Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial.

BACKGROUND: Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. METHODS: We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. FINDINGS: Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5-60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74-1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. CONCLUSION: DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375.

Unintended doses in radiotherapy-over, under and outside?

Radiotherapy is a safe treatment; nevertheless, national reporting of serious incidents allows investigation of potential harm to individuals and failing safety culture. UK guidance has previously been limited to overexposures, but underexposures will be included in the new legislation, and positioning errors have also been explicitly included in recent guidance. This commentary reviews current guidance and suggests practical approaches to the additional categories, including the definition of a local error margin.

Feasibility of portal dosimetry for flattening filter-free radiotherapy.

The feasibility of using portal dosimetry (PD) to verify 6 MV flattening filter-free (FFF) IMRT treatments was investigated. An Elekta Synergy linear accelerator with an Agility collimator capable of delivering FFF beams and a standard iViewGT amorphous silicon (aSi) EPID panel (RID 1640 AL5P) at a fixed SSD of 160 cm were used. Dose rates for FFF beams are up to four times higher than for conventional flattened beams, meaning images taken at maximum FFF dose rate can saturate the EPID. A dose rate of 800 MU/min was found not to saturate the EPID for open fields. This dose rate was subsequently used to characterize the EPID for FFF portal dosimetry. A range of open and phantom fields were measured with both an ion chamber and the EPID, to allow comparison between the two. The measured data were then used to create a model within The Nederlands Kanker Instituut's (NKI's) portal dosimetry software. The model was verified using simple square fields with a range of field sizes and phantom thicknesses. These were compared to calculations performed with the Monaco treatment planning system (TPS) and isocentric ion chamber measurements. It was found that the results for the FFF verification were similar to those for flattened beams with testing on square fields, indicating a difference in dose between the TPS and portal dosimetry of approximately 1%. Two FFF IMRT plans (prostate and lung SABR) were delivered to a homogeneous phantom and showed an overall dose difference at isocenter of ~0.5% and good agreement between the TPS and PD dose distributions. The feasibility of using the NKI software without any modifications for high-dose-rate FFF beams and using a standard EPID detector has been investigated and some initial limitations highlighted.

Radiation-induced second primary cancer risks from modern external beam radiotherapy for early prostate cancer: impact of stereotactic ablative radiotherapy (SABR), volumetric modulated arc therapy (VMAT) and flattening filter free (FFF) radiotherapy.

Risks of radiation-induced second primary cancer following prostate radiotherapy using 3D-conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), flattening filter free (FFF) and stereotactic ablative radiotherapy (SABR) were evaluated. Prostate plans were created using 10 MV 3D-CRT (78 Gy in 39 fractions) and 6 MV 5-field IMRT (78 Gy in 39 fractions), VMAT (78 Gy in 39 fractions, with standard flattened and energy-matched FFF beams) and SABR (42.7 Gy in 7 fractions with standard flattened and energy-matched FFF beams). Dose-volume histograms from pelvic planning CT scans of three prostate patients, each planned using all 6 techniques, were used to calculate organ equivalent doses (OED) and excess absolute risks (EAR) of second rectal and bladder cancers, and pelvic bone and soft tissue sarcomas, using mechanistic, bell-shaped and plateau models. For organs distant to the treatment field, chamber measurements recorded in an anthropomorphic phantom were used to calculate OEDs and EARs using a linear model. Ratios of OED give relative radiation-induced second cancer risks. SABR resulted in lower second cancer risks at all sites relative to 3D-CRT. FFF resulted in lower second cancer risks in out-of-field tissues relative to equivalent flattened techniques, with increasing impact in organs at greater distances from the field. For example, FFF reduced second cancer risk by up to 20% in the stomach and up to 56% in the brain, relative to the equivalent flattened technique. Relative to 10 MV 3D-CRT, 6 MV IMRT or VMAT with flattening filter increased second cancer risks in several out-of-field organs, by up to 26% and 55%, respectively. For all techniques, EARs were consistently low. The observed large relative differences between techniques, in absolute terms, were very low, highlighting the importance of considering absolute risks alongside the corresponding relative risks, since when absolute risks are very low, large relative risks become less meaningful. A calculated relative radiation-induced second cancer risk benefit from SABR and FFF techniques was theoretically predicted, although absolute radiation-induced second cancer risks were low for all techniques, and absolute differences between techniques were small.

A simple model for predicting the signal for a head-mounted transmission chamber system, allowing IMRT in-vivo dosimetry without pretreatment linac time.

