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Radiomics is a fast-growing research area based on converting standard-of-care imaging into quantitative minable data and building subsequent predictive models to personalize treatment. Radiomics has been proposed as a study objective in clinical trial concepts and a potential biomarker for stratifying patients across interventional treatment arms. In recognizing the growing importance of radiomics in oncology, a group of medical physicists and clinicians from NRG Oncology reviewed the current status of the field and identified critical issues, providing a general assessment and early recommendations for incorporation in oncology studies.

Purpose/Objective(s) A data registry was established upon implementation of a program of intra-operative radiation therapy (IORT) using high-dose rate brachytherapy. We evaluated the initial experience of patients with locally recurrent gastrointestinal (GI) cancers to help inform future patient selection and optimal multi-modal treatment management. Materials/Methods All patients treated with surgical resection and IORT at a tertiary referral center were prospectively enrolled in a registry after program implementation in 2015. Candidates for IORT included patients who presented with disease likely to be resected with either close or positive margins based on multi-disciplinary evaluation. Patient, disease, and treatment characteristics including radiation history and acute (within 90 days, Clavien-Dindo grade) were recorded. IORT was administered using a HAM applicator, with field size and location determined intra-operatively, prescribed to 1 cm depth with lead blocking as appropriate. Patterns of failure and toxicity were analyzed. Time to event analysis was conducted using Kaplan Meier method, and contingency tables and chi square statistics evaluated differences in frequency of events. Results Twenty-one patients were identified with locally recurrent GI cancer (rectal 62%, colon 29%, and anal cancer, 9%) who underwent surgical resection and IORT with curative intent. Median age was 58 years. All patients had a history of pelvic external beam radiotherapy (EBRT, median 50.4 Gy); 9 (43%) were treated with pre-operative reirradiation (median dose 43 Gy, median 2 mo prior to surgery). The median IORT dose was 12.5 Gy (range 10-15). Resection was pathologically complete (R0, n = 9), or with microscopic (R1, n = 11) or macroscopic residual (R2, n = 1). Median follow up was 20 months. Twelve (57%) patients had failure at the site of IORT, at a median 7 mo. Freedom from failure (FFF) within the IORT field was associated with resection status (FFF-1y 75% for R0 vs 15% for R1/2, P = 0.0065) but not re-irradiation EBRT or IORT dose (P > 0.05). Pelvic failure beyond the IORT site occurred in 5 (24%) patients at a median 5 mo, and 13 (62%) had eventual distant metastases, at a median 5.5 months. Ultimately, only 3 patients (14%) were disease free at last follow-up. The median hospital stay was 6 days, the 90-day readmission rate was 25%, and acute grade 3 toxicity was observed in 43%, with abscess/sepsis most common (n = 5, 24%). Grade 3 toxicities and 90-day admission were not associated with resection status or EBRT (all P > 0.1). There were no 90-day grade 4/5 toxicities. Conclusion In patients treated with surgical excision and IORT for locally recurrent GI cancer, the ability to achieve a clear resection margin is a critical determinant of in-field local control. Patient selection should consider the chance for R0 resection, as well as the risk of regional or distant progression, when evaluating patients for this aggressive multi-modal treatment.

1007 Background: Prospective and retrospective studies of patients (pts) with oligometastatic (OM) disease have supported that metastases (mets) directed treatment (MDT) with SBRT or SR in addition to standard of care systemic therapy (SOC ST) can improve progression-free (PFS) and overall survival (OS) compared with SOC ST alone. However, randomized evidence in oligometastatic breast cancer (OMBC) are lacking. NRG-BR002, a randomized Phase IIR/III trial, sought to determine the efficacy of SOC ST + MDT (SBRT or SR) as first line treatment of OMBC. Methods: OMBC pts with ≤ 4 extracranial mets on standard imaging with controlled primary disease were eligible if on first line SOC ST for ≤ 12 months without progression. Pts were randomized (1:1) to ARM 1 – SOC ST (mainly chemotherapy, endocrine therapy, anti-HER2) or ARM 2 – SOC ST with MDT of all mets. Stratification included mets number (1 vs > 1), ER/PR and Her2 status, and chemotherapy use. Phase IIR targeted sample size was 128 total/116 eligible pts, for 92% power and 1-sided significance level = 0.15 to determine if adding MDT shows a signal for improved PFS (hazard ratio [HR] = 0.55, corresponding to median PFS (mPFS) from 10.5 to 19 months), in order to continue to the full phase III trial for OS. PFS and OS were estimated by Kaplan-Meier and arms compared with log-rank. Results: 125 of the 129 pts randomized were eligible (ARM 1 = 65, ARM 2 = 60). Key characteristics included median age 54, 79% ER+ or PR+/HER2-, 13% HER2+, 8% triple negative. 60% had 1 metastasis and 20% presented synchronously with primary disease. Following randomization, systemic therapy was delivered to 95% in ARM 1 and 93% in ARM 2; ablation: SBRT 93%, SR 2%, and 5% none. The median follow-up was 30 mo. The mPFS (70% CI) in ARM 1 was 23 mo (18, 29) and 19.5 mo (17, 36) in ARM 2; 24 and 36-mo PFS (70% CI) for ARM 1 were 45.7% (38.9, 52.5) and 32.8% (26.0, 39.5) compared with 46.8 (39.2, 54.3) and 38.1 (29.7, 46.6) in ARM 2; HR (70% CI): 0.92 (0.71, 1.17); and 1-sided log-rank p = 0.36. As PFS did not show signal, OS reporting is included: median OS was not reached in either arm; 36-mo OS (95% CI) in ARM 1 71.8% (58.9, 84.7) and ARM 2 68.9% (55.1, 82.6; 2-sided log-rank p = 0.54). Analysis of first failure showed new mets outside index area (Arm 1) /RT field (Arm 2) developed similarly in both arms at 40%. There were fewer new mets inside treated/index area for Arm 2 6.7% vs ARM 1 29.2%, respectively. There were no grade 5 treatment-related adverse events (AEs), 1 grade 4 AE in ARM 1, and 9.7% and 5.3% grade 3 AEs in ARMS 1 and 2, respectively. Circulating tumor cell counts (0 vs ≥1) at baseline were similar in both arms and were not prognostic HR (95% CI): 1.04 (0.54, 2.02). Conclusions: The addition of MDT to SOC ST did not show signal for improved PFS, nor OS difference in patients with OMBC. The trial will not proceed to the Phase III component. Clinical trial information: NCT02364557.

