Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is increasingly being used to treat oligometastatic cancers, but high-level evidence to provide a basis for policy making is scarce. Additional evidence from a real-world setting is required. We present the results of a national study of patients with extracranial oligometastases undergoing SABR, representing the largest dataset, to our knowledge, on outcomes in this population so far. METHODS: In 2015, National Health Service (NHS) England launched a Commissioning through Evaluation scheme that funded a prospective, registry-based, single-arm, observational, evaluation study of patients with solid cancer and extracranial oligometastases treated with SABR. Prescribed doses ranged from 24-60 Gy administered in three to eight fractions. The study was done at 17 NHS radiotherapy centres in England. Patients were eligible for the scheme if aged 18 years or older with confirmed primary carcinoma (excluding haematological malignancies), one to three extracranial metastatic lesions, a disease-free interval from primary tumour development to metastases of longer than 6 months (with the exception of synchronous colorectal liver metastases), a WHO performance status of 2 or lower, and a life expectancy of at least 6 months. The primary outcome was overall survival at 1 year and 2 years from the start of SABR treatment. The study is now completed. FINDINGS: Between June 15, 2015, and Jan 30, 2019, 1422 patients were recruited from 17 hospitals in England. The median age of the patients was 69 years (IQR 62-76), and the most common primary tumour was prostate cancer (406 [28·6%] patients). Median follow-up was 13 months (IQR 6-23). Overall survival was 92·3% (95% CI 90·5-93·9) at 1 year and 79·2% (76·0-82·1) at 2 years. The most common grade 3 adverse event was fatigue (28 [2·0%] of 1422 patients) and the most common serious (grade 4) event was increased liver enzymes (nine [0·6%]). Notreatment-related deaths were reported. INTERPRETATION: In patients with extracranial oligometastatic cancer, use of SABR was associated with high overall survival and low toxicity. 'The study findings complement existing evidence from a randomised, phase 2 trial, and represent high-level, real-world evidence supporting the use of SABR in this patient cohort, with a phase 3 randomised, controlled trial to confirm these findings underway. Based on the selection criteria in this study, SABR was commissioned by NHS England in March, 2020, as a treatment option for patients with oligometastatic disease. FUNDING: NHS England Commissioning through Evaluation scheme.

Multi-center evaluation of dose conformity in stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: Stereotactic body radiotherapy (SBRT) is an emerging technique for treating oligometastases, but limited data is available on what plan quality is achievable for a range of modalities and clinical sites. METHODS: SBRT plans for lung, spine, bone, adrenal, liver and node sites from 17 participating centers were reviewed. Centers used various delivery techniques including static and rotational intensity-modulation and multiple non-coplanar beams. Plans were split into lung and other body sites and evaluated with different plan quality metrics, including two which are independent of target coverage; "prescription dose spillage" (PDS) and "modified gradient index" (MGI). These were compared to constraints from the ROSEL and RTOG 0813 clinical trials. RESULTS: Planning target volume (PTV) coverage was compromised (PTV V100% < 90%) in 29% of patient plans in order to meet organ-at-risk (OAR) tolerances, supporting the use of plan quality metrics which are independent of target coverage. Both lung (n = 48) and other body (n = 99) site PDS values agreed well with ROSEL constraints on dose spillage, but RTOG 0813 values were too high to detect sub-optimal plans. MGI values for lung plans were mis-matched to both sets of previous constraints, with ROSEL values too high and RTOG 0813 values too low. MGI values were lower for other body plans as expected, though this was only statistically significant for PTV volumes <20 cm3. CONCLUSIONS: Updated guidance for lung and other body site SBRT plan quality using the PDS and MGI metrics is presented.

Clinical implementation of a knowledge based planning tool for prostate VMAT.