The DAVID is a transparent, multi-wire transmission-style detector that attaches to a linear accelerator (linac) collimator for use as an in vivo detector. Currently, the normal method for using the DAVID is to measure a signal at the time of phantom-based pretreatment verification and use that signal as a baseline to compare with in vivo measurements for subsequent treatment fractions. The device has previously been shown to be both stable and accurate.(1,2) This work presents the development of a predictive algorithm for the expected signal, eradicating the need to spend time on the linac prior to treatment, and thereby making the process more efficient. The DAVID response at each wire is a consequence of both primary radiation, from the leaf pair associated with the wire, and scatter radiation as a result of radiation incident on other parts of the detector scattering in the Perspex plate. The primary radiation was shown to be linearly proportional to both leaf separation and delivered monitor units (MU). The scatter signal dropped off exponentially with regard to distance. Both of these effects were modeled; the resulting algorithm was used to predict the response from ten five-field IMRT head and neck plans. The system predicted all DAVID signals to within 5%, and was able to detect artificially generated changes in linac output. Having shown that the algorithm works, a new working paradigm is suggested, and the errors that can be detected are outlined.

Prostate stereotactic ablative radiation therapy using volumetric modulated arc therapy to dominant intraprostatic lesions.

PURPOSE: To investigate boosting dominant intraprostatic lesions (DILs) in the context of stereotactic ablative radiation therapy (SABR) and to examine the impact on tumor control probability (TCP) and normal tissue complication probability (NTCP). METHODS AND MATERIALS: Ten prostate datasets were selected. DILs were defined using T2-weighted, dynamic contrast-enhanced and diffusion-weighted magnetic resonance imaging. Four plans were produced for each dataset: (1) no boost to DILs; (2) boost to DILs, no seminal vesicles in prescription; (3) boost to DILs, proximal seminal vesicles (proxSV) prescribed intermediate dose; and (4) boost to DILs, proxSV prescribed higher dose. The prostate planning target volume (PTV) prescription was 42.7 Gy in 7 fractions. DILs were initially prescribed 115% of the PTV(Prostate) prescription, and PTV(DIL) prescriptions were increased in 5% increments until organ-at-risk constraints were reached. TCP and NTCP calculations used the LQ-Poisson Marsden, and Lyman-Kutcher-Burman models respectively. RESULTS: When treating the prostate alone, the median PTV(DIL) prescription was 125% (range: 110%-140%) of the PTV(Prostate) prescription. Median PTV(DIL) D50% was 55.1 Gy (range: 49.6-62.6 Gy). The same PTV(DIL) prescriptions and similar PTV(DIL) median doses were possible when including the proxSV within the prescription. TCP depended on prostate α/ß ratio and was highest with an α/ß ratio = 1.5 Gy, where the additional TCP benefit of DIL boosting was least. Rectal NTCP increased with DIL boosting and was considered unacceptably high in 5 cases, which, when replanned with an emphasis on reducing maximum dose to 0.5 cm(3) of rectum (Dmax(0.5cc)), as well as meeting existing constraints, resulted in considerable rectal NTCP reductions. CONCLUSIONS: Boosting DILs in the context of SABR is technically feasible but should be approached with caution. If this therapy is adopted, strict rectal constraints are required including Dmax(0.5cc). If the α/ß ratio of prostate cancer is 1.5 Gy or less, then high TCP and low NTCP can be achieved by prescribing SABR to the whole prostate, without the need for DIL boosting.

Developing a class solution for Prostate Stereotactic Ablative Body Radiotherapy (SABR) using Volumetric Modulated Arc Therapy (VMAT).

BACKGROUND AND PURPOSE: To develop a class solution for prostate Stereotactic Ablative Radiotherapy (SABR) using Volumetric Modulated Arc Therapy (VMAT). MATERIALS AND METHODS: Seven datasets were used to compare plans using one 360° arc (1FA), one 210° arc (1PA), two full arcs and two partial arcs. Subsequently using 1PA, fifteen datasets were compared using (i) 6mm CTV-PTV margins, (ii) 8mm CTV-PTV margins and (iii) including the proximal SV within the CTV. Monaco 3.2 (Elekta) was used for planning with the Agility MLC system (Elekta). RESULTS: Highly conformal plans were produced using all four arc arrangements. Compared to 1FA, 1PA resulted in significantly reduced rectal doses, and monitor units and estimated delivery times were reduced in six of seven cases. Using 6mm CTV-PTV margins, planning constraints were met for all fifteen datasets. Using 8mm margins required relaxation of the uppermost bladder constraint in three cases to achieve adequate coverage, and, compared to 6mm margins, rectal and bladder doses significantly increased. Including the proximal SV required relaxation of the uppermost bladder and rectal constraints in two cases, and rectal and bladder doses significantly increased. CONCLUSIONS: Prostate SABR VMAT is optimal using 1PA. 6mm CTV-PTV margins, compatible with daily fiducial-based IGRT, are consistently feasible in terms of target objectives and OAR constraints.

18F-fluorodeoxyglucose positron emission tomography/computed tomography-based radiotherapy target volume definition in non-small-cell lung cancer: delineation by radiation oncologists vs. joint outlining with a PET radiologist?

