Is Ultrahypofractionated Whole Pelvis Radiation Therapy (WPRT) as Well Tolerated as Conventionally Fractionated WPRT in Patients With Prostate Cancer? Early Results From the HOPE Trial.

OBJECTIVE: The aim of this work was to evaluate the acute toxicity and quality-of-life (QOL) impact of ultrahypofractionated whole pelvis radiation therapy (WPRT) compared with conventional WPRT fractionation after high-dose-rate prostate brachytherapy (HDR-BT). METHODS AND MATERIALS: The HOPE trial is a phase 2, multi-institutional randomized controlled trial of men with prostate-confined disease and National Comprehensive Cancer Network unfavorable intermediate-, high-, or very-high-risk prostate cancer. Patients were randomly assigned to receive conventionally fractionated WPRT (standard arm) or ultrahypofractionated WPRT (experimental arm) in a 1:1 ratio. All patients underwent radiation therapy with 15 Gy HDR-BT boost in a single fraction followed by WPRT delivered with conventional fractionation (45 Gy in 25 daily fractions or 46 Gy in 23 fractions) or ultrahypofractionation (25 Gy in 5 fractions delivered on alternate days). Acute toxicities measured during radiation therapy and at 6 weeks posttreatment were assessed using the clinician-reported Common Terminology Criteria for Adverse Events version 5.0, and QOL was measured using the Expanded Prostate Cancer Index Composite (EPIC-50) and International Prostate Symptom Score (IPSS). RESULTS: A total of 80 patients were enrolled and treated across 3 Canadian institutions, of whom 39 and 41 patients received external radiation therapy with conventionally fractionated and ultrahypofractionated WPRT, respectively. All patients received androgen deprivation therapy except for 2 patients treated in the ultrahypofractionated arm. The baseline clinical characteristics of the 2 arms were similar, with 51 (63.8%) patients having high or very-high-risk prostate cancer disease. Treatment was well tolerated with no significant differences in the rate of acute adverse events between arms. No grade 4 adverse events or treatment-related deaths were reported. Ultrahypofractionated WPRT had a less detrimental impact on the EPIC-50 bowel total, function, and bother domain scores compared with conventional WPRT in the acute setting. By contrast, more patients treated with ultrahypofractionated WPRT reached the minimum clinical important difference on the EPIC-50 urinary domains. No significant QOL differences between arms were noted in the sexual and hormonal domains. CONCLUSIONS: Ultrahypofractionated WPRT after HDR-BT is a well-tolerated treatment strategy in the acute setting that has less detrimental impact on bowel QOL domains compared with conventional WPRT.

Alert system for monitoring changes in patient anatomy during radiation therapy of head and neck cancer.

The purpose of this study is to validate a previously developed algorithm for alerting clinicians when to consider re-CT simulation due to changes in the patient's anatomy during radiation therapy of head and neck cancer. Cone beam computed tomography (CBCT) data were collected prospectively for 77 patients. Each CBCT was mathematically compared to a reference CBCT using the gamma index. We defined the match quality parameter (MQP) as an indicator of CBCT image similarity, where a negative MQP value indicates a poorer CBCT match than the match between the first two CBCT acquired during treatment. If three consecutive MQP values were below a chosen threshold, an "alert" is triggered to indicate action required, for example, possible re-CT simulation. The timing of image review requests made by the radiation therapists and any re-CT/re-plan decisions were documented for each patient's treatment course. The MQP for each patient (including any re-plans) was calculated in a manner that was blinded from the clinical process. The MQP as a function of fraction number was compared to actual clinical decisions in the treatment progress to evaluate alert system performance. There was a total of 93 plans (including re-plans) with 34 positives (action required) and 59 negatives (no action required). The sensitivity of the alert system was 0.76 and the false positive rate was 0.37. Only 1 case out of the 34 positive cases would have been missed by both the alert system and our clinical process. Despite the false negatives and false positives, analysis of the timing of alert triggers showed that the alert system could have resulted in seven fewer clinical misses. The alert system has the potential to be a valuable tool to complement human judgment and to provide a quality assurance safeguard to help improve the delivery of radiation treatment of head and neck cancer.

