Dose outside of the prostate is associated with improved outcomes for high-risk prostate cancer patients treated with brachytherapy boost.

Background: One in three high-risk prostate cancer patients treated with radiotherapy recur. Detection of lymph node metastasis and microscopic disease spread using conventional imaging is poor, and many patients are under-treated due to suboptimal seminal vesicle or lymph node irradiation. We use Image Based Data Mining (IBDM) to investigate association between dose distributions, and prognostic variables and biochemical recurrence (BCR) in prostate cancer patients treated with radiotherapy. We further test whether including dose information in risk-stratification models improves performance. Method: Planning CTs, dose distributions and clinical information were collected for 612 high-risk prostate cancer patients treated with conformal hypo-fractionated radiotherapy, intensity modulated radiotherapy (IMRT), or IMRT plus a single fraction high dose rate (HDR) brachytherapy boost. Dose distributions (including HDR boost) of all studied patients were mapped to a reference anatomy using the prostate delineations. Regions where dose distributions significantly differed between patients that did and did-not experience BCR were assessed voxel-wise using 1) a binary endpoint of BCR at four-years (dose only) and 2) Cox-IBDM (dose and prognostic variables). Regions where dose was associated with outcome were identified. Cox proportional-hazard models with and without region dose information were produced and the Akaike Information Criterion (AIC) was used to assess model performance. Results: No significant regions were observed for patients treated with hypo-fractionated radiotherapy or IMRT. Regions outside the target where higher dose was associated with lower BCR were observed for patients treated with brachytherapy boost. Cox-IBDM revealed that dose response was influenced by age and T-stage. A region at the seminal vesicle tips was identified in binary- and Cox-IBDM. Including the mean dose in this region in a risk-stratification model (hazard ratio=0.84, p=0.005) significantly reduced AIC values (p=0.019), indicating superior performance, compared with prognostic variables only. The region dose was lower in the brachytherapy boost patients compared with the external beam cohorts supporting the occurrence of marginal misses. Conclusion: Association was identified between BCR and dose outside of the target region in high-risk prostate cancer patients treated with IMRT plus brachytherapy boost. We show, for the first-time, that the importance of irradiating this region is linked to prognostic variables.

Bayesian methods provide a practical real-world evidence framework for evaluating the impact of changes in radiotherapy.

PURPOSE: Retrospective studies have identified a link between the average set-up error of lung cancer patients treated with image-guided radiotherapy (IGRT) and survival. The IGRT protocol was subsequently changed to reduce the action threshold. In this study, we use a Bayesian approach to evaluate the clinical impact of this change to practice using routine 'real-world' patient data. METHODS AND MATERIALS: Two cohorts of NSCLC patients treated with IGRT were compared: pre-protocol change (N = 780, 5 mm action threshold) and post-protocol change (N = 411, 2 mm action threshold). Survival models were fitted to each cohort and changes in the hazard ratios (HR) associated with residual set-up errors was assessed. The influence of using an uninformative and a skeptical prior in the model was investigated. RESULTS: Following the reduction of the action threshold, the HR for residual set-up error towards the heart was reduced by up to 10%. Median patient survival increased for patients with set-up errors towards the heart, and remained similar for patients with set-up errors away from the heart. Depending on the prior used, a residual hazard ratio may remain. CONCLUSIONS: Our analysis found a reduced hazard of death and increased survival for patients with residual set-up errors towards versus away from the heart post-protocol change. This study demonstrates the value of a Bayesian approach in the assessment of technical changes in radiotherapy practice and supports the consideration of adopting this approach in further prospective evaluations of changes to clinical practice.

Causal relation between heart irradiation and survival of lung cancer patients after radiotherapy.

INTRODUCTION: In a recent study, setup uncertainties in the direction of the heart were shown to impact the overall survival of non-small cell lung cancer (NSCLC) patients after radiotherapy, indicating the causal effect between heart irradiation and survival. The current study aims to externally evaluate this observation within a patient cohort treated using daily IGRT. METHOD: NSCLC patients with locally-advanced disease and daily CBCT were included. For all treatment fractions, the distance between the isocenter and the heart was evaluated based on the clinical setup registrations. The variation in heart position between planning and treatment (DeltaDistance) was estimated from these registrations. The possible impact of DeltaDistance on survival was analysed by a multivariable Cox model of overall survival, allowing for a time-dependent impact of DeltaDistance to allow for toxicity latency. RESULTS: Daily CBCT information was available for 489 patients at Odense University Hospital. The primary Cox model contained GTV volume, patient age, performance status, and DeltaDistance. DeltaDistance significantly impacted overall survival approximately 50 months after radiotherapy. Subanalyses indicated that the observed effect is mainly present among the patients with the least clinical risk factors. CONCLUSION: Our results confirm the impact of setup variations in the direction of the heart on the survival of NSCLC patients, even within a cohort using daily CBCT setup guidance. This result indicates a causal effect between heart irradiation and survival. It will be challenging to reduce the setup uncertainty even further; thus, increased focus on dose constraints on the heart seems warranted.

