Radioactive Iodine Therapy in Differentiated Thyroid Cancer: An Update on Dose Recommendations and Risk of Secondary Primary Malignancies.

Radioactive iodine (RAI) therapy with iodine-131 is performed in select cases of differentiated thyroid cancer (DTC), typically for remnant ablation, adjuvant therapy, or treatment of known persistent disease. Herein, we review updated RAI dose recommendations and associated risks of secondary primary malignancy (SPM). RAI dose is usually chosen empirically based on the risk assessment of tumor recurrence and other factors. Dose recommendations differ slightly among relevant medical societies. As of April 2024, most medical societies, including the American Thyroid Association (ATA), European Thyroid Association (ETA), Society of Nuclear Medicine and Molecular Imaging/European Association of Nuclear Medicine (SNMMI/ EANM), and National Comprehensive Cancer Network (NCCN), recommend a dose of 1.11 GBq (30 mCi) I-131 for remnant ablation. For adjuvant therapy, the recommended RAI dose ranges from 1.11 to 3.7 GBq (30-100) mCi I-131, although doses up to 5.6 GBq (150 mCi) may also be considered. In patients with known or suspected metastatic disease, at least 3.7 GBq (100 mCi) I-131 should be administered, and RAI doses as high as 7.4 GBq (200 mCi) may be justified depending on the suspected tumor burden and extent. Dosimetry has the advantage of tailoring the RAI dose to each patient's pharmacokinetics, resulting in ≥ 7.4 GBq (200 mCi) of I-131 in most cases. There is an ongoing debate about the risk of developing SPM due to RAI therapy, with several multicenter studies and meta-analyses concerning SPM being published in the last 2 years. The incidence of RAI-associated SPM varies according to the study design and detection method. Several studies showed no increased incidence, and there was no specific secondary cancer or cancer group linked to RAI exposures. Some reports indicated that cumulative RAI doses exceeding 5.6-7.4 GBq (150-200 mCi) were found to represent an increased risk for developing SPM. However, a clearly defined dose threshold cannot be provided based on the current literature. Nonetheless, caution should be exercised when considering repeated RAI therapies for persistent metastatic PTC, with a cumulative dose exceeding 37.0 GBq (1,000 mCi), due to the potential risk of developing SPM and other long-term toxicity. Further research is warranted to understand better the relationship between RAI dose and the risk of SPM.

Quality Metric to Assess Adequacy of Hydrogel Rectal Spacer Placement for Prostate Radiation Therapy and Association of Metric Score With Rectal Toxicity Outcomes.

Purpose: Although hydrogel spacer placement (HSP) minimizes rectal dose during prostate cancer radiation therapy, its potential benefit for modulating rectal toxicity could depend on the achieved prostate-rectal separation. We therefore developed a quality metric associated with rectal dose reduction and late rectal toxicity among patients treated with prostate stereotactic body radiation therapy (SBRT). Methods and Materials: A quality metric consisting of prostate-rectal interspace measurements from axial T2-weighted magnetic resonance imaging simulation images was applied to 42 men enrolled in a multi-institutional phase 2 study using HSP with prostate SBRT (45 Gy in 5 fractions). A score of 0, 1, or 2 was assigned to a prostate-rectal interspace measurement of <0.3 cm, 0.3 to 0.9 cm, or ≥1 cm, respectively. An overall spacer quality score (SQS) was computed from individual scores at rectal midline and ±1 cm laterally, located at the prostate base, midgland, and apex. Associations of SQS with rectal dosimetry and late toxicity were evaluated. Results: The majority of the analyzed cohort had an SQS of 1 (n = 17; 41%) or 2 (n = 18; 43%). SQS was associated with maximum rectal point dose (rectal Dmax; P = .002), maximum dose to 1 cc of rectum (D1cc; P = .004), and volume of rectum receiving ≥100% of prescription dose (V45; P = .046) and ≥40 Gy (V40; P = .005). SQS was also associated with a higher incidence of (P = .01) and highest-graded late rectal toxicity (P = .01). Among the 20 men who developed late grade ≥1 rectal toxicity, 57%, 71%, and 22% had an SQS of 0, 1, and 2, respectively. Men with an SQS of 0 or 1 compared with 2 had 4.67-fold (95% CI, 0.72-30.11) or 8.40-fold (95% CI, 1.83-38.57) greater odds, respectively, of developing late rectal toxicity. Conclusions: We developed a reliable and informative metric for assessing HSP, which appears to be associated with rectal dosimetry and late rectal toxicity after prostate SBRT.

