Fraction Stereotactic Body Radiation Therapy Research Articles

Assessment of minimum target dose as a predictor of local failure after spine SBRT

ObjectivesMetastasis-directed stereotactic body radiation therapy (SBRT) has demonstrated robust clinical benefits in carefully selected patients, improving local control and even overall survival (OS). We assess a large database to determine clinical and dosimetric predictors of local failure after spine SBRT. MethodsSpine SBRT treatments with imaging follow-up were identified. Patients were treated with a simultaneous integrated boost technique using 1 or 3 fractions, delivering 20–24 Gy in 1 fraction to the gross tumor volume (GTV) and 16 Gy to the low dose volume (or 27–36 Gy and 21–24 Gy for 3 fraction treatments). Exclusions included: lack of imaging follow-up, proton therapy, and benign primary histologies. Results522 eligible spine SBRT treatments (68 % single fraction) were identified in 377 unique patients. Patients had a median OS of 43.7 months (95 % confidence interval: 34.3–54.4). The cumulative incidence of local failure was 10.5 % (7.4–13.4) at 1 year and 16.3 % (12.6–19.9) at 2 years. Local control was maximized at 15.3 Gy minimum dose for single-fraction treatment (HR = 0.31, 95 % CI: 0.17 – 0.56, p < 0.0001) and confirmed via multivariable analyses. Cumulative incidence of local failure was 6.1 % (2.6–9.4) vs. 14.2 % (8.3–19.8) at 1 year using this cut-off, with comparable findings for minimum 14 Gy. Additionally, epidural and soft tissue involvement were predictive of local failure (HR = 1.77 and 2.30). ConclusionsSpine SBRT offers favorable local control; however, minimum dose to the GTV has a strong association with local control. Achieving GTV minimum dose of 14–15.3 Gy with single fraction SBRT is recommended whenever possible.

Cancer-specific dose and fractionation schedules in stereotactic body radiotherapy for oligometastatic disease: An interim analysis of the EORTC-ESTRO E2-RADIatE OligoCare study

Background and introductionOptimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation. Materials and methodsAnalysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/β of 10 Gy for all primaries, and cancer-specific α/β of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC). ResultsOf the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3–5) and median dose per fraction was 9.7 (IQR, 7.7–12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions. ConclusionThis real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503).

High-volume prostate biopsy core involvement is not associated with an increased risk of cancer recurrence following 5-fraction stereotactic body radiation therapy monotherapy

PurposePercentage of positive cores involved on a systemic prostate biopsy has been established as a risk factor for adverse oncologic outcomes and is a National Comprehensive Cancer Network (NCCN) independent parameter for unfavorable intermediate-risk disease. Most data from a radiation standpoint was published in an era of conventional fractionation. We explore whether the higher biological dose delivered with SBRT can mitigate this risk factor.MethodsA large single institutional database was interrogated to identify all patients diagnosed with localized prostate cancer (PCa) treated with 5-fraction SBRT without ADT. Pathology results were reviewed to determine detailed core involvement as well as Gleason score (GS). High-volume biopsy core involvement was defined as ≥ 50%. Weighted Gleason core involvement was reviewed, giving higher weight to higher-grade cancer. The PSA kinetics and oncologic outcomes were analyzed for association with core involvement.ResultsFrom 2009 to 2018, 1590 patients were identified who underwent SBRT for localized PCa. High-volume core involvement was a relatively rare event observed in 19% of our cohort, which was observed more in patients with small prostates (p < 0.0001) and/or intermediate-risk disease (p = 0.005). Higher PSA nadir was observed in those patients with low-volume core involvement within the intermediate-risk cohort (p = 0.004), which was confirmed when core involvement was analyzed as a continuous variable weighted by Gleason score (p = 0.049). High-volume core involvement was not associated with biochemical progression (p = 0.234).ConclusionsWith a median follow-up of over 4 years, biochemical progression was not associated with pretreatment high-volume core involvement for patients treated with 5-fraction SBRT alone. In the era of prostate SBRT and MRI-directed prostate biopsies, the use of high-volume core involvement as an independent predictor of unfavorable intermediate risk disease should be revisited.

Outcomes of 35 dogs with craniomaxillofacial osteosarcoma treated with stereotactic body radiation therapy.

Canine craniomaxillofacial osteosarcoma (OSA) is most commonly treated surgically; however, in cases where surgery is not feasible or non-invasive treatment is desired, stereotactic body radiation therapy (SBRT) may be elected for local tumour control. In this study, we evaluated 35 dogs treated with SBRT. Nine dogs (26%) had calvarial, seven (20%) had mandibular and 19 (54%) had maxillary OSA. Median time to first event (TFE) was 171 days, and overall median survival time (MST) was 232 days. Site-specific MSTs were 144 days for mandible, 236 days for calvarium and 232 days for maxilla (p = .49). Pulmonary metastatic disease was observed in 12/35 (34%) patients and was detected pre-SBRT in six dogs (17%) and post-SBRT in the remaining six dogs (17%). Eighteen adverse events post-SBRT were documented. Per veterinary radiation therapy oncology group criteria, five were acute (14%) and three were late (9%) grade 3 events. Neurological signs in two dogs were suspected to be early-delayed effects. Cause of death was local progression for 22/35 (63%) patients, metastasis for 9/35 (26%) patients and unknown for four. On univariate analysis, administration of chemotherapy was associated with a longer TFE (p = .0163), whereas volume of gross tumour volume was associated with a shorter TFE (p = .023). Administration of chemotherapy and five fractions versus single fraction of SBRT was associated with increased survival time (p = .0021 and .049). Based on these findings, a treatment protocol incorporating chemotherapy and five fractions of SBRT could be considered for dogs with craniomaxillofacial OSA electing SBRT with careful consideration of normal tissues in the field.

