recurred within the radiation field. There were no grade ⩾3 toxicities.Conclusions: SBRT for patients with MPLC appears to be a safe and effective local treatment alternative to surgery, particularly for medically inoperable patients. Patients with metachronous MPLC have encouraging survival rates, and thus local therapy appears justified. However, patients with synchronous MPLC have poor OS and PFS despite having excellent local control, and thus the utility of local therapy in this population requires further study.

Dose volume histogram analysis of focal liver reaction in follow-up multiphasic CT following stereotactic body radiotherapy for small hepatocellular carcinoma - Corrected Proof

2012-01-16

Abstract: Purpose: To investigate threshold dose (TD) of focal liver reaction (FLR) following stereotactic body radiotherapy (SBRT) for patients with hepatocellular carcinoma (HCC) and liver cirrhosis.Materials and methods: In consecutive 50 patients receiving SBRT for small HCC, 38 patients receiving SBRT and follow up >6months, FLR on follow-up CT had been previously studied. Patients with good concordance between FLR and highly irradiated area were eligible. Dose volume histogram (DVH) was used to identify TDs for FLR. Clinical factors were analyzed for correlation with TDs.Results: Of 24 eligible patients, 23 had Child–Pugh score A and 1 scored B. Presence of FLR peaked at a median of 6 (range; 3–12) months. The median and 95% confidential intervals of TDs of pre-contrast and portal-venous phase CT were 32.4Gy (30.3–35.4) and 34.4Gy (31.9–36.0), respectively. Each median coefficient representing the concordance was 74.9% (range; 55.8–98.0%) and 80.5% (range; 70.8–92.4%), respectively. No clinical factors significantly correlated with the TDs.Conclusion: We proposed 30Gy/5 fractions as TD of FLRs following SBRT for patients with HCC and liver cirrhosis. This TD will enable us to predict injured liver volume and to avoid complication beforehand from toxicity. Further pathological and clinical studies, in addition to more practical and precise data of DVH, are needed to clarify the significance of FLRs.

Volumetric modulated arc therapy for nasopharyngeal carcinoma: A dosimetric comparison with TomoTherapy and step-and-shoot IMRT - Corrected Proof

2012-01-11

Abstract: Purpose: Volumetric modulated arc therapy (VMAT), a novel technique, employs a linear accelerator to conduct dynamic modulation rotation radiotherapy. The goal of this study was to compare VMAT with helical tomotherapy (HT) and step-and-shoot intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC) patients with regard to the sparing effect on organs at risk (OARs), dosimetric quality, and efficiency of delivery.Materials and methods: Twenty patients with NPC treated by HT were re-planned by VMAT (two arcs) and IMRT (7–9 fields) for dosimetric comparison. The target area received three dose levels (70, 60, and 54Gy) in 33 fractions using simultaneous integrated boosts technique. The Philips Pinnacle Planning System 9.0 was adopted to design VMAT, using SmartArc as the planning algorithm. For a fair comparison, the planning target volume (PTV) coverage of the 3 plans was normalized to the same level. Dosimetric comparisons between VMAT, HT, and IMRT plans were analyzed to evaluate (1) coverage, homogeneity, and conformity of PTV, (2) sparing of OARs, (3) delivery time, and (4) monitor units (MUs).Results: The VMAT, HT, and IMRT plans had similar PTV coverage with an average of 96%. There was no significant difference between VMAT and HT in homogeneity, while the homogeneity indices of VMAT (1.06) and HT (1.06) were better than IMRT plans (1.07, p<0.05). HT plans provided a better conformity index (1.17) than VMAT (1.28, p=0.01) and IMRT (1.36, p=0.02). When compared with IMRT, VMAT and HT had a better sparing effect on brain stem and spinal cord (p<0.05). The effect of parotid sparing was similar between VMAT (mean=26.3Gy) and HT (mean=27.5Gy), but better than IMRT (mean=31.3Gy, p<0.01). The delivery time per fraction for VMAT (5.7min) were much lower than for HT (9.5min, p<0.01) and IMRT (9.2min, p<0.01).Conclusions: Our results indicate that VMAT provides better sparing of normal tissue, homogeneity, and conformity than IMRT, and shorter delivery time than HT.