Optimizing Palliative Focal Radiation Therapy Dose in Cutaneous T-Cell Lymphoma: How Low Can You Go?

PURPOSE: Primary cutaneous T-cell lymphomas (CTCLs) are radiosensitive tumors with variable and often relapsing courses. Local disease can be treated with low-dose focal palliative radiation therapy (RT), though little data supports the use of a specific dose. This study assesses clinical outcomes after focal RT to a total dose of 4 Gy, 8 Gy, or 12 Gy. METHODS AND MATERIALS: An International Review Board-approved, retrospective, single-institution study was performed of 225 lesions in 41 patients with primary CTCL treated with low-dose focal RT from 2015 to 2020. Patient, tumor, and treatment characteristics were reviewed. The primary outcome was freedom from treatment failure (FFTF), defined as time to requiring local retreatment, and secondary outcomes included response rates and toxicities. RESULTS: Of the 225 lesions, 90 received 4 Gy, 106 received 8 Gy, and 29 received 12 Gy. Lesions treated with 12 Gy (96%) or 8 Gy (92%) had a significantly higher 1-year FFTF compared with 4 Gy (77%) (P = .034). Overall response rate and complete response rate were not significantly different between different doses (P = .117), though there was a trend toward higher overall response rate at initial assessment with 8 Gy versus 4 Gy (91.5% vs 82.2%, P = .057). Toxicity was low, with 7.1% of lesions having grade 2 or higher radiation dermatitis. CONCLUSIONS: In primary CTCL lesions treated with focal palliative RT, a dose response was noted favoring 8 to 12 Gy, with 1-year FFTF rates over 90%. However, 4 Gy resulted in substantially better outcomes than previously reported, with 77% requiring no further treatment at 1 year and comparable response rates to higher doses. While our data substantiates 8 to 12 Gy as the standard of care, it also suggests that 4 Gy should be considered an acceptable alternative in situations with concern for radiation toxicities, such as with fragile or heavily pretreated skin.

Phase II Randomized Study of Salvage Radiation Therapy Plus Enzalutamide or Placebo for High-Risk Prostate-Specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy: The SALV-ENZA Trial.

PURPOSE: We sought to investigate whether enzalutamide (ENZA), without concurrent androgen deprivation therapy, increases freedom from prostate-specific antigen (PSA) progression (FFPP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer after radical prostatectomy (RP). PATIENTS AND METHODS: Men with biochemically recurrent prostate cancer after RP were enrolled into a randomized, double-blind, phase II, placebo-controlled, multicenter study of SRT plus ENZA or placebo (ClinicalTrials.gov identifier: NCT02203695). Random assignment (1:1) was stratified by center, surgical margin status (R0 v R1), PSA before salvage treatment (PSA ≥ 0.5 v < 0.5 ng/mL), and pathologic Gleason sum (7 v 8-10). Patients were assigned to receive either ENZA 160 mg once daily or matching placebo for 6 months. After 2 months of study drug therapy, external-beam radiation (66.6-70.2 Gy) was administered to the prostate bed (no pelvic nodes). The primary end point was FFPP in the intention-to-treat population. Secondary end points were time to local recurrence within the radiation field, metastasis-free survival, and safety as determined by frequency and severity of adverse events. RESULTS: Eighty-six (86) patients were randomly assigned, with a median follow-up of 34 (range, 0-52) months. Trial arms were well balanced. The median pre-SRT PSA was 0.3 (range, 0.06-4.6) ng/mL, 56 of 86 patients (65%) had extraprostatic disease (pT3), 39 of 86 (45%) had a Gleason sum of 8-10, and 43 of 86 (50%) had positive surgical margins (R1). FFPP was significantly improved with ENZA versus placebo (hazard ratio [HR], 0.42; 95% CI, 0.19 to 0.92; P = .031), and 2-year FFPP was 84% versus 66%, respectively. Subgroup analyses demonstrated differential benefit of ENZA in men with pT3 (HR, 0.22; 95% CI, 0.07 to 0.69) versus pT2 disease (HR, 1.54; 95% CI, 0.43 to 5.47; Pinteraction = .019) and R1 (HR, 0.14; 95% CI, 0.03 to 0.64) versus R0 disease (HR, 1.00; 95% CI, 0.36 to 2.76; Pinteraction = .023). There were insufficient secondary end point events for analysis. The most common adverse events were grade 1-2 fatigue (65% ENZA v 53% placebo) and urinary frequency (40% ENZA v 49% placebo). CONCLUSION: SRT plus ENZA monotherapy for 6 months in men with PSA-recurrent high-risk prostate cancer after RP is safe and delays PSA progression relative to SRT alone. The impact of ENZA on distant metastasis or survival is unknown at this time.