Learning healthcare systems and rapid learning in radiation oncology: Where are we and where are we going?

Learning health systems and rapid-learning are well developed at the conceptual level. The promise of rapidly generating and applying evidence where conventional clinical trials would not usually be practical is attractive in principle. The connectivity of modern digital healthcare information systems and the increasing volumes of data accrued through patients' care pathways offer an ideal platform for the concepts. This is particularly true in radiotherapy where modern treatment planning and image guidance offers a precise digital record of the treatment planned and delivered. The vision is of real-world data, accrued by patients during their routine care, being used to drive programmes of continuous clinical improvement as part of standard practice. This vision, however, is not yet a reality in radiotherapy departments. In this article we review the literature to explore why this is not the case, identify barriers to its implementation, and suggest how wider clinical application might be achieved.

Novel methodology to assess the effect of contouring variation on treatment outcome.

PURPOSE: Contouring variation is one of the largest systematic uncertainties in radiotherapy, yet its effect on clinical outcome has never been analyzed quantitatively. We propose a novel, robust methodology to locally quantify target contour variation in a large patient cohort and find where this variation correlates with treatment outcome. We demonstrate its use on biochemical recurrence for prostate cancer patients. METHOD: We propose to compare each patient's target contours to a consistent and unbiased reference. This reference was created by auto-contouring each patient's target using an externally trained deep learning algorithm. Local contour deviation measured from the reference to the manual contour was projected to a common frame of reference, creating contour deviation maps for each patient. By stacking the contour deviation maps, time to event was modeled pixel-wise using a multivariate Cox proportional hazards model (CPHM). Hazard ratio (HR) maps for each covariate were created, and regions of significance found using cluster-based permutation testing on the z-statistics. This methodology was applied to clinical target volume (CTV) contours, containing only the prostate gland, from 232 intermediate- and high-risk prostate cancer patients. The reference contours were created using ADMIRE® v3.4 (Elekta AB, Sweden). Local contour deviations were computed in a spherical coordinate frame, where differences between reference and clinical contours were projected in a 2D map corresponding to sampling across the coronal and transverse angles every 3°. Time to biochemical recurrence was modeled using the pixel-wise CPHM analysis accounting for contour deviation, patient age, Gleason score, and treated CTV volume. RESULTS: We successfully applied the proposed methodology to a large patient cohort containing data from 232 patients. In this patient cohort, our analysis highlighted regions where the contour variation was related to biochemical recurrence, producing expected and unexpected results: (a) the interface between prostate-bladder and prostate-seminal vesicle interfaces where increase in the manual contour relative to the reference was related to a reduction of risk of biochemical recurrence by 4-8% per mm and (b) the prostate's right, anterior and posterior regions where an increase in the manual contour relative to the reference contours was related to an increase in risk of biochemical recurrence by 8-24% per mm. CONCLUSION: We proposed and successfully applied a novel methodology to explore the correlation between contour variation and treatment outcome. We analyzed the effect of contour deviation of the prostate CTV on biochemical recurrence for a cohort of more than 200 prostate cancer patients while taking basic clinical variables into account. Applying this methodology to a larger dataset including additional clinically important covariates and externally validating it can more robustly identify regions where contour variation directly relates to treatment outcome. For example, in the prostate case we use to demonstrate our novel methodology, external validation will help confirm or reject the counter-intuitive results (larger contours resulting in higher risk). Ultimately, the results of this methodology could inform contouring protocols based on actual patient outcomes.

Impact of small residual setup errors after image guidance on heart dose and survival in non-small cell lung cancer treated with curative-intent radiotherapy.