BACKGROUND: A knowledge based planning tool has been developed and implemented for prostate VMAT radiotherapy plans providing a target average rectum dose value based on previously achievable values for similar rectum/PTV overlap. The purpose of this planning tool is to highlight sub-optimal clinical plans and to improve plan quality and consistency. METHODS: A historical cohort of 97 VMAT prostate plans was interrogated using a RayStation script and used to develop a local model for predicting optimum average rectum dose based on individual anatomy. A preliminary validation study was performed whereby historical plans identified as "optimal" and "sub-optimal" by the local model were replanned in a blinded study by four experienced planners and compared to the original clinical plan to assess whether any improvement in rectum dose was observed. The predictive model was then incorporated into a RayStation script and used as part of the clinical planning process. Planners were asked to use the script during planning to provide a patient specific prediction for optimum average rectum dose and to optimise the plan accordingly. RESULTS: Plans identified as "sub-optimal" in the validation study observed a statistically significant improvement in average rectum dose compared to the clinical plan when replanned whereas plans that were identified as "optimal" observed no improvement when replanned. This provided confidence that the local model can identify plans that were suboptimal in terms of rectal sparing. Clinical implementation of the knowledge based planning tool reduced the population-averaged mean rectum dose by 5.6Gy. There was a small but statistically significant increase in total MU and femoral head dose and a reduction in conformity index. These did not affect the clinical acceptability of the plans and no significant changes to other plan quality metrics were observed. CONCLUSIONS: The knowledge-based planning tool has enabled substantial reductions in population-averaged mean rectum dose for prostate VMAT patients. This suggests plans are improved when planners receive quantitative feedback on plan quality against historical data.

Real-time Cherenkov emission portal imaging during CyberKnife® radiotherapy.

The feasibility of real-time portal imaging during radiation therapy, through the Cherenkov emission (CE) effect is investigated via a medical linear accelerator (CyberKnife(®)) irradiating a partially-filled water tank with a 60 mm circular beam. A graticule of lead/plywood and a number of tissue equivalent materials were alternatively placed at the beam entrance face while the induced CE at the exit face was imaged using a gated electron-multiplying-intensified-charged-coupled device (emICCD) for both stationary and dynamic scenarios. This was replicated on an Elekta Synergy(®) linear accelerator with portal images acquired using the iViewGT(™) system. Profiles across the acquired portal images were analysed to reveal the potential resolution and contrast limits of this novel CE based portal imaging technique and compared against the current standard. The CE resolution study revealed that using the lead/plywood graticule, separations down to 3.4 ± 0.5 mm can be resolved. A 28 mm thick tissue-equivalent rod with electron density of 1.69 relative to water demonstrated a CE contrast of 15% through air and 14% through water sections, as compared to a corresponding contrast of 19% and 12% using the iViewGT(™) system. For dynamic scenarios, video rate imaging with 30 frames per second was achieved. It is demonstrated that CE-based portal imaging is feasible to identify both stationary and dynamic objects within a CyberKnife(®) radiotherapy treatment field.

Parametrized rectal dose and associations with late toxicity in prostate cancer radiotherapy.

OBJECTIVE: We investigated possible associations between planned dose-volume parameters and rectal late toxicity in 170 patients having radical prostate cancer radiotherapy. METHODS: For each patient, the rectum was outlined from anorectal junction to sigmoid colon, and rectal dose was parametrized using dose-volume (DVH), dose-surface (DSH) and dose-line (DLH) histograms. Generation of DLHs differed from previous studies in that the rectal dose was parametrized without first unwrapping onto 2-dimensional dose-surface maps. Patient-reported outcomes were collected using a validated Later Effects in Normal Tissues Subjective, Objective, Management and Analytic questionnaire. Associations between dose and toxicity were assessed using a one-sided Mann-Whitney U test. RESULTS: Associations (p < 0.05) were found between equieffective dose (EQD23) and late toxicity as follows: overall toxicity with DVH and DSH at 13-24 Gy; proctitis with DVH and DSH at 25-36 Gy and with DVH, DSH and DLH at 61-67 Gy; bowel urgency with DVH and DSH at 10-20 Gy. None of these associations met statistical significance following the application of a Bonferroni correction. CONCLUSION: Independently confirmed associations between rectal dose and late toxicity remain elusive. Future work to increase the accuracy of the knowledge of the rectal dose, either by accounting for interfraction and intrafraction rectal motion or via stabilization of the rectum during treatment, may be necessary to allow for improved dose-toxicity comparisons. ADVANCES IN KNOWLEDGE: This study is the first to use parametrized DLHs to study associations with patient-reported toxicity for prostate radiotherapy showing that it is feasible to model rectal dose mapping in three dimensions.

Monitoring dosimetric impact of weight loss with kilovoltage (kV) cone beam CT (CBCT) during parotid-sparing IMRT and concurrent chemotherapy.