Prediction of SBRT response in liver cancer by combining original and delta cone-beam CT radiomics: a pilot study.

This study aims to explore the feasibility of utilizing a combination of original and delta cone-beam CT (CBCT) radiomics for predicting treatment response in liver tumors undergoing stereotactic body radiation therapy (SBRT). A total of 49 patients are included in this study, with 36 receiving 5-fraction SBRT, 3 receiving 4-fraction SBRT, and 10 receiving 3-fraction SBRT. The CBCT and planning CT images from liver cancer patients who underwent SBRT are collected to extract overall 547 radiomics features. The CBCT features which are reproducible and interchangeable with pCT are selected for modeling analysis. The delta features between fractions are calculated to depict tumor change. The patients with 4-fraction SBRT are only used for screening robust features. In patients receiving 5-fraction SBRT, the predictive ability of both original and delta CBCT features for two-level treatment response (local efficacy vs. local non-efficacy; complete response (CR) vs. partial response (PR)) is assessed by utilizing multivariable logistic regression with leave-one-out cross-validation. Additionally, univariate analysis is conducted to validate the capability of CBCT features in identifying local efficacy in patients receiving 3-fraction SBRT. In patients receiving 5-fraction SBRT, the combined models incorporating original and delta CBCT radiomics features demonstrate higher area under the curve (AUC) values compared to models using either original or delta features alone for both classification tasks. The AUC values for predicting local efficacy vs. local non-efficacy are 0.58 for original features, 0.82 for delta features, and 0.90 for combined features. For distinguishing PR from CR, the respective AUC values for original, delta and combined features are 0.79, 0.80, and 0.89. In patients receiving 3-fraction SBRT, eight valuable CBCT radiomics features are identified for predicting local efficacy. The combination of original and delta radiomics derived from fractionated CBCT images in liver cancer patients undergoing SBRT shows promise in providing comprehensive information for predicting treatment response.

Prostate volume variation during 1.5T MR-guided adaptive stereotactic body radiotherapy (SBRT) and correlation with treatment toxicity

IntroductionTo evaluate prostate volume change during daily-adaptive prostate SBRT on 1.5 T MR-linac and to correlate it with treatment toxicity. Methodsa series of patients affected by low-to-intermediate risk prostate cancer was treated by 5-fraction SBRT within a prospective study (Prot. n° 23748). Total dose was 35 Gy and 36.25 Gy delivered every day or on alternate days. Treatment toxicity was recorded with the following patient reported outcomes (PROMs): IPSS, ICIQ-SF, and EPIC-26. Results254 patients were included in the analysis. Baseline median CTV volume was 55 cc (range 15.3–163.3). Mean prostate volume were 58.9 cc, and 62.7 cc at first and last fraction respectively (mean volume increase 6.4 %; p = <0.0001). We observed prostate swelling (mean 15.4 % increase) in 50 % of cases, stable volume (≤5% volume change) in 39 % of patients, and prostate shrinkage in 11 % of cases (mean 12.2 % reduction). Baseline CTV > 55 cc showed a trend towards higher CTV shrinkage (-10.5 % versus −14.5 %; p = 0.052). We found no correlation between CTV change and PROMs. Prostate swelling was generally compensated by the planned PTV expansion, even though the mean setup volume dropped from 47.4 cc to 38.9 cc at last fraction, with few cases not covered by initial setup margins. ConclusionThe present study reported a significant prostate volume change during prostate SBRT on 1.5T MR-linac. We observed both prostate swelling in half of cases and few cases of prostate shrinkage. No correlations were found with PROMs in this population treatment with daily-adaptive strategy.

Disease control outcomes of stereotactic body radiation therapy or moderate hypo-fractionation for prostate cancer: Real-world experience at two Canadian centers.

Advantages of using stereotactic body radiation therapy to treat prostate cancer include short treatment times, decreased costs, and limited toxicity. Randomized trial outcomes comparing 5-fraction stereotactic body radiation therapy to conventionally fractionated radiotherapy or hypo-fractionated radiation therapy are pending. We report the 10-year experience with 5-fraction stereotactic body radiation therapy and hypo-fractionated radiation therapy at two Canadian centers. Patients with low- or intermediate-risk prostate cancer treated with stereotactic body radiation therapy alone (35-40 Gy in 5 fractions) or hypo-fractionated radiation therapy alone (60-62 Gy in 20 fractions) in the period of July 2010 and June 2020. The biochemical relapse-free survival, PSA nadir, interval time to PSA nadir, time to biochemical recurrence (2 ng/ml above PSA nadir) and overall survival were reviewed. Outcomes between treatment groups were compared after propensity-matching by patient baseline characteristics. Kaplan-Meier curves were used to assess biochemical relapse-free survival and overall survival. We identified 205 and 513 patients with low or intermediate-risk prostate cancer who were treated with stereotactic body radiation therapy or hypo-fractionation, respectively. Intermediate-risk category composed 81% and 95% of the stereotactic body radiation therapy and hypo-fractionated radiation therapy cohorts, respectively. After a median follow up of 58.6 months for the stereotactic body radiation therapy cohort and 45.0 months for the hypo-fractionated cohort, biochemical relapse-free survival and overall survival were not significantly different between treatment groups. The 5-year biochemical relapse-free survival rates were 92.1% and 93.6% and overall survival rates were 96.4% and 95.0% for the stereotactic body radiation therapy and hypo-fractionated cohorts, respectively, after propensity-matching. Stereotactic body radiation therapy resulted in a significantly lower PSA nadir (0.18 ng/ml) compared to hypo-fractionated radiation therapy (0.48 ng/ml) in patients with low-risk prostate cancer. Mean time to biochemical recurrence was not different between treatment groups. Stereotactic body radiation therapy is an effective treatment option for low and intermediate-risk prostate cancer with encouraging biochemical relapse-free survival and overall survival rates comparable with hypo-fractionated radiation therapy.