Background: The current standard of care for metastatic breast cancer patients (pts) is to deliver palliative chemotherapy, biologic &/or hormonal therapy when appropriate, with radiation &/or surgery reserved for the management of symptomatic or non-responsive (mets). For selected pts with limited metastatic (met) disease, mets-directed ablative therapy, with either surgical resection or high dose conformal radiotherapy (in addition to standard systemic therapies) to lung, liver, CNS adrenal, & multiple organs has been shown to result in long-term disease control numerically superior to systemic therapy alone. NRG-BR002 is a randomized Phase II trial to evaluate stereotactic body radiotherapy (SBRT) &/or surgical resection (SR) of all met sites in newly oligometastatic breast cancer in addition to standard systemic therapy. Trial Design & Eligibility For the Ph IIR, eligible breast cancer pts with biopsy confirmed metastatic disease to < /= 2 sites will be randomized to receive either standard systemic therapy with mets directed therapy as needed ( control arm) versus ablative therapy of all met sites with either body SBRT &/or surgical resection (SR) ( per the treating physician discretion) to determine if there is an improvement median progression free survival (PFS). If this aim is met the trial continues as a Ph III to evaluate if SBRT/SR improves 5 year overall survival. Secondary aims include local control in the met site, new distant met rate, & technical quality. The primary translational endpoint tests whether < 5 CTCs (per 7.5ml of blood) is an independent prognostic (outcome) marker for improved PFS & OS in oligometastatic breast cancer. Women are within 1 year of metastatic diagnosis, on first line systemic therapy without progression & the primary site disease is controlled. CNS mets are ineligible. ER/PR & HER-2 neu are required on either the primary or met site. Site radiation credentialing & a facility questionnaire are required. Randomization is to standard systemic therapy with local radiotherapy/ surgery for palliation when necessary vs ablative therapy of all mets with SBRT &/or SR. Statistics: For the Ph IIR portion to detect a signal for improved median PFS from 10.5 months to 19 months with 95% power & accounting for ineligible/lost pts, 146 pts will be required. For the Ph III, an additional 246, for a total of 402 pts will be required to definitively determine if ablative therapy improves 5-year overall survival from 28% to 42.5% (HR=0.67), with 85% power & a 1-sided type I error of 0.025. For the translational research, the number of pts accrued in the Ph IIR & Ph III portions will provide sufficient power ≥ 91% to detect whether < 5 CTC's is a prognostic marker for improved PFS & OS. Present Accrual & Target Accrual NRG BR002 activated 12/24/2014 with a target accrual of 146 pts for the Ph II component & 256 additional for the Ph III. Contact Information: Protocol: CTSU member web site https://www.ctsu.org. Enrollment: OPEN at https://open.ctsu.org. Support: Supported by NRG Oncology grants U10CA180868 & U10CA180822 from the National Cancer Institute (NCI). Citation Format: Chmura SJ, Winter KA, Salama JK, Woodward WW, Borges VF, Al-Hallaq H, Martuszak M, Jaskowiak NT, Milano MT, Bandos H, White JR. NRG-BR002: A phase IIR/III trial of standard of care therapy with or without stereotactic body radiotherapy (SBRT) &/or surgical ablation for newly oligometastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-06.