PURPOSE: (18)F-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) has benefits in target volume (TV) definition in radiotherapy treatment planning (RTP) for non-small-cell lung cancer (NSCLC); however, an optimal protocol for TV delineation has not been determined. We investigate volumetric and positional variation in gross tumor volume (GTV) delineation using a planning PET/CT among three radiation oncologists and a PET radiologist. METHODS AND MATERIALS: RTP PET/CT scans were performed on 28 NSCLC patients (Stage IA-IIIB) of which 14 patients received prior induction chemotherapy. Three radiation oncologists and one PET radiologist working with a fourth radiation oncologist independently delineated the GTV on CT alone (GTV(CT)) and on fused PET/CT images (GTV(PETCT)). The mean percentage volume change (PVC) between GTV(CT) and GTV(PETCT) for the radiation oncologists and the PVC between GTV(CT) and GTV(PETCT) for the PET radiologist were compared using the Wilcoxon signed-rank test. Concordance index (CI) was used to assess both positional and volume change between GTV(CT) and GTV(PETCT) in a single measurement. RESULTS: For all patients, a significant difference in PVC from GTV(CT) to GTV(PETCT) exists between the radiation oncologist (median, 5.9%), and the PET radiologist (median, -0.4%, p = 0.001). However, no significant difference in median concordance index (comparing GTV(CT) and GTV(FUSED) for individual cases) was observed (PET radiologist = 0.73; radiation oncologists = 0.66; p = 0.088). CONCLUSIONS: Percentage volume changes from GTV(CT) to GTV(PETCT) were lower for the PET radiologist than for the radiation oncologists, suggesting a lower impact of PET/CT in TV delineation for the PET radiologist than for the oncologists. Guidelines are needed to standardize the use of PET/CT for TV delineation in RTP.

(18)F-FDG PET-CT simulation for non-small-cell lung cancer: effect in patients already staged by PET-CT.

PURPOSE: Positron emission tomography (PET), in addition to computed tomography (CT), has an effect in target volume definition for radical radiotherapy (RT) for non-small-cell lung cancer (NSCLC). In previously PET-CT staged patients with NSCLC, we assessed the effect of using an additional planning PET-CT scan for gross tumor volume (GTV) definition. METHODS AND MATERIALS: A total of 28 patients with Stage IA-IIIB NSCLC were enrolled. All patients had undergone staging PET-CT to ensure suitability for radical RT. Of the 28 patients, 14 received induction chemotherapy. In place of a RT planning CT scan, patients underwent scanning on a PET-CT scanner. In a virtual planning study, four oncologists independently delineated the GTV on the CT scan alone and then on the PET-CT scan. Intraobserver and interobserver variability were assessed using the concordance index (CI), and the results were compared using the Wilcoxon signed ranks test. RESULTS: PET-CT improved the CI between observers when defining the GTV using the PET-CT images compared with using CT alone for matched cases (median CI, 0.57 for CT and 0.64 for PET-CT, p = .032). The median of the mean percentage of volume change from GTV(CT) to GTV(FUSED) was -5.21% for the induction chemotherapy group and 18.88% for the RT-alone group. Using the Mann-Whitney U test, this was significantly different (p = .001). CONCLUSION: PET-CT RT planning scan, in addition to a staging PET-CT scan, reduces interobserver variability in GTV definition for NSCLC. The GTV size with PET-CT compared with CT in the RT-alone group increased and was reduced in the induction chemotherapy group.

Clinical implementation of dynamic and step-and-shoot IMRT to treat prostate cancer with high risk of pelvic lymph node involvement.

BACKGROUND AND PURPOSE: Two systems have been developed for treating patients with locally advanced prostate cancer using intensity-modulated radiotherapy (IMRT): one using dynamic multi-leaf collimator delivery and the other using step-and-shoot. This paper describes the clinical implementation of these two techniques, and presents results from the first 14 patients treated in a clinical setting (nine dynamic, five step-and-shoot). PATIENTS AND METHODS: Dynamic treatments were planned using Corvus, and step-and-shoot using Helax-TMS; all were delivered using Elekta accelerators. Prior to the first clinical treatments, validation measurements were carried out for each system, including measurements for a complete IMRT treatment. The reproducibility of dynamic delivery and the characteristics of the accelerator for low-monitor-unit (MU) deliveries were also assessed. An extensive quality assurance (QA) program was performed for each of the patients. Additionally, timing measurements were carried out to assess the practicalities of the technique. RESULTS: The planning objectives were met in most cases. Absolute doses for complete IMRT treatments were within 2%, on average, with dose distributions generally showing agreement within 3% or 3 mm. Beam modulation measurements made throughout each patient's treatment indicated that both delivery methods were reproducible. The dynamic plans required an average of 765 MU per beam, with a treatment delivery time of 14 min; corresponding results for step-and-shoot plans were 105 MU and 10 min. CONCLUSIONS: Two IMRT techniques for this group of patients have been successfully implemented in the clinic. The more complex dynamic treatments showed no advantages over the step-and-shoot approach. QA results have shown accurate and reproducible delivery for both techniques, giving increased confidence in the techniques and allowing a reduction in the QA program.