Is hypofractionated whole pelvis radiotherapy (WPRT) as well tolerated as conventionally fractionated WPRT in prostate cancer patients? The HOPE trial.

BACKGROUND: Patients with high-risk prostate cancer are at increased risk of lymph node metastasis and are thought to benefit from whole pelvis radiotherapy (WPRT). There has been recent interest in the use of hypofractionated radiotherapy in treating prostate cancer. However, toxicity and cancer outcomes associated with hypofractionated WPRT are unclear at this time. This phase II study aims to investigate the impact in quality of life associated with hypofractionated WPRT compared to conventionally fractionated WPRT. METHODS: Fifty-eight patients with unfavourable intermediate-, high- or very high-risk prostate cancer will be randomized in a 1:1 ratio between high-dose-rate brachytherapy (HDR-BT) + conventionally fractionated (45 Gy in 25 fractions) WPRT vs. HDR-BT + hypofractionated (25 Gy in 5 fractions) WPRT. Randomization will be performed with a permuted block design without stratification. The primary endpoint is late bowel toxicity and the secondary endpoints include acute and late urinary and sexual toxicity, acute bowel toxicity, biochemical failure-, androgen deprivation therapy-, metastasis- and prostate cancer-free survival of the hypofractionated arm compared to the conventionally fractionated arm. DISCUSSION: To our knowledge, this is the first study to compare hypofractionated WPRT to conventionally fractionated WPRT with HDR-BT boost. Hypofractionated WPRT is a more attractive and convenient treatment approach, and may become the new standard of care if demonstrated to be well-tolerated and effective. TRIAL REGISTRATION: This trial was prospectively registered in ClinicalTrials.gov as NCT04197141 on December 12, 2019.

Using gamma index to flag changes in anatomy during image-guided radiation therapy of head and neck cancer.

During radiation therapy of head and neck cancer, the decision to consider replanning a treatment because of anatomical changes has significant resource implications. We developed an algorithm that compares cone-beam computed tomography (CBCT) image pairs and provides an automatic alert as to when remedial action may be required. Retrospective CBCT data from ten head and neck cancer patients that were replanned during their treatment was used to train the algorithm on when to recommend a repeat CT simulation (re-CT). An additional 20 patients (replanned and not replanned) were used to validate the predictive power of the algorithm. CBCT images were compared in 3D using the gamma index, combining Hounsfield Unit (HU) difference with distance-to-agreement (DTA), where the CBCT study acquired on the first fraction is used as the reference. We defined the match quality parameter (MQPx ) as a difference between the xth percentiles of the failed-pixel histograms calculated from the reference gamma comparison and subsequent comparisons, where the reference gamma comparison is taken from the first two CBCT images acquired during treatment. The decision to consider re-CT was based on three consecutive MQP values being less than or equal to a threshold value, such that re-CT recommendations were within ±3 fractions of the actual re-CT order date for the training cases. Receiver-operator characteristic analysis showed that the best trade-off in sensitivity and specificity was achieved using gamma criteria of 3 mm DTA and 30 HU difference, and the 80th percentile of the failed-pixel histogram. A sensitivity of 82% and 100% was achieved in the training and validation cases, respectively, with a false positive rate of ~30%. We have demonstrated that gamma analysis of CBCT-acquired anatomy can be used to flag patients for possible replanning in a manner consistent with local clinical practice guidelines.

On bolus for megavoltage photon and electron radiation therapy.

