Dosimetric Evaluation of PSMA PET-Delineated Dominant Intraprostatic Lesion Simultaneous Infield Boosts

Purpose: Prostate cancer is multifocal. However, there often exists a single dominant focus in the gland responsible for driving the biology of the disease. Dose escalation to the dominant lesion is a proposed strategy to increase tumor control. We applied radiobiological modeling to evaluate the dosimetric feasibility and benefit of dominant intraprostatic lesion simultaneous in-field boosts (DIL-SIB) to the gross tumor volume (GTV), defined using a novel molecular positron emission tomography (PET) probe (18F-DCFPyL) directed against prostate specific membrane antigen (PSMA). Methods and Materials: Patients with clinically localized, biopsy-proven prostate cancer underwent preoperative [ F]-DCFPyL PET/computed tomography (CT). DIL-SIB plans were generated by importing the PET/CT into the RayStation treatment planning system. GTV-PET for the DIL-SIB was defined by the highest %SUVmax (percentage of maximum standardized uptake value) that generated a biologically plausible volume. Volumetric arc–based plans incorporating prostate plus DIL-SIB treatment were generated. Tumor control probability (TCP) and normal tissue complication probability (NTCP) with fractionation schemes and boost doses specified in the FLAME (Investigate the Benefit of a Focal Lesion Ablative Microboost in Prostate Cancer; NCT01168479), PROFIT (Prostate Fractionated Irradiation Trial; NCT00304759), PACE (Prostate Advances in Comparative Evidence; NCT01584258), and hypoFLAME (Hypofractionated Focal Lesion Ablative Microboost in prostatE Cancer 2.0; NCT02853110) protocols were compared. Results: Comparative DIL-SIB plans for 6 men were generated from preoperative [ F]-DCFPyL PET/CT. Median boost GTV volume was 1.015 cm (0.42-1.83 cm ). Median minimum (D99%) DIL-SIB dose for F35 , F20 , F5 , and F5 were 97.3 Gy, 80.8 Gy, 46.5 Gy, and 51.5Gy. TCP within the GTV ranged from 84% to 88% for the standard plan and 95% to 96% for the DIL-SIB plans. Within the rest of the prostate, TCP ranged from 89% to 91% for the standard plans and 90% to 92% for the DIL-SIB plans. NTCP for the rectum NTCP was similar for the DIL-SIB plans (0.3%-2.7%) compared with standard plans (0.7%-2.6%). Overall, DIL-SIB plans yielded higher uncomplicated TCP (NTCP, 90%-94%) versus standard plans (NTCP, 83%-85%). Conclusions: PSMA PET provides a novel approach to define GTV for SIB-DIL dose escalation. Work is ongoing to validate PSMA PET-delineated GTV through correlation to coregistered postprostatectomy digitized histopathology. 18 18 3 3 BS BS BS BS

Imaging Biomarkers in Prostate Stereotactic Body Radiotherapy: A Review and Clinical Trial Protocol

Advances in imaging have changed prostate radiotherapy through improved biochemical control from focal boost and improved detection of recurrence. These advances are reviewed in the context of prostate stereotactic body radiation therapy (SBRT) and the ARGOS/CLIMBER trial protocol. ARGOS/CLIMBER will evaluate 1) the safety and feasibility of SBRT with focal boost guided by multiparametric MRI (mpMRI) and 18F-PSMA-1007 PET and 2) imaging and laboratory biomarkers for response to SBRT. To date, response to prostate SBRT is most commonly evaluated using the Phoenix Criteria for biochemical failure. The drawbacks of this approach include lack of lesion identification, a high false-positive rate, and delay in identifying treatment failure. Patients in ARGOS/CLIMBER will receive dynamic 18F-PSMA-1007 PET and mpMRI prior to SBRT for treatment planning and at 6 and 24 months after SBRT to assess response. Imaging findings will be correlated with prostate-specific antigen (PSA) and biopsy results, with the goal of early, non-invasive, and accurate identification of treatment failure

Modeling progression in radiation-induced lung adenocarcinomas

Quantitative multistage carcinogenesis models are used in radiobiology to estimate cancer risks and latency periods (time from exposure to clinical cancer). Steps such as initiation, promotion and transformation have been modeled in detail. However, progression, a later step during which malignant cells can develop into clinical symptomatic cancer, has often been approximated simply as a fixed lag time. This approach discounts important stochastic mechanisms in progression and evidence on the high prevalence of dormant tumors. Modeling progression more accurately is therefore important for risk assessment. Unlike models of earlier steps, progression models can readily utilize not only experimental and epidemiological data but also clinical data such as the results of modern screening and imaging. Here, a stochastic progression model is presented. We describe, with minimal parameterization: the initial growth or extinction of a malignant clone after formation of a malignant cell; the likely dormancy caused, for example, by nutrient and oxygen deprivation; and possible escape from dormancy resulting in a clinical cancer. It is shown, using cohort simulations with parameters appropriate for lung adenocarcinomas, that incorporating such processes can dramatically lengthen predicted latency periods. Such long latency periods together with data on timing of radiation-induced cancers suggest that radiation may influence progression itself