PURPOSE: Parotid-sparing head-and-neck intensity-modulated radiotherapy (IMRT) can reduce long-term xerostomia. However, patients frequently experience weight loss and tumor shrinkage during treatment. We evaluate the use of kilovoltage (kV) cone beam computed tomography (CBCT) for dose monitoring and examine if the dosimetric impact of such changes on the parotid and critical neural structures warrants replanning during treatment. METHODS AND MATERIALS: Ten patients with locally advanced oropharyngeal cancer were treated with contralateral parotid-sparing IMRT concurrently with platinum-based chemotherapy. Mean doses of 65 Gy and 54 Gy were delivered to clinical target volume (CTV)1 and CTV2, respectively, in 30 daily fractions. CBCT was prospectively acquired weekly. Each CBCT was coregistered with the planned isocenter. The spinal cord, brainstem, parotids, larynx, and oral cavity were outlined on each CBCT. Dose distributions were recalculated on the CBCT after correcting the gray scale to provide accurate Hounsfield calibration, using the original IMRT plan configuration. RESULTS: Planned contralateral parotid mean doses were not significantly different to those delivered during treatment (p > 0.1). Ipsilateral and contralateral parotids showed a mean reduction in volume of 29.7% and 28.4%, respectively. There was no significant difference between planned and delivered maximum dose to the brainstem (p = 0.6) or spinal cord (p = 0.2), mean dose to larynx (p = 0.5) and oral cavity (p = 0.8). End-of-treatment mean weight loss was 7.5 kg (8.8% of baseline weight). Despite a ≥10% weight loss in 5 patients, there was no significant dosimetric change affecting the contralateral parotid and neural structures. CONCLUSIONS: Although patient weight loss and parotid volume shrinkage was observed, overall, there was no significant excess dose to the organs at risk. No replanning was felt necessary for this patient cohort, but a larger patient sample will be investigated to further confirm these results. Nevertheless, kilovoltage CBCT is a valuable tool for patient setup verification and monitoring of dosimetric variation during radiotherapy.

Evaluation of the impact of dental artefacts on intensity-modulated radiotherapy planning for the head and neck.

BACKGROUND AND PURPOSE: High density materials create severe artefacts in the computed tomography (CT) scans used for radiotherapy dose calculations. Increased use of intensity-modulated radiotherapy (IMRT) to treat oropharyngeal cancers raises concerns over the accuracy of the resulting dose calculation. This work quantifies their impact and evaluates a simple corrective technique. MATERIALS AND METHODS: Fifteen oropharyngeal patients with severe artefacts were retrospectively planned with IMRT using two different CT/density look-up tables. Each plan was recalculated using a corrected CT dataset to evaluate the dose distribution delivered to the patient. Plan quality in the absence of dental artefacts was similarly assessed. A range of dosimetric and radiobiological parameters were compared pre- and post-correction. RESULTS: Plans using a standard CT/density look-up table (density 1.8 g/cm(3)) revealed inconsistent inter-patient errors, mostly within clinical acceptance, although potentially significantly reducing target coverage for individual patients. Using an extended CT/density look-up table (density 10.0 g/cm(3)) greatly reduced the errors for 13/15 patients. In 2/15 patients with residual errors the CTV extended into the severely affected region and could be corrected by applying a simple manual correction. CONCLUSIONS: Use of an extended CT/density look-up table together with a simple manual bulk density correction reduces the impact of dental artefacts on head and neck IMRT planning to acceptable levels.

Dosimetry audit for a multi-centre IMRT head and neck trial.

BACKGROUND AND PURPOSE: PARSPORT was a multi-centre randomised trial in the UK which compared Intensity-Modulated Radiotherapy (IMRT) and conventional radiotherapy (CRT) for patients with head and neck cancer. The dosimetry audit goals were to verify the plan delivery in participating centres, ascertain what tolerances were suitable for head and neck IMRT trials and develop an IMRT credentialing program. MATERIALS AND METHODS: Centres enrolling patients underwent rigorous quality assurance before joining the trial. Following this each centre was visited for a dosimetry audit, which consisted of treatment planning system tests, fluence verification films, combined field films and dose point measurements. RESULTS: Mean dose point measurements were made at six centres. For the primary planning target volume (PTV) the differences with the planned values for the IMRT and CRT arms were -0.6% (1.8% to -2.4%) and 0.7% (2.0% to -0.9%), respectively. Ninety-four percent of the IMRT fluence films for individual fields passed gamma criterion of 3%/3mm and 75% of the films for combined fields passed gamma criterion 4%/3mm (no significant difference between dynamic delivery and step and shoot delivery). CONCLUSIONS: This audit suggests that a 3% tolerance could be applied for PTV point doses. For dose distributions tolerances of 3%/3mm on individual fields and 4%/3mm for combined fields are proposed for multi-centre head and neck IMRT trials.