A feasibility trial of skin surface motion-gated stereotactic body radiotherapy for treatment of upper abdominal or lower thoracic targets using a novel O-ring gantry

Background and purposeA novel O-ring gantry can deliver stereotactic body radiation therapy (SBRT) with artificial intelligence-facilitated, CT-guided online plan adaptation. It gates mobile targets by optically monitoring skin surface motion. However, this gating solution has not been clinically validated. We conducted a trial to evaluate the feasibility of optical skin surface-guided gating for patients with mobile upper abdominal or lower thoracic malignancies treated with SBRT on this platform (NCT05030454). Materials and methodsTen patients who were prescribed SBRT to a thoracic or abdominal target and were capable of breath-hold for at least 17 s enrolled. They received SBRT in five fractions with breath-hold technique and optical skin surface motion monitored-gating with a ± 2 mm tolerance. Online plan adaptation was left to the discretion of the daily treating physician. The primary endpoint was defined as successful completion of > 75 % of attempted fractions. Exploratory endpoints included local control and acute grade ≥ 3 toxicity rates after three months. For adapted fractions the contouring, planning, quality assurance, and treatment delivery times were recorded. ResultsForty-seven of 51 SBRT fractions (92 %) were successfully gated at breath-hold by optical skin surface motion monitoring. The tumor centroid position during breath-hold varied by a mean of approximately 2 mm. Sixty-three percent of fractions were adapted online with a median total treatment time of 78.5 min. After three months no local recurrences or acute grade ≥ 3 toxicities were observed. ConclusionsSBRT treatment to mobile targets with surface-monitored gating on a novel O-ring gantry was prospectively validated.

Differential Use of Radiotherapy Fractionation Regimens in Prostate Cancer

Technical advances in treatment of prostate cancer and a better understanding of prostate cancer biology have allowed for hypofractionated treatment courses using a higher dose per fraction. Use of ultrahypofractionated stereotactic body radiotherapy (SBRT) has also been characterized. To characterize US national trends of different RT fractionation schemes across risk groups of prostate cancer. This retrospective cohort study used data collected by the National Cancer Database (NCDB) to characterize the fractionation regimens used for 302 035 patients diagnosed as having prostate cancer from January 1, 2004, to December 31, 2020, who underwent definitive RT. The analysis was performed between February 1 and April 30, 2023. Stereotactic body RT or ultrahypofractionation, defined as 5 or fewer fractions of external beam RT (EBRT), moderate hypofractionation, defined as 20 to 28 fractions of EBRT, or conventional fractionation, defined as all remaining EBRT fractionation schemes. Temporal trends and clinical and sociodemographic factors associated with SBRT, moderate hypofractionation, and conventional fractionation use. A total of 302 035 men receiving EBRT for localized prostate cancer between 2004 and 2020 were identified (40.1% aged 60-69 years). Black patients comprised 17.6% of this cohort; White patients, 77.9%; and other races and ethnicities, 4.5%. Patients with low-risk disease comprised 17.5% of the cohort; favorable intermediate-risk disease, 23.5%; unfavorable intermediate-risk disease, 23.9%; and high-risk disease, 35.1%. Treatment consisted of conventional fractionation for 81.2%, moderate hypofractionation for 12.9%, and SBRT for 6.0%. The rate of increase over time in patients receiving SBRT compared with conventional fractionation was higher (adjusted odds ratio [AOR] for 2005 vs 2004, 3.18 [95% CI, 2.04-4.94; P < .001]; AOR for 2020 vs 2004, 264.69 [95% CI, 179.33-390.68; P < .001]) than the rate of increase in patients receiving moderate hypofractionation compared with conventional fractionation (AOR for 2005 vs 2004, 1.05 [95% CI, 0.98-1.12; P = .19]; AOR for 2020 vs 2004, 4.41 [95% CI, 4.15-4.69; P < .001]). Compared with White patients, Black patients were less likely to receive SBRT compared with conventional fractionation or moderate hypofractionation (AOR for conventional fractionation, 0.84 [95% CI, 0.80-0.89; P < .001]; AOR for moderate hypofractionation, 0.77 [95% CI, 0.72-0.81; P < .001]). Compared with 2019, patients treated with all fractionation regimens declined in 2020 by 24.4%. In this hospital-based cohort study of patients with prostate cancer treated with definitive EBRT, use of moderate hypofractionation and SBRT regimens for definitive prostate cancer treatment has increased from 2004 to 2020. Despite this increasing trend, findings suggest potential health care disparities for Black patients receiving EBRT for localized prostate cancer. The number of patients treated with EBRT in the year 2020 decreased, coinciding with official onset of the COVID-19 pandemic in March 2020.

Is the Motion Causing a Commotion? Two-Fraction Prostate SBRT on the MR-Linac.

