to report feasibility, PSA response, treatment-related toxicity and patient-reported quality of life (QoL) after 24Gy Single-Dose (SDRT) versus 45Gy SBRT (5x9Gy) from a randomized Phase 2 study of patients with histologically proven intermediate-risk prostate adenocarcinoma. between November 2015 and December 2016, 30 hormone-naïve intermediate-risk prostate cancer patients with gland volume ≤ 100 cm3 were accrued in an IRB-approved prospectively randomized phase II study and treated with either 5 consecutive daily fractions of 9Gy SBRT or 24Gy SDRT. No patient had androgen-ablation therapy. MR-imaging was used for target delineation. The same VMAT-IGRT treatment technique was used in both arms. The PTV consisted of a 2mm isotropic margin around the CTV (prostate gland and seminal vesicles) except at the prostate-rectum interface where a 0mm margin was used. Accurate urethral sparing (20% dose reduction in both arms) was obtained via inverse dose-painting. Anatomical reproducibility and precise PTV targeting were achieved via placement of an endorectal air-filled balloon (150 cc) for target motion mitigation and a beacon transponder-loaded Foley catheter for real-time motion management. Online tracking ensured treatment delivery within the 2 mm PTV margin. PSA response was assessed at 1, 3 and 6 months and every 6 months thereafter. Genito-urinary (GU) and gastro-intestinal (GI) toxicity were graded according to the NCI CTCAE v.4. The use of alpha-antagonist therapy for GU symptoms was not considered grade 2 GU toxicity. QoL was assessed by EPIC and IPSS questionnaires at the same follow-up time points as above. baseline median PSA was 7.5 and 6.0ng/mL for the SBRT and SDRT group, respectively, and declined to a median of 0.28 and 0.48ng/mL at 36 months, respectively. There were 3 biochemical failures (nadir +2), 2 in the SBRT and 1 in the SDRT group. The 4-year actuarial probabilities of freedom from biochemical failure (bRFS) were 86% and 92% for SBRT and SDRT, respectively (P = .50). At a median follow-up of 46 months (range, 38-52), no grade ≥2 acute GU or GI toxicities were observed in either group. Grade 1 GU and GI toxicities were 13% and 6% in the SBRT arm. The respective values for the SDRT arm were 30% and 6%. There were no significant differences between the two arms in median IPSS and EPIC scores in all domains. the technique used in this study assured anatomical reproducibility at the planning session and during treatment delivery, thus allowing precise PTV targeting and organ at risk sparing. The trial outcomes indicate that 24Gy SDRT can be consistently and safely delivered provided strict on-line tracking is used to assure accuracy during treatment. The favorable PSA decline after treatment and the similar low mid-term normal tissue toxicities in the two arms, both associated with excellent QoL measures, underscore the need for larger clinical studies of single dose radiotherapy in intermediate-risk prostate cancer treatment.

To assess pre-treatment and early post-treatment Positron Emission Tomography (PET) standardized metrics as predictors of long-term local outcomes of single dose radiation therapy (SDRT) and hypofractionated stereotactic body radiotherapy (SBRT) in extracranial oligometastatic lesions. Between November 2011 and July 2018, 559 lesions in 169 consecutive patients were treated in a phase II study of oligometastasis-directed ablative radiotherapy using a PTV prescription dose of 24Gy SDRT, or a non-toxic 3x9Gy SBRT schedule when 24Gy was unfeasible due to dose/volume serial organs constraints. A total of 427/559 (76%) and 132/559 (24%) lesions were treated with SDRT and SBRT respectively. SUVmax values were computed pre-treatment, at 3 and 6 months post-treatment, and at 6 months intervals thereafter. Tumor response was scored according to PERCIST criteria, confirmed by morphologic imaging. Correlations of baseline SUVmax and its decline (ΔSUVmax) with