Case Report: Adaptive radiotherapy in the radiation salvage of prostate cancer.

Adaptive radiotherapy has the potential to reduce margins, improve target coverage, and decrease toxicity to organs at risk (OARs) by optimizing radiation delivery to daily anatomic changes. Salvage for locally recurrent prostate cancer after definitive radiation remains a challenging clinical scenario given the risks to normal tissue in a setting of re-irradiation. Here, we present a case series of five patients with locally recurrent prostate cancer treated with an adaptive online linear accelerator or a 3-T MR-based linear accelerator to demonstrate excellent target coverage. All patients completed the planned treatment course with acceptable acute toxicities but a short follow-up time does not inform subacute/late toxicities.

Alterations in BRCA2 as Determinants of Therapy Response in Prostate Cancer.

Prostate cancer (PCa) is one of the leading causes of cancer diagnoses and cancer-related deaths in the United States. Mutations or deletions in the genes involved in the DNA damage response (DDR) are common in aggressive primary PCa (germline alterations) and further enriched in advanced therapy-resistant PCa (somatic alterations). Among the DDR genes, BRCA2 is the most commonly altered (~ 13%) in advanced therapy-resistant PCa. Patients with BRCA2-altered PCas are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis). Indeed, two PARPis-olaparib and rucaparib have recently gained U.S. Food & Drug Administration approval for the treatment of advanced PCas harboring a BRCA2 mutation. This review seeks to explore the role of BRCA2 in DNA damage repair, the pathogenesis and progression of BRCA2 mutant PCa, and the utility of radiation therapy, targeted therapies, and platinum-based chemotherapies for patients with BRCA2 alterations.

Primary central nervous system lymphoma: a real-world comparison of therapy access and outcomes by hospital setting.

Background: This study analyzes sociodemographic barriers for primary CNS lymphoma (PCNSL) treatment and outcomes at a public safety-net hospital versus a private tertiary academic institution. We hypothesized that these barriers would lead to access disparities and poorer outcomes in the safety-net population. Methods: We reviewed records of PCNSL patients from 2007-2020 (n = 95) at a public safety-net hospital (n = 33) and a private academic center (n = 62) staffed by the same university. Demographics, treatment patterns, and outcomes were analyzed. Results: Patients at the safety-net hospital were significantly younger, more commonly Black or Hispanic, and had a higher prevalence of HIV/AIDS. They were significantly less likely to receive induction chemotherapy (67% vs 86%, P = .003) or consolidation autologous stem cell transplantation (0% vs. 47%, P = .001), but received more whole-brain radiation therapy (35% vs 16%, P = .001). Younger age and receiving any consolidation therapy were associated with improved progression-free (PFS, P = .001) and overall survival (OS, P = .001). Hospital location had no statistical impact on PFS (P = .725) or OS (P = .226) on an age-adjusted analysis. Conclusions: Our study shows significant differences in treatment patterns for PCNSL between a public safety-net hospital and an academic cancer center. A significant survival difference was not demonstrated, which is likely multifactorial, but likely was positively impacted by the shared multidisciplinary care delivery between the institutions. As personalized therapies for PCNSL are being developed, equitable access including clinical trials should be advocated for resource-limited settings.

ACR-ACNM-ASTRO-SNMMI Practice Parameter for Lutetium-177 (Lu-177) DOTATATE Therapy.