In HERMES (NCT04595019) men with localized prostate cancer are treated on the Unity MR-Linac platform (MRL, Elekta AB, Stockholm) and randomized between stereotactic body radiotherapy (SBRT) with 36.25 Gy in 5 fractions and 24 Gy in 2 fractions. Patients randomized to two fractions receive 24 Gy to the high risk PTV, 20 Gy to the low risk PTV and a boost of 27 Gy to the dominant intraprostatic lesion. This study explores dose received by the target and organs at risk (OARs) when considering intrafraction motion in two fraction SBRT. Targets and OARs were delineated and a reference plan generated on Monaco v5.40.01 (Elekta). An Adapt-to-Shape (ATS) workflow was used. Contours were propagated to the session MRI (MRIsession) and edited accordingly. Prior to delivery, a verification MRI (MRIverif) was acquired with baseline shifts corrected for using the Adapt-to-Position (ATP-of-ATS) workflow. A post treatment MRI (MRIpost) was acquired after delivery. Men in the 2-fraction arm received each fraction in 2 sub-fractions sequentially on the same day, to mitigate intrafraction motion. The plans of 5 men receiving 2 fraction SBRT were analyzed. The targets, urethra, bladder and rectum were recontoured on the MRIverif and MRIpost. Delivered plans were recalculated on the corresponding MRIverif and MRIpost. The percentage of optimal and mandatory target dose constraints met were calculated. Accumulated OAR doses were calculated by averaging their respective dose statistics across all sub-fractions, conservatively assuming that the same area of the OAR receives the maximum dose each fraction. Analysis was carried out separately for MRIverif and MRIpost as the true 'delivered dose' most likely lies between these two estimates. There was good coverage across all fractions. The mandatory constraints of CTVpsv V24.0 Gy > 95% and CTVsv V20.0 Gy > 95% were met in 100% of fractions and V2700cGy > 95% in 90% on the MRIpost. Table 3 shows OAR dose. This work demonstrates that target coverage is good, even for the GTV where no margin is applied. With our conservative dose calculation approach, we found dose constraints are exceeded for some patients. However, treatment has been well tolerated, suggesting that that our current dose constraints may be cautious. Once Elekta's True Tracking and automated gating software is implemented at our center we will be able to further improve OAR clinical goal compliance.

Multifocal MRI-Directed Simultaneous Integrated Boost (SIB) in the Treatment of Prostate Cancer with Stereotactic Body Radiation Therapy (SBRT).

Conventionally fractionated MRI-directed radiation boosts in the treatment of prostate cancer have been shown to improve oncologic outcomes in the FLAME trial. Moreover, recent data has demonstrated local recurrences following SBRT predominately occur at the site of the dominant intraprostatic lesion. Modern protocols including HYPO-Flame have demonstrated early safety profiles of a 5-fraction intraprostatic SBRT boost. This study aims to determine if multifocal SIB treatment is associated with additional acute toxicity relative to unifocal boosts. In this single-center retrospective analysis, we identified all patients who underwent SBRT with a SIB using a robotic radiosurgical platform. Fiducial markers and hydrogel rectal spacers were placed prior to simulation. All patients underwent treatment planning MRI with documented PI-RADS 3-5 lesions targeted for SIB delineation. Patients were treated to a prescription dose of 3500 to 3625 cGy in 5 fractions, or 1800 to 2100 cGy in 3 fractions in concert with pelvic nodal irradiation. The SIB prescription dose ranged from 4000 to 4200 cGy and 2100 to 2300 cGy for the 5- and 3-fraction regimens, respectively. Acute toxicity was defined as that occurring within 60 days of treatment completion using the CTCAE v. 5.0. A total of 35 patients with a median age of 70 underwent SBRT SIB from 5/2022 to 1/2023 with the following risk distribution: low (3%), intermediate (66%), high (28%), and regional (3%). Most patients received rectal spacers (77%) and neoadjuvant ADT (71%) prior to treatment. The majority of patients underwent 5-fraction SBRT (74%) with the remainder receiving SBRT as a boost. Approximately half (51%) of the cohort was treated with a multifocal SIB to multiple PI-RADS lesions. Mean SIB dose was 4105 and 2377 cGy in 5- and 3-fractions, respectively. With a median follow up of 33 days, we identified no grade 3+ acute toxicities. Crude rate of grade 2 GU and GI toxicity was 51% and 6%, respectively, on par with prior unifocal publications. There was no difference in median SIB volume between uni- and multifocal boosts (1.47 vs. 1.72 cc, p = 0.57), nor was SIB volume associated with an increased risk of grade 2 GU toxicity (p = 0.28). Dominant lesion location was not associated with increased grade 2 GU toxicity (p = 0.29). No grade 2 GI toxicities occurred in the multifocal group. Finally, univariate analysis did not identify multifocal boost as a risk of grade 2 GU toxicity (35%) relative to unifocal (67%) boost (p = 0.09). In the first analysis of its kind in the literature, we demonstrate that multifocal MRI-directed intraprostatic SBRT SIB yields no acute high-grade toxicity and is not associated with a higher risk of low-grade GU and GI toxicity relative to unifocal boost. Longer follow is necessary to determine risk of late toxicity and oncologic efficacy.

Evaluation of kV Triggered Fiducial Tracking for Prostate SBRT Intrafraction Motion Management.