actuarial local relapse free survival (LRFS) were analyzed by Cox proportional regression. at a median follow-up of 32.4 (range 6 - 74.3) months the actuarial 5-year LRFS was 92% for 24 Gy SDRT and 38% for 3 x9Gy SBRT, respectively (P < .0001). A total of 70/559 lesions (12%) developed recurrences within the irradiated region, 24/427 (6%) and 46/132 (34%) for SDRT and SBRT, respectively. Baseline SUVmax value of 10.2, a statistically calculated optimal cut-off point, significantly dichotomized the probability of LRFS, yielding 86% vs 63% (P = .001) probability for <10.2 and ≥10.2, respectively. The respective values for the SDRT- and SBRT-treated lesions were 93% vs 92% (P = .29) for 24Gy SDRT, and 63% vs 31% (P = .03) for 3x9Gy SBRT. A ΔSUVmax decline of >75% was associated with 86% actuarial 5-year LRFS vs. 72% for ΔSUVmax ≤75% (P < 0.0001) for the entire cohort, differing for 24Gy SDRT (96% vs 88%; P = .007) and 3x9Gy SBRT (66% vs 30%; P < .0001), respectively. A multivariate Cox analysis confirmed ΔSUVmax as the only independent covariate in predicting LRFS. Bivariate analyses using permutations of baseline SUVmax and ΔSUVmax at three months categorized the probability of 5-year actuarial LRFS, yielding 93% for lesions with <10.2 SUVmax at baseline and >75% ΔSUVmax decline post-treatment, 77% tor lesions with one adverse PET metric, and 53% for both adverse (>10.2 SUVmax and ≤75% ΔSUVmax} PET metrics, respectively (P < .0001). For 3x9Gy SBRT-treated lesions alone the respective probabilities were 90% vs 42% vs 11% (P < .0001), respectively. A combination of pretreatment and early post radiation PET metabolic metrics can be used to generate of a nomogram for use in clinical decision-making on whether to re-treat areas at high risk of local failure adjuvantly, when early and definitive tumor ablation is deemed critical for cure of oligometastatc disease. An approach to prospectively study this hypothesis is currently under consideration.

The analysis of the SPARK trial primary outcome measure showed that the KIM real-time target tracking is clinically useful in improving the prostate and rectal dose in the presence of target motion.

Purpose or ObjectiveTo report initial response, acute treatment-related toxicity and patient-reported quality of life (QoL) after Single-Dose SBRT (SDRT) at a prescription dose of 24Gy from a randomized Phase II study of patients with histologically proven intermediate-risk adenocarcinoma of the prostate (NCCN definition). Material and MethodsBetween November 2015 and December 20 16, 30 hormone-naïve patients were enrolled in an IRB-approved prospectively randomized phase II study to receive either 45Gy in 5 consecutive daily fractions (Hypo-SBRT) or 24Gy SDRT.This protocol was based on a previous phase I/II single arm hypofractionated study of intermediate-risk prostate cancer (5x9Gy daily, in 200 patients accrued between 05/2013 and 09/2016) and a phase I pilot study of 24Gy SDRT of stage IV prostate cancer with radiationand surgery-naïve prostates failing androgen ablation using the same technique as implemented in the presently reported randomized trial.Treatment in both arms was based on VMAT-IGRT with urethral sparing via a dose-painting technique and realtime motion management with beacon transponders.The PTV included the prostate gland and seminal vesicles, and a 2 mm margin beyond the CTV.Precise PTV targeting and anatomical reproducibility was achieved via placement of an endorectal air-filled balloon (150 cc) and a Foley catheter.This setup also conferred organ motion mitigation, and online tracking ensured treatment delivery within the 2 mm PTV margin.Genito-urinary (GU) and gastro-intestinal (GI) toxicity were graded according to the NCI CTCAE v.4, and QoL was assessed by EPIC and IPSS questionnaires.Tumor response was assessed biochemically (PSA) and by follow-up MRI at 3 months after treatment and at 6 months intervals thereafter.