Accuracy and precision of an IGRT solution.

Image-guided radiotherapy (IGRT) can potentially improve the accuracy of delivery of radiotherapy treatments by providing high-quality images of patient anatomy in the treatment position that can be incorporated into the treatment setup. The achievable accuracy and precision of delivery of highly complex head-and-neck intensity modulated radiotherapy (IMRT) plans with an IGRT technique using an Elekta Synergy linear accelerator and the Pinnacle Treatment Planning System (TPS) was investigated. Four head-and-neck IMRT plans were delivered to a semi-anthropomorphic head-and-neck phantom and the dose distribution was measured simultaneously by up to 20 microMOSFET (metal oxide semiconductor field-effect transmitter) detectors. A volumetric kilovoltage (kV) x-ray image was then acquired in the treatment position, fused with the phantom scan within the TPS using Syntegra software, and used to recalculate the dose with the precise delivery isocenter at the actual position of each detector within the phantom. Three repeat measurements were made over a period of 2 months to reduce the effect of random errors in measurement or delivery. To ensure that the noise remained below 1.5% (1 SD), minimum doses of 85 cGy were delivered to each detector. The average measured dose was systematically 1.4% lower than predicted and was consistent between repeats. Over the 4 delivered plans, 10/76 measurements showed a systematic error > 3% (3/76 > 5%), for which several potential sources of error were investigated. The error was ultimately attributable to measurements made in beam penumbrae, where submillimeter positional errors result in large discrepancies in dose. The implementation of an image-guided technique improves the accuracy of dose verification, particularly within high-dose gradients. The achievable accuracy of complex IMRT dose delivery incorporating image-guidance is within +/- 3% in dose over the range of sample points. For some points in high-dose gradients, submillimeter errors in position can lead to errors > 3%. The precision of the delivery system was demonstrated to be within the experimental noise of the detector system of 1.5% (1 SD).

Evaluation of larynx-sparing techniques with IMRT when treating the head and neck.

PURPOSE: Concern exists that widespread implementation of whole-field intensity-modulated radiotherapy (IMRT) for the treatment of head-and-neck cancer has resulted in increased levels of dysphagia relative to those seen with conventional planning. Other investigators have suggested an alternative junctioned-IMRT (J-IMRT) method, which matches an IMRT plan to a centrally blocked neck field to restrict the laryngeal dose and reduce dysphagia. The effect on target coverage and sparing of organs at risk, including laryngeal sparing, in the optimization was evaluated and compared with that achieved using a J-IMRT technique. METHODS AND MATERIALS: A total of 13 oropharyngeal cancer whole-field IMRT plans were planned with and without including laryngeal sparing in the optimization. A comparison of the target coverage and sparing of organs at risk was made using the resulting dose-volume histograms and dose distribution. The nine plans with disease located superior to the level of the larynx were replanned using a series of J-IMRT techniques to compare the two laryngeal-sparing techniques. RESULTS: An average mean larynx dose of 29.1 Gy was achieved if disease did not extend to the level of the larynx, with 38.8 Gy for disease extending inferiorly and close to the larynx (reduced from 46.2 and 47.7 Gy, respectively, without laryngeal sparing). Additional laryngeal sparing could be achieved with J-IMRT (mean dose 24.4 Gy), although often at the expense of significantly reduced coverage of the target volume and with no improvement to other areas of the IMRT plan. CONCLUSION: The benefits of J-IMRT can be achieved with whole-field IMRT if laryngeal sparing is incorporated into the class solution. Inclusion of laryngeal sparing had no effect on other parameters in the plan.

Design and implementation of a head-and-neck phantom for system audit and verification of intensity-modulated radiation therapy.