OBJECTIVES: This practice parameter (PP) for Lutetium-177 (Lu-177) DOTATATE peptide receptor radionuclide therapy (PRRT) aims to guide authorized users in selection of appropriate adult candidates with gastroeneropancreatic neuroendocrine tumors (GEP-NETs) from foregut, midgut, and hindgut. The essential selection criteria include somatostatin receptor-positive GEP-NETs, which are usually inoperable and progressed despite standard therapy. Lu-177 DOTATATE is a radiopharmaceutical with high avidity for somatostatin receptors that are overexpressed by these tumors. This document ensures safe handling of Lu-177 DOTATATE by the authorized users and safe management of affected patients. METHODS: The document was developed according to the systematic process developed by the American College of Radiology (ACR) and described on the ACR Web site (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards). The PP development was led by 2 ACR Committees on Practice Parameters (Nuclear Medicine and Molecular Imaging and Radiation Oncology) collaboratively with the American College of Nuclear Medicine, American Society of Radiation Oncology, and Society of Nuclear Medicine and Molecular Imaging. RESULTS: The Lu-177 DOTATATE PP reviewed pharmacology, indications, adverse effects, personnel qualifications, and required clinical evaluation before starting the treatment, as well as the recommended posttherapy monitoring, quality assurance, documentation, and appropriate radiation safety instructions provided in written form and explained to the patients. CONCLUSIONS: Lu-177 DOTATATE is available for therapy of inoperable and/or advanced GEP-NETs when conventional therapy had failed. It can reduce tumor size, improve symptoms, and increase the progression free survival. The PP document provides clinical guidance for authorized users to assure an appropriate, consistent, and safe practice of Lu-177 DOTATATE.

ACR-ACNM-ASTRO-SNMMI Practice Parameter for Lutetium-177 (Lu-177) DOTATATE Therapy.

OBJECTIVES: This practice parameter (PP) for Lutetium-177 (Lu-177) DOTATATE peptide receptor radionuclide therapy (PRRT) aims to guide authorized users in selection of appropriate adult candidates with gastroeneropancreatic neuroendocrine tumors (GEP-NETs) from foregut, midgut, and hindgut. The essential selection criteria include somatostatin receptor-positive GEP-NETs, which are usually inoperable and progressed despite standard therapy. Lu-177 DOTATATE is a radiopharmaceutical with high avidity for somatostatin receptors that are overexpressed by these tumors. This document ensures safe handling of Lu-177 DOTATATE by the authorized users and safe management of affected patients. METHODS: The document was developed according to the systematic process developed by the American College of Radiology (ACR) and described on the ACR Web site (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards). The PP development was led by 2 ACR Committees on Practice Parameters (Nuclear Medicine and Molecular Imaging and Radiation Oncology) collaboratively with the American College of Nuclear Medicine, American Society of Radiation Oncology, and Society of Nuclear Medicine and Molecular Imaging. RESULTS: The Lu-177 DOTATATE PP reviewed pharmacology, indications, adverse effects, personnel qualifications, and required clinical evaluation before starting the treatment, as well as the recommended posttherapy monitoring, quality assurance, documentation, and appropriate radiation safety instructions provided in written form and explained to the patients. CONCLUSIONS: Lu-177 DOTATATE is available for therapy of inoperable and/or advanced GEP-NETs when conventional therapy had failed. It can reduce tumor size, improve symptoms, and increase the progression free survival. The PP document provides clinical guidance for authorized users to assure an appropriate, consistent, and safe practice of Lu-177 DOTATATE.

A Combined Biomarker of Bright CD38 and MYC ≥55% Is Highly Predictive of Double-/Triple-Hit High-Grade B-Cell Lymphoma.

OBJECTIVES: Diagnosis of high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements (double-/triple-hit lymphoma [DTHL]) appears to mandate fluorescence in situ hybridization (FISH) testing for all large B-cell lymphoma (LBCL). Given the low incidence of DTHL, we aimed to identify flow cytometry (FC) and immunohistochemistry (IHC) features of DTHL that could be used to develop an optimal screening strategy. This combined FC-IHC approach has not yet been studied. METHODS: We compared features of 40 cases of DTHL and 39 cases of diffuse LBCL (DLBCL) without MYC rearrangement. RESULTS: Bright CD38 expression (CD38bright) by FC, high MYC expression (≥55%), and double-expressor phenotype by IHC were significantly associated with DTHL. The biomarker combining FC and IHC, CD38bright and/or MYC ≥55%, was superior to FC and IHC markers alone in predicting DTHL. Restricting FISH testing to approximately 25% of LBCL based on CD38brightand/or MYC ≥55% would detect approximately 95% of DTHL-BCL2 and approximately 75% of DHL-BCL6. CONCLUSIONS: Our study demonstrated that the novel biomarker of CD38bright and/or MYC ≥55% is highly predictive of DTHL. Awareness of the advantages and limitations of this screening strategy would facilitate development of a rational diagnostic workflow to provide high-quality patient care.