Studies of Single Dose Radiotherapy (SDRT) of Oligometastatic (OM) lesions reported a steep dose-dependent increase of OM ablation within a narrow range of 18-24Gy, rendering >90% ablation at 24Gy, reflecting a unique biological mechanism of SDRT. The present study was designed to define the ablative efficacy and limitations of 24Gy SDRT in a group of consecutive patients with clinical presentations of OM disease. A secondary endpoint was to assess the impact of OM ablation on the timing and rate of conversion of the OM state into polymetastatic (PM) dissemination. Between November 2011 and September 2016, 155 consecutive eligible patients with extra-cranial ≤5 OM PET/CT detectable lesions were recruited to this phase II study. The primary aim was to treat all detected lesions with SDRT at a PTV prescription dose of 24Gy. However, lesions adjacent to serial normal tissue structures, where SDRT was deemed unfeasible, were diverted to a hypofractionated regimen of 3 x 9Gy SBRT. Local relapse free survival (LRFS) and freedom from PM dissemination (PMFS) were assessed at 3, 6 and every 6 months thereafter until patient demise or inability to be assessed. Local response was exclusively assessed by metabolic PET/CT imaging according to the PERCIST criteria. Detectable lesions were characterized in terms of GTV volume, location, and metabolic parameters (SUVmax). PET/CT scans were also used to determine the timing of PM dissemination. At a median follow-up of 21 months (range, 3-60) OM lesions treated with SDRT showed an actuarial 5-year LRFS of 92.3% compared to 34.4% for SBRT (p <0.0001). Tumor size, type, OM target organ, or adjuvant systemic therapy did not significantly affect LRFS following SDRT. PM conversion, defined as-PET/CT first evidence of concomitant ≥6 OM lesions, was not affected by treatment regimen, exhibiting actuarial 4-year PMFS of 44% in the 109 patients at risk treated by SDRT alone vs. 57.2% in the 46 patients receiving SBRT (p =0.9). A univariate analysis disclosed two factors impacting PMFS, namely, the total overall tumor burden at initial referral and the intensity of its highest SUVmax 18F-FDG metabolic signal. A bivariate analysis revealed a favorable prognostic group of patients with an initial low tumor burden of <14.8cc and a low SUVmax signal of <6.5, who exhibited a 5-year actuarial PMFS of 89.4%, compared to 46.3% in a bivariate presentation of a low tumor burden of <14.8cc and a concomitant high SUVmax of ≥6.5 (p =0.0001). The present study validates the efficacy of 24Gy SDRT in permanently ablating OM disease. Furthermore, the use of PET/CT in initial treatment planning and in periodic post-SDRT follow-up evaluations discloses the dynamics of PM dissemination, and enables characterization of a subgroup of OM patients that exhibit a low incidence of PM conversion and an actuarial 89% tumor-free survival at 5 years after SDRT, likely providing an opportunity to define in future studies the elusive OM phenotype.

to evaluate acute treatment-related toxicity and patient-reported quality of life (QoL) after 24Gy SDRT derived from a randomized Phase II study in patients with histologically proven intermediate-risk adenocarcinoma of the prostate (NCCN definition). since November 2015, 30 patients were enrolled in an IRB approved prospectively randomized study to receive either 45Gy in 5 daily fractions (Hypo-SBRT) or 24Gy SDRT. Patients with a baseline IPSS score >15, a previous transurethral prostate resection, or a gland size >100 cc were not eligible. Treatment protocols were based on VMAT-IGRT techniques with urethral sparing and real-time motion management with beacon transponders, and the CTV included the prostate gland and seminal vesicles, and a 2 mm margin for PTV expansion. Accurate anatomical reproducibility was achieved via the placement of an endorectal balloon filled with air (150 cc) and a Foley catheter loaded with the becon trasponders. This setup conferred excellent organ motion mitigation and online tracking ensured treatment delivery was always within the 2 mm PTV/CTV margin. Acute toxicity within the first three months was defined as a primary endpoint. Genito-urinary (GU) and gastro-intestinal (GI) toxicity were graded according to the NCI CTCAE v.4 and QoL was assessed by EPIC and IPSS questionnaires. a total of 15 patients were accrued to each protocol arm, and a minimum follow-up of 3 months was achieved in all patients (range, 3-15). Treatment acceptance and protocol compliance were complete. No grade ≥2 acute GI or GU toxicities were observed in either group. G1 GU and GI toxicities in the hypo arm were 18% and 0%, respectively and 41% and 8%, respectively in the SDRT arm. There were no significant differences in mean EPIC scores in all domains between the two groups. At one-month post treatment, a 6% and 8% drop in the EPIC urinary domain scores occurred in the hypo and SDRT arm, respectively. The scores returned to baseline at the 3 months in both groups. Similarly, at 1-month median IPSS values in the hypo and SDRT arm increased from 7 to 11 and from 7 to 10, respectively, but returned to the baseline value of 7 at 3-months. These observations recapitulated the acute toxicity profiles observed in a phase I/II single arm hypofractionated study (5x9Gy daily, in 200 cases) and a phase I pilot study of 24Gy SDRT in radiation- surgery-naïve prostates failing androgen ablation (28 patients) using the same technique as described above, both completed before initiation of the presently reported trial. These early trial endpoints indicate that 24Gy SDRT with urethral sparing and real-time motion management can be consistently and safely delivered and is associated with acceptable treatment-related symptoms. QoL profiles are consistent with the low rates of mild GU and GI toxicities. Other primary endpoints (i.e. late toxicity, biochemical outcomes and 24 months post-treatment biopsy) have not been reached.