Stereotactic body radiation therapy (SBRT) is a safe and effective treatment for localized prostate cancer. Given the high dose per fraction, a high degree of precision is needed during SBRT treatment delivery. Fiducial marker tracking is a means of monitoring intrafraction motion, ensuring precise treatment delivery and potentially allowing for decreased planning target volume (PTV) margins. We present a 5-year single institution experience to characterize the performance of fiducial tracking. We analyzed 132 consecutive patients treated at our institution with prostate SBRT between July 2017 and November 2022 using fiducial tracking with the TrueBeam Auto Beam Hold feature. Patients were treated using a 5-fraction dose escalation protocol, with many receiving a simultaneous integrated boost to the GTV up to 45 Gy. All patients underwent pre-treatment cone-beam CT and planar kV imaging with rigid registration to the fiducial markers. Cine kV images were acquired every 3-5 seconds during treatment delivery and the beam was paused when a fiducial deviated from a given 4 mm diameter tolerance region. Additional intrafraction 2D or 3D imaging techniques were then used to realign the fiducials. Data was retrieved from the record and verify system including: number and type of intrafraction images, number of treatment interruptions, number of and magnitude of shifts, and total treatment time. The average number of cine kV images acquired per fraction and for the total 5 fraction SBRT course were 86.6 ± 26.8 and 425.6 ± 136.8 respectively. Assuming 1.3 mGy/kV image, the fiducial tracking process delivered an average additional 55.3 cGy over the full treatment course. On average, the beam was paused 5.0 ± 2.5 times per fraction (range 1-21 interruptions) and shifts were applied 4.1 ± 2.1 times (range 0-10.2 times) per fraction. Over the 2560 total shifts applied for all the patients, the average(max) translations were 0.6 (12) mm vrt, 0.7 (22) mm lng, and 0.9 (5) mm lat and the average(max) rotations were 0.19 (5.9)° pitch, 0.01 (2.4)° roll, and 0.16 (6.4)° rtn. Overall, 2.4% of shifts were greater than the 4 mm PTV margin and 4.2% of vertical shifts were greater than the 2.5 mm posterior margin. Average fraction treatment time was 27 ± 9.7 minutes. Fiducial tracking affords the potential to increase daily treatment precision when delivering prostate SBRT. Our data indicate that the beam is typically paused several times during a prostate SBRT fraction, with occasional large shifts required, suggesting the importance of intrafraction motion management. Downsides of kV triggered fiducial tracking include extension of treatment times and delivery of additional radiation dose to the patient. We are investigating if this method of motion management might allow for a reduction in PTV margins to reduce normal tissue dosing.

Robotic SBRT in Prostate Cancer Patients Younger Than 50 Years Old-Updated Results.

Stereotactic Body Radiation Therapy (SBRT) is a standard therapeutic option for men with prostate adenocarcinoma. The median age of prostate cancer in the US is 66 but patients as young as 35 have been reported. Many younger patients will have surgery rather than SBRT for localized prostate cancer but some will be treated with SBRT. There is a paucity of data on the outcomes of this younger subset. This study reports updated outcomes on patients younger than 50 treated with SBRT at a single institution and compares outcomes to older patients. Between April 2006 and December 2022, 6,130 patients with prostate cancer were treated with inhomogeneous-dosed SBRT using a robotic linear accelerator. Information was available for 4,143 patients. 3568 (86.12%) of patients were treated with a median dose of 3500cGY (3500-3625) delivered over 5 consecutive fractions prescribed to the 83-85% isodose line, and the remaining 575 (13.88%) other patients receiving a median dose of 4500cGY (4500-5400) to the pelvis in conventional fractionation followed by a 3 fraction SBRT boost of 2100 cGY (1950-2100) over 3 consecutive fractions. Androgen deprivation Therapy (ADT) was prescribed in 1,035 (24.98%) of these cases. The mean age was 67.4 years old. 48 patients were younger than 50 years old (mean age 46.6). 4,095 patients were 50 or older. Patients were divided into prognostic D'Amico risk groups with 43.75%, 50.00%, 6.25% of patients falling in the low, intermediate, and high-risk stratifications in the younger cohort and 23.88%, 57.05%, 19.07% in the older cohort respectively. Pretreatment PSA was 1.72 - 43.2 (median: 5.4) in the younger group and 0.3 - 661 (median: 6.5) in the older group. In the younger group, Gleason scores were 6 in 47.92%, 7 in 47.92%, and 8-10 in 4.16%. 44 younger patients were treated with SBRT alone. 4 patients also received supplemental external beam radiation (median dose 4500cGY) and 5 patients (10.42%) received Androgen Deprivation Therapy (ADT) as part of their treatment regimen. In the older group, Gleason scores were 6 in 29.84%, 7 in 54.14%, and 8-10 in 16.02%. 3522 were treated with SBRT alone. 573 patients also received supplemental external beam radiation (median dose 4500cGY) and 1030 patients (25.15%) received Androgen Deprivation Therapy (ADT) as part of their treatment. At 75 months the 6-year biochemical relapse free survival was 95.83% in younger patients compared to 98.41% in older patients using the Phoenix definition of biochemical failure. The 6-year median post treatment PSA was 0.3 in younger patients and 0.2 in the older patients. There were no significant differences in the risk stratification between the 2 groups. This represents the largest series evaluating outcomes in very young patients treated with definitive SBRT for prostate cancer. With updated 6-year follow up, SBRT remains an effective treatment for this younger subset of patients. Continued follow up will be required to see if these results remain durable.

A randomized phase II trial of MR-guided prostate stereotactic body radiotherapy administered in 5 or 2 fractions for localized prostate cancer (FORT)