Repopulation of interacting tumor cells during fractionated radiotherapy: Stochastic modeling of the tumor control probability

Purpose: Optimal treatment planning for fractionated external beam radiation therapy requires inputs from radiobiology based on recent thinking about the “five Rs” (repopulation, radiosensitivity, reoxygenation, redistribution, and repair). The need is especially acute for the newer, often individualized, protocols made feasible by progress in image guided radiation therapy and dose conformity. Current stochastic tumor control probability (TCP) models incorporating tumor repopulation effects consider “stem-like cancer cells” (SLCC) to be independent, but the authors here propose that SLCC-SLCC interactions may be significant. The authors present a new stochastic TCP model for repopulating SLCC interacting within microenvironmental niches. Our approach is meant mainly for comparing similar protocols. It aims at practical generalizations of previous mathematical models. Methods: The authors consider protocols with complete sublethal damage repair between fractions. The authors use customized open-source software and recent mathematical approaches from stochastic process theory for calculating the time-dependent SLCC number and thereby estimating SLCC eradication probabilities. As specific numerical examples, the authors consider predicted TCP results for a 2 Gy per fraction, 60 Gy protocol compared to 64 Gy protocols involving early or late boosts in a limited volume to some fractions. Results: In sample calculations with linear quadratic parameters α = 0.3 per Gy, α/β = 10 Gy, boosting is predicted to raise TCP from a dismal 14.5% observed in some older protocols for advanced NSCLC to above 70%. This prediction is robust as regards: (a) the assumed values of parameters other than α and (b) the choice of models for intraniche SLCC-SLCC interactions. However, α = 0.03 per Gy leads to a prediction of almost no improvement when boosting. Conclusions: The predicted efficacy of moderate boosts depends sensitively on α. Presumably, the larger values of α are the ones appropriate for individualized treatment protocols, with the smaller values relevant only to protocols for a heterogeneous patient population. On that assumption, boosting is predicted to be highly effective. Front boosting, apart from practical advantages and a possible advantage as regards iatrogenic second cancers, also probably gives a slightly higher TCP than back boosting. If the total number of SLCC at the start of treatment can be measured even roughly, it will provide a highly sensitive way of discriminating between various models and parameter choices. Updated mathematical methods for calculating repopulation allow credible generalizations of earlier results

Planning for the Effect of the SC.24 Trial on Spine Stereotactic Body Radiation Therapy Utilization at a Tertiary Cancer Center

Purpose: The goal of this study was to assess the potential real-world effect of the recently reported SC.24 trial on spine stereotactic body radiation therapy (SBRT) utilization. We estimated the proportion of patients treated with conventional radiation therapy (CRT) who would have been eligible for spine SBRT per trial inclusion criteria and analyzed the potential estimated increased costs to our institution. Methods and Materials: This was a retrospective review of patients who received spine CRT at our institution between August and October 2020. Data abstracted included demographics, SC.24 eligibility criteria, provider-reported pain response, and survival. A cost analysis and time survey was performed using institutional and provincial data. Results: Of 73 patients reviewed, 24 patients (33%) were eligible. The most common exclusion factors included irradiation of ≥3 consecutive spinal segments (n = 32, 44%), Eastern Cooperative Oncology Group performance status >2 (n = 17, 23%), and symptomatic spinal cord compression (n = 13, 18%). Of eligible patients, the mean age was 68.92 years, median spinal instability in neoplasia score was 8 (interquartile range, 7-9), and median Eastern Cooperative Oncology Group performance status was 2 (interquartile range, 1-2). The most common primary cancer types among eligible patients were lung (n = 10) and breast (n = 4). The median survival of eligible patients was 10 months (95% confidence interval, 4 months to not reached) with 58% surviving longer than 3 months. Of patients who had subjective pain documented after CRT, 54% had at least some response. The cost of spine SBRT was estimated at CA$4764.80 compared with$3589.10 for CRT, and tasks for spine SBRT took roughly 3 times as long as those for CRT. Conclusions: One-third of patients who received palliative spine CRT met eligibility criteria for SC.24. This possible expanded indication for spine SBRT can have a substantial effect on resource utilization. These data may be useful in guiding resource planning at institutions looking to commence a spine SBRT program