The aim of this study was to assess the feasibility and safety of prostate cancer (PCa) extreme hypofractionated IGRT using beacon transponder technology to guide strict dose/volume constraints to reduce risk of treatment-related toxicity and its impact on quality of life (QOL). Between November 2013 and October 2015, 86 hormone-naïve patients with low- and intermediate-risk PCa and an IPSS score < 15 were recruited to a phase I/II study of extreme hypofractionated IGRT to assess feasibility of urethral and rectal sparing. Minimum follow-up was 12 months. Median age was 73 years (range 53-83). CT/MR fusion was used to delineate the CTV and organs-at-risk. Beacon transponders were placed inside the urethra via a preloaded Foley catheter at the time of simulation. Mean CTV was 49 cc (range 31-95) and CTV to PTV margin was 2 mm in all directions. The prescription dose was 9 Gy in five fractions delivered over five consecutive days. With a 2 mm expansion around the catheter, negative dose-painting was implemented to fulfill D1cc <36 Gy. Patients were treated with 10MV FFF VMAT and an endorectal balloon (air filling of 150 cc) was used to mitigate prostate motion. Accurate patient set-up was assisted by beacon transponders and confirmed by CBCT before treatment. On-line tracking was used to monitor intrafractional motion, with a tolerance threshold of 2 mm in all directions. Quality of life was assessed using the Expanded Prostate Cancer Index Composite (EPIC-26) acquired at baseline, one week, 1 month, every 3 months for the first year, and every 6 months thereafter. Patient compliance to treatment was excellent with all treatments completed in five consecutive sessions. Beacon transponders-detected target motion was compatible with the prescribed 2mm CTV-PTV expansion. Median follow-up was 20 months (range, 12-31). Mean PSA at baseline was 9.2 ng/mL, reduced to 1.5 ng/mL, and 0.4 ng/mL at 12 and 24 months, respectively. There was 2.4% acute ≤G2 urinary toxicity, and no instances of acute ≥G2 bowel toxicity. Late GU and GI toxicity was limited to G1. No G3 events, acute or late, have been observed. EPIC GU and GI summary scores declined transiently at 1 month post-treatment. The mean declines for GU and GI EPIC summary scores were 16% and 9%, respectively. Both recovered to baseline values within the first 3 months and maintained mean scores similar to baseline thereafter. EPIC sexual summary scores declined for the first three months but eventually recovered to baseline levels at 6 months. Extreme hypofractionated IGRT with urethral and rectal sparing with prostate motion mitigation and on-line tracking is feasible and can be delivered with millimeter accuracy. Transient minimal (≤G2) acute declines in the urinary, bowel and sexual functions were observed, recovering to baseline. This study indicates this technique is feasible and safe, rendering exquisite sparing of healthy tissues.