The International Atomic Energy Agency (IAEA): An active role in the global fight against cancer - Corrected Proof

2011-12-14

The International Atomic Energy Agency (IAEA) is an independent, intergovernmental science and technology-based organization, in the United Nations, that serves as the global focal point for nuclear cooperation. Article II of the IAEA Statute states: “The Agency shall seek to accelerate and enlarge the contribution of atomic energy to peace, health and prosperity throughout the world. It shall ensure, so far as it is able, that assistance provided by it or at its request or under its supervision or control is not used in such a way as to further any military purpose” .

External validation of three dimensional conformal radiotherapy based NTCP models for patient-rated xerostomia and sticky saliva among patients treated with intensity modulated radiotherapy - Corrected Proof

2011-12-14

Abstract: Purpose: The purpose of this study was to investigate the ability of predictive models for patient-rated xerostomia (XER6M) and sticky saliva (STIC6M) at 6months after completion of primary (chemo)radiation developed in head and neck cancer patients treated with 3D-conformal radiotherapy (3D-CRT) to predict outcome in patients treated with intensity modulated radiotherapy (IMRT).Methods and materials: Recently, we published the results of a prospective study on predictive models for patient-rated xerostomia and sticky saliva in head and neck cancer patients treated with 3D-CRT (3D-CRT based NTCP models). The 3D-CRT based model for XER6M consisted of three factors, including the mean parotid dose, age, and baseline xerostomia (none versus a bit). The 3D-CRT based model for STIC6M consisted of the mean submandibular dose, age, the mean sublingual dose, and baseline sticky saliva (none versus a bit).In the current study, a population consisting of 162 patients treated with IMRT was used to test the external validity of these 3D-CRT based models. External validity was described by the explained variation (R2 Nagelkerke) and the Brier score. The discriminative abilities of the models were calculated using the area under the receiver operating curve (AUC) and calibration (i.e. the agreement between predicted and observed outcome) was assessed with the Hosmer–Lemeshow “goodness-of-fit” test.Results: Overall model performance of the 3D-CRT based predictive models for XER6M and STIC6M was significantly worse in terms of the Brier score and R2 Nagelkerke among patients treated with IMRT. Moreover the AUC for both 3D-CRT based models in the IMRT treated patients were markedly lower. The Hosmer–Lemeshow test showed a significant disagreement for both models between predicted risk and observed outcome.Conclusion: 3D-CRT based models for patient-rated xerostomia and sticky saliva among head and neck cancer patients treated with primary radiotherapy or chemoradiation turned out to be less valid for patients treated with IMRT. The main message from these findings is that models developed in a population treated with a specific technique cannot be generalised and extrapolated to a population treated with another technique without external validation.

Does IGRT ensure target dose coverage of head and neck IMRT patients? - Corrected Proof

Pierre Graff, Weigang Hu, Sue S. Yom, Jean Pouliot — 2011-12-07

Abstract: Purpose: To determine if image-guided radiotherapy (IGRT) ensures dose coverage to the target, and to assess the dosimetric impact of anatomic changes using megavoltage cone-beam CT (MVCBCT) for patient positioning during head and neck IMRT.Methods and materials: Forty-eight MVCBCT from 10 head and neck IMRT/IGRT patients were analyzed off-line. Target volumes and organs at risk (OARs) contours delineated on CT were transferred and adjusted on MVCBCT images. Each MVCBCT was processed to allow dose recalculation, resulting in 469 dose–volume histograms (DVHs). The concept of dosimetric latitude was introduced to provide a clinical perspective.Results: MVCBCT target DVHs showed a moderate level of difference in D95 (dose to ⩾95% of volume), generally less than a 5% difference from the planned dose. Delivered-dose increases to the spinal cord and brainstem showed no apparent time trend. The 4mm margin around OARs was a useful precaution to prevent exceeding critical dose thresholds. The parotid glands showed progressive increases in mean dose related to shrinkage of the external contours.Conclusion: IGRT repositioning ensured target volume coverage, but significant dose variations were observed for OARs. The dosimetric impact of anatomic changes during radiotherapy was of lesser importance than the effects of IGRT repositioning.