BackgroundUltra-hypofractionated regimens for definitive prostate cancer (PCa) radiotherapy are increasingly utilized due in part to promising safety and efficacy data complemented by greater patient convenience from a treatment course requiring fewer sessions. As such, stereotactic body radiation therapy (SBRT) is rapidly emerging as a standard definitive treatment option for patients with localized PCa. The commercially available magnetic resonance linear accelerator (MR-LINAC) integrates MR imaging with radiation delivery, providing several theoretical advantages compared to computed tomography (CT)-guided radiotherapy. MR-LINAC technology facilitates improved visualization of the prostate, real-time intrafraction tracking of prostate and organs-at-risk (OAR), and online adaptive planning to account for target movement and anatomical changes. These features enable reduced treatment volume margins and improved sparing of surrounding OAR. The theoretical advantages of MR-guided radiotherapy (MRgRT) have recently been shown to significantly reduce rates of acute grade ≥ 2 GU toxicities as reported in the prospective randomized phase III MIRAGE trial, which compared MR-LINAC vs CT-based 5 fraction SBRT in patients with localized PCa (Kishan et al. JAMA Oncol 9:365-373, 2023). Thus, MR-LINAC SBRT–utilizing potentially fewer treatments–is warranted and clinically relevant for men with low or intermediate risk PCa electing for radiotherapy as definitive treatment.Methods/DesignA total of 136 men with treatment naïve low or intermediate risk PCa will be randomized in a 1:1 ratio to 5 or 2 fractions of MR-guided SBRT using permuted block randomization. Randomization is stratified by baseline Expanded PCa Index Composite (EPIC) bowel and urinary domain scores. Patients undergoing 5 fractions will receive 37.5 Gy to the prostate over 10–14 days and patients undergoing 2 fractions will receive 25 Gy to the prostate over 7–10 days. The co-primary endpoints are GI and GU toxicities as measured by change scores in the bowel and urinary EPIC domains, respectively. The change scores will be calculated as pre-treatment (baseline) score subtracted from the 2-year score.DiscussionFORT is an international, multi-institutional prospective randomized phase II trial evaluating whether MR-guided SBRT delivered in 2 fractions versus 5 fractions is non-inferior from a gastrointestinal (GI) and genitourinary (GU) toxicity standpoint at 2 years post-treatment in men with low or intermediate risk PCa.Trial registrationClinicaltrials.gov identifier: NCT04984343. Date of registration: July 30, 2021.Protocol version: 4.0, Nov 8, 2022.

Borderline Resectable Pancreatic Cancer: Impact on Neoadjuvant Response Post Integration of MRI Guided Adaptive Radiation Therapy

The optimal neoadjuvant therapy regimen for patients with borderline resectable pancreas cancer (BRPC) remains to be defined, with a recent ALLIANCE study reporting that chemotherapy alone prior to resection is an acceptable standard of care. However, pathologic differences in response between patients receiving chemotherapy alone and chemotherapy with radiation with stereotactic technique is not clear. In this study, we sought to compare differences in pathologic outcomes between patients undergoing surgery in 2018 compared with 2021 at our comprehensive cancer center, after the new data of chemotherapy alone had been reported and after our center integrated stereotactic MRI guided online adaptive radiotherapy (SMART). Newly diagnosed BRPC patients were included on this IRB approved study if they were treated on our institutional clinical pathway with initial chemotherapy (FOLFIRINOX or Gemcitabine based) followed by 5 fraction stereotactic body radiation therapy (SBRT) with the intention of primary tumor resection. After surgical resection, tumor response was classified by the Tumor Regression Grading (TRG) System of the College of American Pathology on a scale from 0 (complete response) to 3 (poor response). In 2018 when patients were treated on a conventional Linac, the median SBRT dose was 40.5 Gy compared with 46.1 Gy in 2021 after SMART integration. In 2018, 54 BRPC patients were treated and 52% were explored. Of those, 72% were resected with a 95% (19/20) rate of R0 resection. In 2021, 66 BRPC patients were treated and 45% were explored. Of those, 74% were resected with a 100% (22/22) rate of R0 resection. In 2018, pathological results showed that 55% (11/20) had lymphovascular invasion (LVI) and 90% (18/20) had perineural invasion (PNI) with a median tumor size of 2.5 cm. The average lymph node ratio in 2018 was 0.06 in 2018 and 0.05 in 2021. In 2021, pathological results showed that 36% (8/22) had LVI and 64% (14/22) had PNI with a median tumor size of 2.2 cm. In 2018, 43% of surgeries required portal vein (PV) resection compared with 27% in 2021. In 2018, of those patients who underwent surgery, 65% (13/20) received both chemotherapy and SBRT compared to 10% (2/20) with chemotherapy alone. In 2021, 73% (16/22) received chemotherapy and SBRT prior to surgery compared with 27% (6/22) who received chemotherapy only. Patients who received chemotherapy only (n = 8) had an average TRG of 2.1 compared to the patients receiving combination therapy (29) with an average TRG of 1.8. This data suggests that higher ablative dose delivery with SMART following systemic therapy may be associated with improved pathologic outcomes, with less LVI, PNI, portal vein resection and improved TRG scores. Further prospective study is needed to confirm improved pathologic outcomes with SMART and to optimize patient selection regarding which patients benefit the most from the combination of chemotherapy and SBRT.

Analysis of the Measured FDG Uptake from the First-in-Human Clinical Trial of Biology-Guided Radiotherapy

The RefleXion X1 system is a novel linear accelerator equipped with dual 90° PET arcs incorporated into its architecture to capture emissions from tumors and designed to respond by directing the radiation beam towards target. This study reports on the measured FDG uptake from the first in human multi-institutional clinical trial (BIOGUIDE-X) evaluating the performance and safety of the RefleXion X1 PET-LINAC. A total of nine patients treated with stereotactic body radiotherapy (SBRT) for lung (5) and bone (4) tumors were enrolled in the Cohort II of this study after screening their pre-study diagnostic PET/CT, acquired up to 60 days prior to enrollment, to ensure their tumor size between 2 to 5 cm and SUVmax >6. After CT simulation, the tumor and OARs were delineated, and patients had a 4-pass Imaging-only (BgRT Modeling) PET/CT acquisition on the X1 system to generate biology-guided radiotherapy (BgRT) plans. Before the patients' first and last SBRT fractions, they were injected with FDG, and short PET pre-scan (1-pass) was performed on the X1 followed by a long-PET acquisition (4-pass) to emulate the expected BgRT dose distribution without firing beam. Patients were also imaged on a third-party diagnostic PET/CT scanner after the last-fraction X1 scan. This study compares the SUVmax from the screening PET/CT, X1 Imaging-only scan, X1 PET pre-scan and long scan before the first and last-fractions, and final diagnostic PET/CT. The median time from injection to PET imaging was 84 ± 15.4 mins for X1 Imaging-only (used for generating BgRT plans), 77 ± 21.6 mins for X1 pre-scan (safety check before treatment start), 108+/- 22 mins for X1 long-PET (used to emulate treatment delivery), and 161 ± 23 mins for final diagnostic PET. For a nominal 10 mCi injection, the mean SUVmax for screening imaging performed on the diagnostic PET/CT was 10.8 ± 4.3. For a 15 mCi nominal injection, the mean SUVmax calculated on the X1 was 5.3 ± 2.6, 5.4 ± 2.0, 5.5 ± 2.6, 5.2 ± 1.8 and 5.4 ± 2.2 for the Imaging-only, first-fraction PET pre-scan, first-fraction long PET scan, last-fraction PET pre-scan, and last-fraction long PET scan, respectively. The overall median SUVmax for all patients across all timepoints and scans with X1 was calculated to be 4.8 with a range of 2.4 to 9.8. The median SUVmax for the diagnostic PET/CT scan after the last fraction X1 scan was 15.8 with a range of 8.5 to 27.7. The dual PET arcs and limited axial extent of the X1 PET subsystem results in lower system sensitivity in comparison to diagnostic PET scanners equipped with full ring and larger axial extent, as expected. With the same FDG injection, the RefleXion X1 produced SUVmax values that were 30.4 % of the diagnostic PET/CT scanners' values. Nevertheless, the X1 collected sufficient emission data to enable successful completion of emulated BgRT deliveries that met dose accuracy criteria in a clinical setting.