Purpose/Objective(s)18F-fluoro-2-deoxy-D-glucose (FDG) Positron Emission Tomography (PET) Standardized Uptake Value (SUVmax) is a standard PERCIST variable in assessing metabolic response to cancer therapy. Here we explore the predictive value of early post-treatment SUVmax in patients receiving SDRT in extracranial oligometastatic lesions.Materials/Methods201 metastatic lesions in 93 consecutive patients (mean 2.1 lesions/patient, range 1-9) were treated before 9/2014 with image-guided SDRT to a PTV dose of 24 Gy. Tumor histologies included NSCLC (73), colorectal (49), breast (23), prostate (23), renal cell (14), bladder (9), sarcoma (4), melanoma (4), and pancreatic tumors (2). Sites of metastases were lung (68), bone (62), lymph-nodes (29), liver (21), soft tissues (13), adrenal (8). SUVmax were acquired before SDRT, at 3 months post-treatment and at every 6 months thereafter. Tumor response was scored according to the PERCIST criteria, with metabolic relapse defined as any increase of SUVmax >30% above nadir level. All metabolic relapses were confirmed by morphologic imaging. Lesions had a minimum of 2 post-treatment scans (mean 4; range 2-9). Correlation of SUVmax declines (ΔSUVmax) and actuarial local control were analyzed by recursive partitioning.ResultsAt a median follow-up of 22 months (range 6-39), 21 lesions developed PERCIST failures yielding a 3 year actuarial local relapse-free of 90%. Baseline SUVmax (median 8.9; range 1-52) did not correlate with the probability of local metabolic progression (p=0.9). At 3 months post-SDRT 18% (37/201) of the lesions had a >90% reduction in SUVmax (PERCIST complete metabolic response), and 78 lesions (38%) showed >75% (ΔSUV(>75%)). Actuarial relapse-free survival showed ΔSUV(>75%) was associated with 93% local control at 36 months vs. 77% for ΔSUV(≤75%) (p=0.02). ΔSUV(>70%) also showed significance as predictor of local control (p=0.05), but lower partitioning values were not significant. All relapses occurred within 20 months post-treatment. The actuarial 3-year PERCIST local control was 95% for lesions in bone regardless of histological subtypes, 79% for lesions in mobile organs (lung, liver, adrenal) and 75% for soft tissue and lymph node metastases.ConclusionΔSUV(>75%) at 3 months appears a predictor of durable local control in tumor lesions treated with SDRT, providing a readily accessible tool for rapid evaluation of outcome in treatment protocols exploring SDRT. Whether a more sensitive discriminator of SDRT outcome can be provided by current PET technology is yet to be established. The PERCIST outcomes by target organs indicate a need for improved tumor segmentation of lesions in soft tissue locations, and improved tumor tracking during treatment delivery in mobile target organs. Purpose/Objective(s)18F-fluoro-2-deoxy-D-glucose (FDG) Positron Emission Tomography (PET) Standardized Uptake Value (SUVmax) is a standard PERCIST variable in assessing metabolic response to cancer therapy. Here we explore the predictive value of early post-treatment SUVmax in patients receiving SDRT in extracranial oligometastatic lesions. 18F-fluoro-2-deoxy-D-glucose (FDG) Positron Emission Tomography (PET) Standardized Uptake Value (SUVmax) is a standard PERCIST variable in assessing metabolic response to cancer therapy. Here we explore the predictive value of early post-treatment SUVmax in patients receiving SDRT in extracranial oligometastatic lesions. Materials/Methods201 metastatic lesions in 93 consecutive patients (mean 2.1 lesions/patient, range 1-9) were treated before 9/2014 with image-guided SDRT to a PTV dose of 24 Gy. Tumor histologies included NSCLC (73), colorectal (49), breast (23), prostate (23), renal cell (14), bladder (9), sarcoma (4), melanoma (4), and pancreatic tumors (2). Sites of metastases were lung (68), bone (62), lymph-nodes (29), liver (21), soft tissues (13), adrenal (8). SUVmax were acquired before SDRT, at 3 months post-treatment and at every 6 months thereafter. Tumor response was scored according to the PERCIST criteria, with metabolic relapse defined as any increase of SUVmax >30% above nadir level. All metabolic relapses were confirmed by morphologic imaging. Lesions had a minimum of 2 post-treatment scans (mean 4; range 2-9). Correlation of SUVmax declines (ΔSUVmax) and actuarial local control were analyzed by recursive partitioning. 