Enrichment of "Cribriform" morphologies (intraductal and cribriform adenocarcinoma) and genomic alterations in radiorecurrent prostate cancer.

Locally relapsed prostate cancer (PCa) after radiation therapy (RT) is associated with substantial morbidity and mortality. Morphological and molecular consequences that may contribute to RT resistance and local recurrence remain poorly understood. Locally recurrent PCa tissue from 53 patients with clinically localized PCa who failed with primary RT and subsequently underwent salvage radical prostatectomy (RP) was analyzed for tumor focality, clinicopathological, molecular, and genomic characteristics. Targeted next-generation sequencing with full exon coverage of 1,425 cancer-related genes was performed on 10 representative radiorecurrent PCas exhibiting no RT effect with matched adjacent benign prostate tissue. At RP, 37 (70%) of PCas had no RT effect with the following characteristics: grade group (GG) ≥ 3 (70%), unifocal tumor (75%), extraprostatic disease (78%), lymph node metastasis (8%), and "cribriform" morphologies (84%) [cribriform PCa (78%) or intraductal carcinoma (IDC-P) (61%)] at a median percentage of approximately 80% of tumor volume. In the setting of multifocal tumors (25%) at RP, the cribriform morphologies were restricted to index tumors. Of 32 patients with available pre-RT biopsy information, 16 had GG1 PCa, none had cribriform morphologies at baseline but 81% demonstrated cribriform morphologies at RP. Notable alterations detected in the sequenced tumors included: defects in DNA damage response and repair (DDR) genes (70%) (TP53, BRCA2, PALB2, ATR, POLQ), PTEN loss (50%), loss of 8p (80%), and gain of MYC (70%). The median tumor mutational burden was 4.18 mutations/Mb with a range of 2.16 to 31.86. Our findings suggest that most radiorecurrent PCas are enriched in cribriform morphologies with potentially targetable genomic alterations. Understanding this phenotypic and genotypic diversity of radiorecurrent PCa is critically important to facilitate optimal patient management.

Dose-Intensified Stereotactic Ablative Radiation for Localized Prostate Cancer.

Purpose: Stereotactic ablative radiation (SAbR) has been increasingly used in prostate cancer (PCa) given its convenience and cost efficacy. Optimal doses remain poorly defined with limited prospective comparative trials and long-term safety/efficacy data at higher dose levels. We analyzed toxicity and outcomes for SAbR in men with localized PCa at escalated 45 Gy in 5 fractions. Methods and Materials: This study retrospectively analyzed men from 2015 to 2019 with PCa who received linear-accelerator-based SAbR to 45 Gy in 5 fractions, along with perirectal hydrogel spacer, fiducial placement, and MRI-based planning. Disease control outcomes were calculated from end of treatment. Minimally important difference (MID) assessing patient-reported quality of life was defined as greater than a one-half standard deviation increase in American Urological Association (AUA) symptom score after SAbR. Results: Two-hundred and forty-nine (249) low-, intermediate-, and high-risk PCa patients with median follow-up of 14.9 months for clinical toxicity were included. Acute urinary grade II toxicity occurred in 20.4% of patients. Acute grade II GI toxicity occurred in 7.3% of patients. For follow-up > 2 years (n = 69), late GU and GI grade ≥III toxicity occurred in 5.8% and 1.5% of patients, respectively. MID was evident in 31.8%, 23.4%, 35.8%, 37.0%, 33.3%, and 26.7% of patients at 3, 6, 12, 24, 36, and 48 months, respectively. The median follow-up for biochemical recurrence was 22.6 months with biochemical failure-free survival of 100% at 1 year (n = 226) and 98.7% for years 2 (n = 113) and 3 (n = 54). Conclusions: SAbR for PCa at 45 Gy in 5 fractions shows an encouraging safety profile. Prospective studies with longer follow-up are warranted to establish this dose regimen as standard of care for PCa.

Volumetric Modulated Arc Therapy Enabled Total Body Irradiation (VMAT-TBI): Six-year Clinical Experience and Treatment Outcomes.