Frequently, in radiation therapy one must treat superficial lesions on cancer patients; these are at or adjacent to the skin. Megavoltage photon radiotherapy penetrates through the skin to irradiate deep-seated tumors, with skin-sparing property. Hence, to treat superficial lesions, one must use a layer of scattering material to feign as the skin surface. Although megavoltage electron beams are used for superficial treatments, one occasionally needs to enhance the dose near the surface. Such is the function of a "bolus," a natural or synthetically developed material that acts as a layer of tissue to provide a more effective treatment to the superficial lesions. Other uses of boluses are to correct for varying surface contours and to add scattering material around the patient's surface. Materials used as bolus vary from simple water to metal and include various mixtures and compounds. Even with the modernization of the technology for external-beam therapy and the emergence of various commercial boluses, the preparation and utilization of a bolus in clinical radiotherapy remains an art. Considering the varying experiences and practices, this paper briefly summarizes available boluses that have been proposed and are employed in clinical radiotherapy. Although this review is not exhaustive, it provides some initial guidance and answers questions that may arise in clinical practice.

Automatic image guidance for prostate IMRT using low dose CBCT.

PURPOSE: Varian's On-Board Imager is a linac-integrated cone-beam CT (CBCT) system used at the authors' institution to acquire images prior to delivering each fraction of prostate intensity modulated radiotherapy. The images are used to determine a couch shift that realigns the tumor with the position obtained in the planning CT. However, this manual image-guided radiotherapy (IGRT) technique is operator dependent, time consuming, offers limited degrees of freedom, and requires significant imaging dose over the course of treatment. To overcome these problems, the authors propose two fully automatic IGRT techniques that require significantly less imaging dose. METHODS: Dose is reduced by lowering the x-ray tube mA s during CBCT acquisition at the cost of increasing image noise. In "forward" IGRT, the CBCT image is automatically registered to the planning CT to obtain the necessary couch shift. The "reverse" technique offers additional degrees of freedom as it involves nonrigid registration of the planning CT to the CBCT. Both techniques were evaluated using images of an anthropomorphic phantom with simulated motion and by retrospectively analyzing data from ten prostate cancer patients. RESULTS: IGRT error for the phantom data at 100% relative imaging dose was 8.2 +/- 3.7, 3.5 +/- 1.2,, and 2.1 +/- 0.6 mm for setup only, forward, and reverse techniques, respectively. For patient images acquired at 100% relative imaging dose, the errors were 5.4 +/- 1.7, 5.0 +/- 1.6, 5.0 +/- 2.0, and 4.0 +/- 1.6 mm for setup only, manual forward (performed clinically), automatic forward, and reverse IGRT, respectively. Furthermore, imaging dose could be reduced to 20% without a significant loss in image guidance accuracy. CONCLUSIONS: The presented image guidance methods are accurate while requiring only 20% of the standard imaging dose. The combination of low dose, automation, and accuracy enables frequent corrections during treatment, possibly leading to reduced margins and improved treatment outcomes.

Dose assessment from an online kilovoltage imaging system in radiation therapy.

We have investigated the dosimetric properties of a commercial kilovoltage cone beam computerised tomography (kV-CBCT) system. The kV-CBCT doses were measured in 16 and 32 cm diameter standard cylindrical Perspex computerised tomography (CT) and Rando anthropomorphic phantoms using 125 kVp and 1.0-2.0 mA s per projection. We also measured skin doses using thermoluminescence dosimeters placed on the skin surfaces of prostate cancer patients undergoing kV-kV image matching for daily set-up. The skin doses from kV-kV image matching of prostate cancer patients on the anterior and lateral skin surfaces ranged from 0.03 +/- 0.01 to 0.64 +/- 0.01 cGy depending on the beam filtration and technique factors employed. The mean doses on the Rando phantom ranged from 3.0 +/- 0.1 to 5.1 +/- 0.3 cGy for full-fan scans and from 3.8 +/- 0.1 to 6.6 +/- 0.2 cGy for half-fan scans using 125 kVp and 2 mA s per projection. The isocentre cone beam dose index (CBDI) in the 16 and 32 cm Perspex phantoms is 4.65 and 1.81 cGy, respectively (using a 0.6 cm(3) Capintec PR06C Farmer chamber) for full-fan scans, and the corresponding normalised CBDIs are 0.72 and 0.28 cGy/100 mA s, respectively. The mean weighted CBDIs are 4.93 and 2.14 cGy, and the normalised weighted CBDIs are 0.76 and 0.33 cGy/100 mA s for the 16 and 32 cm phantoms, respectively (full-fan scans). The normalised weighted CBDI for the half-fan scan is 0.41 cGy/100 mA s for the 32 cm diameter phantom. All measurements of the CBDI using the 0.6 cm(3) Farmer chamber are within 2-5% of measurements taken with the 100 mm CT chamber. The CBDI technique and definitions can be used to benchmark CBCT systems and to provide estimates of imaging doses to patients undergoing on-board imager (OBI)/CBCT image guided radiation therapy.