201 metastatic lesions in 93 consecutive patients (mean 2.1 lesions/patient, range 1-9) were treated before 9/2014 with image-guided SDRT to a PTV dose of 24 Gy. Tumor histologies included NSCLC (73), colorectal (49), breast (23), prostate (23), renal cell (14), bladder (9), sarcoma (4), melanoma (4), and pancreatic tumors (2). Sites of metastases were lung (68), bone (62), lymph-nodes (29), liver (21), soft tissues (13), adrenal (8). SUVmax were acquired before SDRT, at 3 months post-treatment and at every 6 months thereafter. Tumor response was scored according to the PERCIST criteria, with metabolic relapse defined as any increase of SUVmax >30% above nadir level. All metabolic relapses were confirmed by morphologic imaging. Lesions had a minimum of 2 post-treatment scans (mean 4; range 2-9). Correlation of SUVmax declines (ΔSUVmax) and actuarial local control were analyzed by recursive partitioning. ResultsAt a median follow-up of 22 months (range 6-39), 21 lesions developed PERCIST failures yielding a 3 year actuarial local relapse-free of 90%. Baseline SUVmax (median 8.9; range 1-52) did not correlate with the probability of local metabolic progression (p=0.9). At 3 months post-SDRT 18% (37/201) of the lesions had a >90% reduction in SUVmax (PERCIST complete metabolic response), and 78 lesions (38%) showed >75% (ΔSUV(>75%)). Actuarial relapse-free survival showed ΔSUV(>75%) was associated with 93% local control at 36 months vs. 77% for ΔSUV(≤75%) (p=0.02). ΔSUV(>70%) also showed significance as predictor of local control (p=0.05), but lower partitioning values were not significant. All relapses occurred within 20 months post-treatment. The actuarial 3-year PERCIST local control was 95% for lesions in bone regardless of histological subtypes, 79% for lesions in mobile organs (lung, liver, adrenal) and 75% for soft tissue and lymph node metastases. At a median follow-up of 22 months (range 6-39), 21 lesions developed PERCIST failures yielding a 3 year actuarial local relapse-free of 90%. Baseline SUVmax (median 8.9; range 1-52) did not correlate with the probability of local metabolic progression (p=0.9). At 3 months post-SDRT 18% (37/201) of the lesions had a >90% reduction in SUVmax (PERCIST complete metabolic response), and 78 lesions (38%) showed >75% (ΔSUV(>75%)). Actuarial relapse-free survival showed ΔSUV(>75%) was associated with 93% local control at 36 months vs. 77% for ΔSUV(≤75%) (p=0.02). ΔSUV(>70%) also showed significance as predictor of local control (p=0.05), but lower partitioning values were not significant. All relapses occurred within 20 months post-treatment. The actuarial 3-year PERCIST local control was 95% for lesions in bone regardless of histological subtypes, 79% for lesions in mobile organs (lung, liver, adrenal) and 75% for soft tissue and lymph node metastases. ConclusionΔSUV(>75%) at 3 months appears a predictor of durable local control in tumor lesions treated with SDRT, providing a readily accessible tool for rapid evaluation of outcome in treatment protocols exploring SDRT. Whether a more sensitive discriminator of SDRT outcome can be provided by current PET technology is yet to be established. The PERCIST outcomes by target organs indicate a need for improved tumor segmentation of lesions in soft tissue locations, and improved tumor tracking during treatment delivery in mobile target organs. ΔSUV(>75%) at 3 months appears a predictor of durable local control in tumor lesions treated with SDRT, providing a readily accessible tool for rapid evaluation of outcome in treatment protocols exploring SDRT. Whether a more sensitive discriminator of SDRT outcome can be provided by current PET technology is yet to be established. The PERCIST outcomes by target organs indicate a need for improved tumor segmentation of lesions in soft tissue locations, and improved tumor tracking during treatment delivery in mobile target organs.