Total body irradiation is an important part of the conditioning regimens frequently used to prepare patients for allogeneic hematopoietic stem cell transplantation (SCT). Volumetric-modulated arc therapy enabled total body irradiation (VMAT-TBI), an alternative to conventional TBI (cTBI), is a novel radiotherapy treatment technique that has been implemented and investigated in our institution. The purpose of this study is to (1) report our six-year clinical experience in terms of treatment planning strategy and delivery time and (2) evaluate the clinical outcomes and toxicities in our cohort of patients treated with VMAT-TBI. This is a retrospective single center study. Forty-four patients at our institution received VMAT-TBI and chemotherapy conditioning followed by allogeneic SCT between 2014 and 2020. Thirty-two patients (73%) received standard-dose TBI (12-13.2 Gy in 6-8 fractions twice daily), whereas 12 (27%) received low-dose TBI (2-4 Gy in one fraction). Treatment planning, delivery, and treatment outcome data including overall survival (OS), relapse-free survival (RFS), and toxicities were analyzed. The developed VMAT-TBI planning strategy consistently generated plans satisfying our dose constraints, with planning target volume coverage >90%, mean lung dose ∼50% to 75% of prescription dose, and minimal hotspots in critical organs. Most of the treatment deliveries were <100 minutes (range 33-147, mean 72). The median follow-up was 26 months. At the last follow-up, 34 of 44 (77%) of patients were alive, with 1- and 2-year OS of 90% and 79% and RFS of 88% and 71%, respectively. The most common grade 3+ toxicities observed were mucositis (31 patients [71%]) and nephrotoxicity (6 patients [13%]), both of which were deemed multifactorial in cause. Four patients (9%) in standard-dose cohort developed grade 3+ pneumonitis, with 3 cases in the setting of documented respiratory infection and only 1 (2%) deemed likely related to radiation alone. VMAT-TBI provides a safe alternative to cTBI. The dose modulation capability of VMAT-TBI may lead to new treatment strategies, such as simultaneous boost and further critical organ sparing, for better malignant cell eradication, immune suppression, and lower toxicities.

SABR for High-Risk Prostate Cancer: A Prospective Multilevel MRI-Based Dose Escalation Trial.

PURPOSE: Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa. METHODS AND MATERIALS: This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate <33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events. RESULTS: Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively. CONCLUSIONS: SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity.

Hydrogel Spacer Rectal Wall Infiltration Associated With Severe Rectal Injury and Related Complications After Dose Intensified Prostate Cancer Stereotactic Ablative Radiation Therapy.

The risk of rectal toxicity during and after prostate cancer radiation therapy is common to all treatment regimens. Hydrogel rectal spacers are increasingly being used to mitigate this risk and to facilitate dose-escalation, but also may infiltrate the rectal wall, with unclear clinical implication. We present a case of significant infiltration associated with severe late rectal injury (grade 4) and further grade 3 to 4 sequelae (recto-urethral fistula and associated osteomyelitis requiring exenteration) after high-dose stereotactic body radiation therapy for localized prostate cancer. The injury's temporal pattern associated with the expected timing of gel dissolution and displacement of infiltrated rectal layers potentially toward high dose regions together suggest a contributing role of the infiltration to the injury. In light of the rapid increase of hydrogel rectal spacer utilization, we review the case's evolution, concerning imaging findings, and associated literature and make suggestions regarding treatment planning and endoscopic assessment in the setting of infiltration or expected injury.

A Multi-Institutional Phase 2 Trial of High-Dose SAbR for Prostate Cancer Using Rectal Spacer.