The head and neck is a challenging anatomic site for intensity-modulated radiation therapy (IMRT), requiring thorough testing of planning and treatment delivery systems. Ideally, the phantoms used should be anatomically realistic, have radiologic properties identical to those of the tissues concerned, and allow for the use of a variety of devices to verify dose and dose distribution in any target or normaltissue structure. A phantom that approaches the foregoing characteristics has been designed and built; its specific purpose is verification for IMRT treatments in the head-andneck region. This semi-anatomic phantom, HANK, is constructed of Perspex (Imperial Chemical Industries, London, U.K.) and provides for the insertion of heterogeneities simulating air cavities in a range of fixed positions. Chamber inserts are manufactured to incorporate either a standard thimble ionization chamber (0.125 cm3: PTW, Freiburg, Germany) or a smaller PinPoint chamber (0.015 cm3: PTW), and measurements can be made with either chamber in a range of positions throughout the phantom. Coronal films can also be acquired within the phantom, and additional solid blocks of Perspex allow for transverse films to be acquired within the head region. Initial studies using simple conventional head-and-neck plans established the reproducibility of the phantom and the measurement devices to within the setup uncertainty of +/- 0.5 mm. Subsequent verification of 9 clinical head-and-neck IMRT plans demonstrated the efficacy of the phantom in making a range of patient-specific dose measurements in regions of dosimetric and clinical interest. Agreement between measured values and those predicted by the Pinnacle3 treatment planning system (Philips Medical Systems, Andover, MA) was found to be generally good, with a mean error on the calculated dose to each point of +0.2% (range: -4.3% to +2.2%; n = 9) for the primary planning target volume (PTV), -0.1% (range: -1.5% to +2.0%; n = 8) for the nodal PTV, and +0.0% (range: -1.8% to +4.3%, n = 9) for the spinal cord. The suitability of the phantom for measuring combined dose distributions using radiographic film was also evaluated. The phantom has proved to be a valuable tool in the development and implementation of clinical head-and-neck IMRT, allowing for accurate verification of absolute dose and dose distributions in regions of clinical and dosimetric interest.

Development of an optimum photon beam model for head and-neck intensity-modulated radiotherapy.

Intensity-modulated radiotherapy (IMRT) for complex sites such as tumors of the head and neck requires a level of accuracy in dose calculation beyond that currently used for conformal treatment planning. Recent advances in treatment planning systems have aimed to improve the dose calculation accuracy by improving the modeling of machine characteristics such as interleaf leakage, tongue and groove, and rounded multileaf collimator (MLC) leaf ends. What is uncertain is the extent to which these model parameters improve the agreement between dose calculation and measurements for IMRT treatments. We used Pinnacle version 7.4f (Philips Medical Systems, Andover, MA) to carry out optimization of additional photon-beam model parameters for both an Elekta Precise (Elekta, Stockholm, Sweden) and a Varian (Varian Medical Systems, Palo Alto, CA) linear accelerator (LINAC). One additional parameter was added to the beam models in turn, and associated models were commissioned to investigate the dosimetric impact of each model parameter on 5 clinical head-and-neck IMRT plans. The magnitude and location of differences between the models was determined from gamma analysis of the calculated planar dose maps. A final model that incorporated all of the changes was then commissioned. For the Elekta Precise, the impact of all the changes was determined using a gamma analysis as compared with measured films. Cumulative differences of up to more than 3%/3 mm were observed when dose distributions with and without all of the model changes were compared. Individually, for both LINACs, the addition of modeling for the rounded MLC leaf ends caused the most dramatic change to the calculation of the dose distribution, generating a difference of 3%/3 mm in up to 5% of pixels for the 5 patient plans sampled. The effect of tongue-and-groove modeling was more significant for the Varian LINAC (at 1%/1 mm, mean of 25% of pixels as compared with 5% of pixels with the Elekta Precise LINAC). The combined changes to the Elekta model were found to improve agreement with measurement. Current commercially available treatment planning systems offer accuracy sufficient for clinical implementation of head-and-neck IMRT. For this treatment site, the ability to accurately model the rounded MLC leaf ends has the greatest affect on the similarity of the calculated dose distribution to measurements. In addition, for the Varian LINAC, modeling of the tongue-and-groove effect was also advantageous.