Combination of quercetin with radiotherapy enhances tumor radiosensitivity in vitro and in vivo - Corrected Proof

Chenghe Lin, Yan Yu, Hong-guan Zhao, Aimin Yang, Hong Yan, Yali Cui — 2011-11-28

Abstract: Purpose: Quercetin (3, 3,′ 4′, 5, 7 – five-flavonoids) is one of the main components of flavonoids, with multifunctions on immune function, anti-oxidation, anti-viral, anti-inflammatory, and cardiovascular protection. We hypothesize that a combination of quercetin with radiation would increase tumor radiosensitivity. To test this hypothesis, we conducted in vitro and in vivo studies.Methods and materials: The in vitro radio-sensitization activity of quercetin was tested in DLD1, HeLa and MCF-7 tumor cell lines by colony formation assays. The in vivo activity was assessed in the DLD-1 human colorectal cancer xenograft model in nude mice. Mechanistic studies were conducted in several cell lines using Western blot analysis and immunofluorescence microscopy.Results: We found that quercetin can significantly increase tumor radiosensitivity both in vitro and in vivo. The in vitro Sensitizing Enhancement Ratios in DLD1, HeLa and MCF-7 cells were 1.87, 1.65, and 1.74, respectively. The mean doubling time of tumor xenografts was significantly increased in irradiated mice treated with quercetin. At the cellular level, exposure to quercetin resulted in prolonged DNA repair. The mechanistic studies demonstrated that quercetin induced radio-sensitization is through inhibiting the ATM kinase, one of the critical DNA damage response proteins.Conclusion: We demonstrate both in vitro and in vivo evidence that combination of quercetin with radiotherapy can enhance tumor radiosensitivity by targeting the ATM-mediated pathway in response to radiation.

The seventh edition of the UICC/AJCC staging system for nasopharyngeal carcinoma is prognostically useful for patients treated with intensity-modulated radiotherapy from an endemic area in China - Corrected Proof

2011-11-21

Abstract: Purpose: To evaluate the 7th edition of the International Union against Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system for nasopharyngeal carcinoma (NPC) in patients treated with intensity-modulated radiotherapy.Methods and materials: We performed a retrospective data review from 512 patients with biopsy-proven, nonmetastatic NPC in our cancer center (South China) between January 2003 and December 2006.Results: The local relapse-free survival rates (LRFS) and disease failure-free survival rates (DFS) in the 6th edition system T1 and T2a stages were not significantly different (P=0.629 and P=0.820), while the LRFS and DFS of T1 and T2 using the 7th edition system were significantly different (P=0.019 and P=0.009). The LRFS and DFS between T2 and T3 in the 7th edition systems were lack of significance (P=0.874 and P=0.589). The total difference in distant metastasis-free survival rate and DFS between N0 and N3 was slightly larger using the 7th edition system than the 6th edition. The nodal dimension of a cervical lymph node was not a significant prognostic factor.Conclusions: We observed a better segregation of survival curves by using the 7th edition system. It seems reasonable to downstage T3 as T2 and reject nodal greatest dimension from the N-staging system in the future revised edition.

Erratum to “Time course of hypothalamic-pituitary deficiency in adults receiving cranial radiotherapy for primary extrasellar brain tumors” [Radiother. Oncol. 99 (2011) 23–28] - Corrected Proof

2011-11-07

The Publisher regrets that in the above published article the authors’ first and family names appeared in reverse order. The authors’ names are presented in the correct order above.

Second cancer after radiotherapy, 1981–2007 - Corrected Proof

2011-10-12

Abstract: Background and purpose: Today, there is growing concern about radiotherapy induced secondary malignancies. We analysed the incidence and dose dependence of second cancer.Material and methods: The study includes 12,000 one-year survivors of radiotherapy, treated between 1981 and 2007. For risk estimates a public databank on cancer in Germany served as reference. Contralateral second breast cancer, second oesophageal and colorectal cancer were analysed with retrospective dosimetry. GI-tract data were used for risk modelling.Results: The incidence rate of second cancers (493 cases) was ∼1% per year. Contralateral breast cancer was the most frequent entity (relative risk RR=2.8). The scatter-dose gradient (2–3Gy) across the contralateral breast did not cause a detectable risk gradient. There was an increased risk for second head and neck cancer (RR=5.1) and for male oesophageal cancer (RR=5.8). For both entities, dose response modelling with case-control data predicted maximum curves with peak induction at 1–5Gy and positive excess absolute risk values at high doses.Conclusions: A survey of second cancer after radiotherapy requires follow-up over decades. Preliminary dose response modelling albeit with low case numbers suggests an increased risk from multiportal techniques. To improve risk assessment, prospective out-of-field dosimetry and long-term multicentre data collection are recommended.