PURPOSE: High-dose SABR for prostate cancer offers the radiobiologic potency of the most intensified radiation therapy regimens but was associated with >90% rates of ulceration of the anterior rectal wall on endoscopic assessment; this infrequently progressed to severe rectal toxicity in prior prospective series. A multi-institutional phase 2 prospective trial was conducted to assess whether placement of a perirectal hydrogel spacer would reduce acute periprostatic rectal ulcer events after high-dose (>40 Gy) SABR. METHODS AND MATERIALS: Eligible patients included men with stage ≤T2c localized grade group 1 to 3 prostate cancer, a prostate-specific antigen (PSA) level ≤15 ng/mL, American Urological Association Symptom Index = AUA-SI scores ≤18, and a gland volume ≤80 cm3. Patients underwent perirectal hydrogel spacer placement, followed by SABR of 45 Gy in 5 fractions every other day to the prostate only. Androgen deprivation was not allowed except for cytoreduction. The rectal wall was directly assessed by serial anoscopy during follow-up to determine whether the spacer would reduce acute periprostatic rectal ulcer events from >90% to <70% within 9 months of treatment. RESULTS: Forty-four men were enrolled and 43 were eligible for protocol analysis. The median follow-up for surviving patients was 48 months. Acute periprostatic ulcers were observed in 6 of 42 patients (14.3%; 95% confidence interval, 6.0%-27%; P < .001) at a median of 2.9 months posttreatment (range, 1.7-5.6 months). All ulcers (grade 1, 5 ulcers; grade 2, 1 ulcer) resolved on repeat anoscopy within 8 months of incidence. There were no grade ≥3 late gastrointestinal toxicities; the incidence of late grade-2 gastrointestinal toxicities was 14.3%, with a prevalence at 3 years of 0%. No toxicities greater than grade 3 occurred in any domain. Four-year freedom from biochemical failure was 93.8% (95% CI, 85.2%-100.0%). CONCLUSIONS: Temporary hydrogel spacer placement before high-dose SABR treatment for localized prostate cancer and use of strict dose constraints are associated with a significant reduction in the incidence of rectal ulcer events compared with prior phase 1/2 trial results.

Dynamic differences between DNA damage repair responses in primary tumors and cell lines.

The study of DNA damage repair response (DDR) in prostate cancer is restricted by the limited number of prostate cancer cell lines and lack of surrogates for heterogeneity in clinical samples. Here, we sought to leverage our experience with patient derived explants (PDEs) cultured ex vivo to study dynamics of DDR in primary tumors following application of clinically relevant doses of ionizing radiation (IR) to tumor cells in their native 3-dimensional microenvironment. We compared DDR dynamics between prostate cancer cell lines, PDEs and xenograft derived explants (XDEs) following treatment with IR (2Gy) either alone or in combination with pharmacological modulators of DDR. We have shown that following treatment with 2Gy, DDR can be consistently detected in PDEs from multiple solid tumors, including prostate, kidney, testes, lung and breast, as evidenced by γ-H2AX, 53BP1, phospho-ATM and phospho-DNA-PKcs foci. By examining kinetics of resolution of IR-induced foci, we have shown that DDR in prostate PDEs (complete resolution in 8 h) is much faster than in prostate cancer cell lines (<50% resolution in 8 h). The transcriptional profile of DDR genes following 2Gy IR appears to be distinct between PDEs and cell lines. Pre-treatment with drugs targeting DDR pathways differentially alter the kinetics of DDR in the PDEs and cell lines, as evidenced by altered kinetics of foci resolution. This study highlights the utility of PDEs as a robust model system for short-term evaluation of DDR in primary solid tumors in clinically relevant microenvironment.

ACR-ASTRO Practice Parameter for the Performance of Stereotactic Body Radiation Therapy.

AIM/OBJECTIVES/BACKGROUND: To standardize the practice of stereotactic body radiation therapy (SBRT), the American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO) cooperatively developed the practice parameter for SBRT. SBRT is a treatment technique that delivers radiation dose to a well-defined extracranial target in 5 fractions or less and usually employs a higher dose per fraction than used in conventional radiation. METHODS: The ACR-ASTRO Practice Parameter for the Performance of Stereotactic Body Radiation Therapy was revised according to the process described on the ACR website ("The Process for Developing ACR Practice Parameters and Technical Standards," www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the ASTRO. Both societies then reviewed and approved the document. RESULTS: Given the complexities of SBRT, a separate document was created to develop a technical standard for the medical physics of SBRT (ACR-AAPM Technical Standard for Medical Physics Performance Monitoring of Stereotactic Body Radiation Therapy). Workflow, qualifications and responsibilities of personnel, specifications, documentation, quality control/safety/improvement, simulation/treatment, and follow-up were addressed in this practice parameter. CONCLUSIONS: This practice parameter assists practitioners in providing safe and appropriate SBRT treatment and care for patients when clinically indicated. As technologies and techniques continue to evolve, this document will be reviewed, revised and renewed accordingly to a 5 year or sooner timeline specified by the ACR.