Assessment of Daily Target Motion to Optimize ITV Margins in Online Adaptive Plan for Liver and Pancreatic SBRT on MR-LINAC

Accurate measurement of daily target motion on online plan adaptation is essential for re-optimizing the internal target volume (ITV) margins. In this study, by analyzing 2D cine MR images acquired in a 1.5T MR-Linac, we assessed daily target motion and its inter-fractional variations, which is then used to customize ITV margins for MR-based online adaptive plan of liver and pancreatic stereotactic body radiotherapy (SBRT). Twenty-threepatients, enrolled in this study, underwent MR-guided online adaptive SBRT on 1.5 T MR-Linac: liver (n = 12 without compression belt (CB), n = 2 with CB) and pancreas (n = 9 with CB). Target motion in a 2D coronal and sagittal MR images (> 200 cine images to cover multiple breathing cycles), as well as a set of 4D-CT images during the simulation, was analyzed to determine patient specific ITV margins for a reference plan. On every fraction of online adaptive SBRT, the 2D MR images were exported to commercially available software along with a planning MR images: a T1-wighted MR image set for pancreas and or a navigated T2-wighted MR image set for liver. Daily target motion was then measured by overlaying the orthogonal cine image set on the T1- or T2-wighted image set. The ITV margin was adjusted when required prior to online plan optimization RESULTS: Thisstudy successfully assessed the daily target motion and inter-fractional variations in 23 liver or pancreatic cancer patients. We found a discrepancy of daily target motion of orthogonal 2D cine MR images from that of 4D-CT, required to adjust the ITV margin for online plan adaptation. In liver SBRT without CB, 15 out of 45 fractions from 12 patients (33.3 %) went through adjusted ITV margin. The tumor motion was large up to a 2.2 cm along the inferior direction in a patient without CB and thus the patient was treated on a conventional Linac with the active breathing control (ABC) unit for breath-hold. On the other hand, no adjustments were necessary for 2 liver patients with CB. In 9 patients with pancreatic cancers, we found the inter-fractional ITV variations in 3 out of 45 fractions (6.7 %) adjusted the ITV margin. The daily target motion in the pancreatic patients with CB was more stable and relatively smaller than that of the liver patients. Theorthogonal 2D cine MR images are evidently essential for assessing daily target motion to evaluate the inter-fractional variation and achieve daily ITV-customized liver and pancreatic SBRT in the 1.5 T MR-Linac. The customized ITV approach will improve the treatment outcome of the MR-guided online adaptive therapy.

Cost Analysis of MR-Guided vs. CT-Guided Radiation Therapy for Locally Advanced Pancreatic Cancer

Stereotactic magnetic resonance guided on-table adaptive radiotherapy (SMART) is an increasingly utilized radiotherapy (RT) treatment for locally advanced pancreatic cancer (LAPC), providing improved local control and overall survival with reduced toxicity. Computed tomography (CT) guided RT options include stereotactic body radiotherapy (SBRT) and hypofractionated RT with volumetric modulated arc therapy (VMAT). Currently there are no financial comparisons for MR vs CT-guided RT for LAPC. We completed a cost analysis comparing the physician and hospital charges associated with RT options for LAPC. To compare RT costs, we identified Current Procedural Terminology (CPT) codes utilized for 5-fraction SMART with adaptation (50 Gy, biological effective dose (BED) 100 Gy), 5-fraction CT-guided SBRT (33 Gy, BED 55 Gy), and 15-fraction CT-guided hypofractionated VMAT (67.5 Gy, BED 98 Gy) in a hospital-based practice setting. Physician and hospital Medicare prices associated with these codes together summarize the overall cost. We determined physician fees using the Centers for Medicare and Medicaid Services (CMS) Physician Fee Schedule Search to search the Healthcare Common Procedure Coding System (HCPCS) for "professional" costs included within "facility" costs. We determined hospital fees using the Outpatient Prospective Payment System addendum. To standardize costs, we searched for national payment amounts for the 2022 calendar year. Total cost of SMART with adaptation was 136% higher than the cost of CT-SBRT and 149% higher than the cost of hypofractionated RT. Physician fees for SMART were 173% higher and 157% higher than the fees for CT-SBRT and hypofractionated RT, respectively. Hospital fees for SMART were 129% higher and 147% higher than the fees for CT-SBRT and hypofractionated RT, respectively. The total cost of CT-SBRT was only 5% higher than cost of hypofractionated RT. The physician fees for hypofractionated RT were 6% higher than those for CT-SBRT, while the outpatient fees for CT SBRT were 7% higher than those for hypofractionated RT. With recent data demonstrating favorable efficacy and toxicity rates for SMART, practices may increasingly consider investing in this treatment modality. This is the first cost analysis comparing SMART to CT-guided SBRT and hypofractionated RT in LAPC. We demonstrate higher costs of SMART compared to CT-guided RT, attributable primarily to higher number of dosimetry calculations for this modality and for adapted fractions. We also demonstrate comparable costs of lower BED CT-guided SBRT and higher BED hypofractionated RT. Further investigation is needed to assess whether the survival benefit of SMART translates to favorable cost per quality adjusted life year.