Predictive modelling for swallowing dysfunction after primary (chemo)radiation: Results of a prospective observational study - Corrected Proof

2011-09-12

Abstract: Background and purpose: The purpose of this large multicentre prospective cohort study was to identify which dose volume histogram parameters and pre-treatment factors are most important to predict physician-rated and patient-rated radiation-induced swallowing dysfunction (RISD) in order to develop predictive models for RISD after curative (chemo) radiotherapy ((CH) RT).Material and methods: The study population consisted of 354 consecutive head and neck cancer patients treated with (CH) RT. The primary endpoint was grade 2 or more swallowing dysfunction according to the RTOG/EORTC late radiation morbidity scoring criteria at 6months after (CH) RT. The secondary endpoints were patient-rated swallowing complaints as assessed with the EORTC QLQ-H&N35 questionnaire. To select the most predictive variables a multivariate logistic regression analysis with bootstrapping was used.Results: At 6months after (CH) RT the bootstrapping procedure revealed that a model based on the mean dose to the superior pharyngeal constrictor muscle (PCM) and mean dose to the supraglottic larynx was most predictive.For the secondary endpoints different predictive models were found: for problems with swallowing liquids the most predictive factors were the mean dose to the supraglottic larynx and radiation technique (3D-CRT versus IMRT). For problems with swallowing soft food the mean dose to the middle PCM, age (18–65 versus >65years), tumour site (naso/oropharynx versus other sites) and radiation technique (3D-CRT versus IMRT) were the most predictive factors. For problems with swallowing solid food the most predictive factors were the mean dose to the superior PCM, the mean dose to the supraglottic larynx and age (18–65 versus >65years). And for choking when swallowing the V60 of the oesophageal inlet muscle and the mean dose to the supraglottic larynx were the most predictive factors.Conclusions: Physician-rated and patient-rated RISD in head and neck cancer patients treated with (CH) RT cannot be predicted with univariate relationships between the dose distribution in a single organ at risk and an endpoint. Separate predictive models are needed for different endpoints and factors other than dose volume histogram parameters are important as well.

Development of NTCP models for head and neck cancer patients treated with three-dimensional conformal radiotherapy for xerostomia and sticky saliva: The role of dosimetric and clinical factors - Corrected Proof

2011-06-01

Abstract: Purpose: The purpose of this multicentre prospective study was to investigate the significance of the radiation dose in the major and minor salivary glands, and other pre-treatment and treatment factors, with regard to the development of patient-rated xerostomia and sticky saliva among head and neck cancer (HNC) patients treated with primary (chemo-) radiotherapy ((CH)RT).Methods and materials: The study population was composed of 167 consecutive HNC patients treated with three-dimensional conformal (3D-CRT) (CH) RT. The primary endpoint was moderate to severe xerostomia (XER6m) as assessed by the EORTC QLQ-H&N35 at 6months after completing (CH)RT. The secondary endpoint was moderate to severe sticky saliva at 6months (STIC6m). All organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate to severe xerostomia or sticky saliva at baseline were excluded. The optimum number of variables for a multivariate logistic regression model was determined using a bootstrapping method.Results: The multivariate analysis showed the mean parotid dose, age and baseline xerostomia (none versus a bit) to be the most important predictors for XER6m. The risk of developing xerostomia increased with age and was higher when minor baseline xerostomia was present in comparison with patients without any xerostomia complaints at baseline. Model performance was good with an area under the curve (AUC) of 0.82.For STIC6m, the mean submandibular dose, age, the mean sublingual dose and baseline sticky saliva (none versus a bit) were most predictive for sticky saliva. The risk of developing STIC6m increased with age and was higher when minor baseline sticky saliva was present in comparison with patients without any sticky saliva complaints at baseline. Model performance was good with an AUC of 0.84.Conclusions: Dose distributions in the minor salivary glands in patients receiving 3D-CRT have limited significance with regard to patient-rated symptoms related to salivary dysfunction. Besides the parotid and submandibular glands, only the sublingual glands were significantly associated with sticky saliva. In addition, reliable risk estimation also requires information from other factors such as age and baseline subjective scores. When these selected factors are included in predictive models, instead of only dose volume histogram parameters, model performance can be improved significantly.

REMOVED: Boron neutron capture therapy (BNCT) for glioblastoma multiforme: A phase 2 study evaluating a prolonged high dose of boronophenylalanine (BPA) - Corrected Proof

2006-05-24

This article has been removed consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.

REMOVED: Boron neutron capture therapy in the treatment of glioblastoma: As effective, more effective or less effective than photon irradiation? - Corrected Proof

Rolf F. Barth, Heikki Joensuu — 2006-05-09

This article has been removed, consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.