Evaluation of image-guided radiation therapy (IGRT) technologies and their impact on the outcomes of hypofractionated prostate cancer treatments: a radiobiologic analysis.

PURPOSE: To quantify the mitigation of geometric uncertainties achieved with the application of various patient setup techniques during the delivery of hypofractionated prostate cancer treatments, using tumor control probability (TCP) and normal tissue complication probability. METHODS AND MATERIALS: Five prostate cancer patients with approximately 16 treatment CT studies, taken during the course of their radiation therapy (77 total), were analyzed. All patients were planned twice with an 18 MV six-field conformal technique, with 10- and 5-mm margin sizes, with various hypofractionation schedules (5 to 35 fractions). Subsequently, four clinically relevant patient setup techniques (laser guided and image guided) were simulated to deliver such schedules. RESULTS: As hypothesized, the impact of geometric uncertainties on clinical outcomes increased with more hypofractionated schedules. However, the absolute gain in TCP due to hypofractionation (up to 21.8% increase) was significantly higher compared with the losses due to geometric uncertainties (up to 8.6% decrease). CONCLUSIONS: The results of this study suggest that, although the impact of geometric uncertainties on the treatment outcomes increases as the number of fractions decrease, the reduction in TCP due to the uncertainties does not significantly offset the expected theoretical gain in TCP by hypofractionation.

Image-guided adaptive radiation therapy (IGART): Radiobiological and dose escalation considerations for localized carcinoma of the prostate.

The goal of this work was to evaluate the efficacy of various image-guided adaptive radiation therapy (IGART) techniques to deliver and escalate dose to the prostate in the presence of geometric uncertainties. Five prostate patients with 15-16 treatment CT studies each were retrospectively analyzed. All patients were planned with an 18 MV, six-field conformal technique with a 10 mm margin size and an initial prescription of 70 Gy in 35 fractions. The adaptive strategy employed in this work for patient-specific dose escalation was to increase the prescription dose in 2 Gy-per-fraction increments until the rectum normal tissue complication probability (NTCP) reached a level equal to that of the nominal plan NTCP (i.e., iso-NTCP dose escalation). The various target localization techniques simulated were: (1) daily laser-guided alignment to skin tattoo marks that represents treatment without image-guidance, (2) alignment to bony landmarks with daily portal images, and (3) alignment to the clinical target volume (CTV) with daily CT images. Techniques (1) and (3) were resimulated with a reduced margin size of 5 mm to investigate further dose escalation. When delivering the original clinical prescription dose of 70 Gy in 35 fractions, the "CTV registration" technique yielded the highest tumor control probability (TCP) most frequently, followed by the "bone registration" and "tattoo registration" techniques. However, the differences in TCP among the three techniques were minor when the margin size was 10 mm (< or = 1.1 %). Reducing the margin size to 5 mm significantly degraded the TCP values of the "tattoo registration" technique in two of the five patients, where a large difference was found compared to the other techniques (< or = 11.8 %). The "CTV registration" technique, however, did maintain similar TCP values compared to their 10 mm margin counterpart. In terms of normal tissue sparing, the technique producing the lowest NTCP varied from patient to patient. Reducing the margin size seemed the only sure way to reduce the NTCP significantly, irrespective of the IGART technique employed. In escalating the dose with the iso-NTCP constraint, the largest average gain in dose was observed with the "tattoo registration" technique, followed by the "CTV registration" and "bone registration" techniques. This is attributed to the fact that in three of the five patients, the "tattoo registration" technique yielded the lowest NTCP, hence a greater window of opportunity to escalate the dose was possible with this technique. However, the variation among the five patients was also largest with the "tattoo registration" technique where, in the case of one patient, the required dose actually needed to be below the original prescription dose of 70 Gy to satisfy the iso-NTCP constraint. This was not the case with the "CTV registration" technique where positive and similar dose escalation was allowed on all five patients. Based on these data, an attractive dose escalation strategy may be to implement the "CTV registration" technique (for consistent dosimetric coverage) for daily target localization in combination with a margin reduction (for increased normal tissue sparing).