Intratumoral Dose Escalation Using Lattice Radiotherapy for Hepatocellular Carcinoma with Unfavorable Size and Location

Stereotactic body radiation therapy (SBRT) is a standard of care for unresectable hepatocellular carcinoma (HCC). However, its safe delivery is limited by tumor size and adjacent organs-at-risk (OARs). RTOG 1112 showed a survival benefit with local control in advanced HCC, but median dose was limited to 35 Gy in 5 fractions due to OARs. Here, we demonstrate the dosimetric feasibility of lattice radiation therapy (LRT) for dose escalation in advanced HCC. Five-fraction volumetric arc-based (VMAT) LRT plans were generated using a customized Python v3.6 script. For each combination of peak/valley doses and sphere size and spacing, a bounding box was generated around the gross tumor volume (GTV) and divided into equal segments in the x, y, and z planes. Individual spheres were constructed for a given parameter set and those fully encompassed within the target contracted by 2 cm were used to create peak dose targets with values of 30, 40, or 50 Gy. Valley dose target volumes over a range of 2 to 45 Gy were generated by subtracting an 8 mm expansion of the peak dose spheres from the overall target volume. Multi-criteria optimization (MCO) was applied to generate a final plan. The planning target volume (PTV) was a 5-mm uniform expansion from the GTV. All plans were generated at maximum inspiration on 4D-CT. OAR parameters were compared against a standard 5-fraction SBRT plan using Wilcoxon signed-rank testing. GTV and PTV measured 593 (23%) and 804 (32%) cm3, respectively, of a total liver volume of 2525 cm3. The minimum distance of GTV from stomach and duodenum was 6 mm and 2 mm, respectively. Plans were evaluated as per RTOG 1112 with stepwise reduction from a maximum PTV dose of 50 Gy based upon ability to meet mean liver dose (MLD, defined as liver-GTV) constraints; the 30 Gy threshold was the highest achievable. Of 7 eligible LRT plans, 5 with ablative 50 Gy peak doses were analyzed. Associated valley doses were 15 or 20 Gy. Median values of mean GTV and PTV doses for these plans were 36.2 (IQR, 34.6 - 37.8) and 32.9 (IQR, 31.3 - 33.4) Gy, respectively. A median of 12.4% (IQR, 7.4 - 28.4) of the GTV received a dose of 50 Gy. Median doses to 0.5 cc of stomach and duodenum were 16.7 Gy (range, 15.6 - 19.6) and 14.4 Gy (range, 12.3 - 23.9), respectively. The median value for MLD was 13.9 Gy (range, 13.6 to 14.8) and the median volume of normal liver spared 15 Gy was 1114 cm3 (range, 969 to 1154). These hepatic parameters were significantly decreased compared to a standard 30 Gy SBRT plan (18.1 Gy and 611.3 cc spared, p = 0.043 for both) which did not meet constraints. Dose escalation of advanced HCC using LRT is dosimetrically feasible. Though mean target doses remained limited by MLD, LRT allowed delivery of ablative dose to 12.4% of the GTV while meeting critical OAR constraints. Intratumoral dose-escalation may improve local control in advanced HCC patients.

Change in Quality of Life after Stereotactic Body Radiation Therapy (SBRT) on a Prospective Trial of Peripheral Stage I or II Non-Small Cell Lung Cancer Predicts Survival

We previously reported the results of a randomized, multi-institutional phase II clinical trial evaluating one versus three fractions of SBRT for peripheral Stage I to II non-small cell lung cancer (NSCLC). A secondary objective to compare quality of life (QOL) data and its association with survival outcomes is reported. Medically inoperable patients with biopsy-proven peripheral T1-2N0M0 NSCLC were enrolled. Patients were randomized to 30 Gy in 1 fraction (arm 1) or 60 Gy in 3 fractions (arm 2) and stratified by performance status. QOL scores from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC QLQ Lung Cancer-Specific Module (EORTC QLQ-LC13) questionnaires were required at baseline and each follow-up visit. Univariate models were generated to evaluate associations between QOL scores and survival with 95% confidence intervals (CI) calculated at each time point. Among 98 patients enrolled (49 in each arm), 88 patients had data available for QOL analysis. At 6 month follow up, patients with stable or decreased (n = 49) versus those with increased global QOL scores (n = 27) had worse progression-free survival (HR [Hazards' Ratio] 2.32 [CI, 1.14-4.73], p = 0.021) and overall survival (HR 2.13 [CI, 1.01-4.51], p = 0.048). Similar results persisted at the 12 month follow up for progression-free survival (HR 3.90 [CI, 1.52-10.04], p = 0.016) and overall survival (HR 3.25 [CI, 1.25-8.43], p = 0.016). Median overall survival for patients with stable or decreased global QOL versus increased global QOL at 6 month follow up was 39.0 vs 60.3 months (p = 0.032). Change in QOL is an early predictor of survival following SBRT for patients with peripheral early-stage NSCLC.