BACKGROUND AND PURPOSE: A recent study of NSCLC patients showed small residual setup errors (shifts) in the direction of the heart following image-guidance were significantly related to overall survival. This study of the dosimetric effects of these residual shifts investigates the hypothesis that observed survival differences were related to a change in heart dose. MATERIALS AND METHODS: Accumulated doses including shifts for each fraction were determined for 475 NSCLC patients. Planning CTs and corresponding dose distributions were deformed to a reference. Image-based data-mining techniques were then applied to the difference between the planned and accumulated dose (Δdose) to determine where Δdose relates to 1-year survival. The significance of Δdose in the identified region was assessed using multivariable Cox analysis. The cohort was then split into octiles, based upon planned dose to the region, and multivariable Cox analysis performed for each sub-cohort to explore the dose response relationship. The identified dose threshold for damage was then tested in an independent validation cohort of 1482 NSCLC patients from the same institution. RESULTS: Permutation testing identified a small region in the heart base where Δdose significantly correlated with 1-year survival. Δdose in this region showed no correlation with common clinical variables, and was significant in multivariable Cox regression (p < 0.001, hazard ratio 1.221/Gy), with increasing change in dose from plan resulting in greater risk of death. Octile analysis revealed Δdose to be significant only in the 7th octile, planning dose 16.2-23.4 Gy, suggesting a steep dose-effect relation for heart damage in this range. Taking 16.2 Gy as a conservative threshold dose, this result was successfully validated, with a significant difference being seen between patients with a region dose above or below 16.2 Gy. CONCLUSIONS: This study suggests the relation between residual set-up errors and survival is explained by changes in cardiac dose, and identifies an area at the heart base where dose is correlated with survival. Our results suggest the dose threshold for cardiac damage is between 16.2 and 23.4 Gy in the base of the heart, which was validated in an independent cohort. However, the dose effect in other regions of the heart should also be investigated.

The impact of baseline shifts towards the heart after image guidance on survival in lung SABR patients.

BACKGROUND AND PURPOSE: A recent study of NSCLC patients showed small residual shifts of the high dose region towards/away from the heart after image-guidance were significantly related to overall survival. This study investigates whether the effect is observed in a SABR cohort, who have significantly different baseline outlook and are treated using an imaging protocol matching on the tumour rather than bony-anatomy alone. MATERIALS AND METHODS: 136 NSCLC patients treated with SABR were studied. The mean baseline shift of the tumour in the direction of the heart over the course of treatment was determined for each patient and used to categorise patients into risk groups. Kaplan-Meier survival curves were plotted and multivariable analysis performed to assess significance of the vector shift to the heart alongside common clinical variables. RESULTS: The vector shift to the heart was independent of all tested clinical variables. A significant difference was seen in patient survival, with patients with shifts towards the heart having significantly worse prognosis as compared to patients with shifts away. Multivariable analysis found a hazard ratio of 1.262 per mm (p = 0.013) for the vector shift to the heart, i.e. for every 1 mm shift of the high dose region towards the heart there is a 1.262 higher chance of death. CONCLUSIONS: Baseline shifts towards the heart significantly correlate with overall survival in a cohort of NSCLC SABR patients, with increased risk with increasing shifts towards the heart. These results provide further evidence for the use of stricter heart dose planning constraints for thoracic radiotherapy and suggest a heart planning organ at risk volume may be required for SABR treatments to account for baseline shifts.

Residual Setup Errors Towards the Heart After Image Guidance Linked With Poorer Survival in Lung Cancer Patients: Do We Need Stricter IGRT Protocols?

PURPOSE: Image guided radiation therapy (IGRT) is widely used, but data directly relating set-up errors to patient outcome are scarce. This study investigates the relationship between residual IGRT shifts and overall patient survival and uses the observed relations to identify structures sensitive to radiation dose. METHODS AND MATERIALS: Residual shift data for 780 patients with non-small cell lung cancer were summarized for each patient over the course of treatment by determining the mean shifts, standard deviations, and the vector shift in the direction of the heart. These variables were related to overall survival, and significant variables were used to produce Kaplan-Meier plots of survival. The effect of shift directionality was studied by splitting the cohort into left, right, anterior, posterior, superior, and inferior groups and by analyzing the vector shift in the direction of the heart. The observed relationship was independently validated in an esophageal cancer cohort (n = 177). RESULTS: The shift data showed strong associations with survival. Left and right cohorts showed opposite directional shift effects, suggesting shifts toward the mediastinum have a negative effect on survival. Projection of the vector shift in the direction of the heart showed that patients with a residual shift toward the heart have significantly worse overall survival (P = .007, hazard ratio 1.091). The same effect was observed in the esophageal cancer cohort (P = .041, hazard ratio 1.164). CONCLUSIONS: Residual shift metrics derived from IGRT data can categorize patients with non-small cell lung cancer and those with esophageal cancer into populations with significantly different survival times on the basis of the size of the residual shift in the direction of the heart, thus providing evidence of the importance of using strict IGRT protocols to spare organs at risk and highlighting the heart as a dose-sensitive organ.