Image-guided adaptive radiation therapy (IGART): Radiobiological and dose escalation considerations for localized carcinoma of the prostate.

The goal of this work was to evaluate the efficacy of various image-guided adaptive radiation therapy (IGART) techniques to deliver and escalate dose to the prostate in the presence of geometric uncertainties. Five prostate patients with 15-16 treatment CT studies each were retrospectively analyzed. All patients were planned with an 18 MV, six-field conformal technique with a 10 mm margin size and an initial prescription of 70 Gy in 35 fractions. The adaptive strategy employed in this work for patient-specific dose escalation was to increase the prescription dose in 2 Gy-per-fraction increments until the rectum normal tissue complication probability (NTCP) reached a level equal to that of the nominal plan NTCP (i.e., iso-NTCP dose escalation). The various target localization techniques simulated were: (1) daily laser-guided alignment to skin tattoo marks that represents treatment without image-guidance, (2) alignment to bony landmarks with daily portal images, and (3) alignment to the clinical target volume (CTV) with daily CT images. Techniques (1) and (3) were resimulated with a reduced margin size of 5 mm to investigate further dose escalation. When delivering the original clinical prescription dose of 70 Gy in 35 fractions, the "CTV registration" technique yielded the highest tumor control probability (TCP) most frequently, followed by the "bone registration" and "tattoo registration" techniques. However, the differences in TCP among the three techniques were minor when the margin size was 10 mm (⩽1.1%). Reducing the margin size to 5 mm significantly degraded the TCP values of the "tattoo registration" technique in two of the five patients, where a large difference was found compared to the other techniques (⩽11.8%). The "CTV registration" technique, however, did maintain similar TCP values compared to their 10 mm margin counterpart. In terms of normal tissue sparing, the technique producing the lowest NTCP varied from patient to patient. Reducing the margin size seemed the only sure way to reduce the NTCP significantly, irrespective of the IGART technique employed. In escalating the dose with the iso-NTCP constraint, the largest average gain in dose was observed with the "tattoo registration" technique, followed by the "CTV registration" and "bone registration" techniques. This is attributed to the fact that in three of the five patients, the "tattoo registration" technique yielded the lowest NTCP, hence a greater window of opportunity to escalate the dose was possible with this technique. However, the variation among the five patients was also largest with the "tattoo registration" technique where, in the case of one patient, the required dose actually needed to be below the original prescription dose of 70 Gy to satisfy the iso-NTCP constraint. This was not the case with the "CTV registration" technique where positive and similar dose escalation was allowed on all five patients. Based on these data, an attractive dose escalation strategy may be to implement the "CTV registration" technique (for consistent dosimetric coverage) for daily target localization in combination with a margin reduction (for increased normal tissue sparing).