An interstitial brachytherapy approach for gynecologic cancers is typically considered for patients with lesions exceeding 5 mm within tissue or that are not easily accessible for intracavitary applications. Recommendations for treating gynecologic malignancies with this approach are available through the American Brachytherapy Society, but vary based on available resources, staffing, and logistics. The intent of this manuscript is to share the collective experience of 3 academic centers that routinely perform interstitial gynecologic brachytherapy. Discussion points include indications for interstitial implants, procedural preparations, applicator selection, anesthetic options, imaging, treatment planning objectives, clinical workflows, timelines, safety, and potential challenges. Interstitial brachytherapy is a complex, high-skill procedure requiring routine practice to optimize patient safety and treatment efficacy. Clinics planning to implement this approach into their brachytherapy practice may benefit from considering the discussion points shared in this manuscript.

Importance Stereotactic body radiotherapy (SBRT) for oligometastases is hypothesized to improve survival and is increasingly used. Little evidence supports its safe use to treat patients with multiple metastases. Objective To establish safety of SBRT dose schedules in patients with 3 to 4 metastases or 2 metastases in close proximity to each other. Design, Setting, and Participants This phase 1 trial opened on August 4, 2014, and closed to accrual on March 20, 2018. Metastases to 7 anatomic locations were included: bone/osseous (BO), spinal/paraspinal (SP), peripheral lung (PL), central lung (CL), abdominal-pelvic (AP), mediastinal/cervical lymph node (MC), and liver (L). Six patients could be enrolled per anatomic site. The setting was a consortium of North American academic and community practice cancer centers participating in NRG Oncology trials. Patients with breast, prostate, or non–small cell lung cancer with 3 to 4 metastases or 2 metastases in close proximity (≤5 cm) amenable to SBRT were eligible for this phase 1 study. Statistical analyses were performed from December 31, 2017, to September 19, 2019. Interventions The starting dose was 50 Gy in 5 fractions (CL, MC), 45 Gy in 3 fractions (PL, AP, L), and 30 Gy in 3 fractions (BO, SP). Main Outcomes and Measures The primary end point was dose-limiting toxicity (DLT) defined by the Common Terminology Criteria for Adverse Events, version 4.0, as specific adverse events (AEs) of grades 3 to 5 (definite or probable per the protocol DLT definition) related to SBRT within 180 days of treatment. Dose levels were considered safe if DLTs were observed in no more than 1 of 6 patients per location; otherwise, the dose at that location would be de-escalated. Results A total of 42 patients enrolled, 39 were eligible, and 35 (mean [SD] age, 63.1 [14.2] years; 20 men [57.1%]; 30 White patients [85.7%]) were evaluable for DLT. Twelve patients (34.3%) had breast cancer, 10 (28.6%) had non–small cell lung cancer, and 13 (37.1%) had prostate cancer; there was a median of 3 metastases treated per patient. Median survival was not reached. No protocol-defined DLTs were observed. When examining all AEs, 8 instances of grade 3 AEs, most likely related to protocol therapy, occurred approximately 125 to 556 days from SBRT initiation in 7 patients. Conclusions and Relevance This phase 1 trial demonstrated the safety of SBRT for patients with 3 to 4 metastases or 2 metastases in close proximity. There were no treatment-related deaths. Late grade 3 AEs demonstrate the need for extended follow-up in long-surviving patients with oligometastatic disease. Treatment with SBRT for multiple metastases has been expanded into multiple ongoing randomized phase 2/3 National Cancer Institute–sponsored trials (NRG-BR002, NRG-LU002). Trial Registration ClinicalTrials.gov Identifier:NCT02206334

Purpose Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1–treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors. Patients and Methods Patients progressing on standard treatment received SBRT to two to four metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. SBRT dosing varied by site and ranged from 30 to 50 Gy in three to five fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Pembrolizumab was initiated within 7 days after completion of SBRT. Pre- and post-SBRT biopsy specimens were analyzed in a subset of patients to quantify interferon-γ–induced gene expression. Results A total of 79 patients were enrolled; three patients did not receive any treatment and three patients only received SBRT. Patients included in the analysis were treated with SBRT and at least one cycle of pembrolizumab. Most (94.5%) of patients received SBRT to two metastases. Median follow-up for toxicity was 5.5 months (interquartile range, 3.3 to 8.1 months). Six patients experienced dose-limiting toxicities with no radiation dose reductions. In the 68 patients with imaging follow-up, the overall objective response rate was 13.2%. Median overall survival was 9.6 months (95% CI, 6.5 months to undetermined) and median progression-free survival was 3.1 months (95% CI, 2.9 to 3.4 months). Expression of interferon-γ–associated genes from post–SBRT tumor biopsy specimens significantly correlated with nonirradiated tumor response. Conclusion Multisite SBRT followed by pembrolizumab was well tolerated with acceptable toxicity. Additional studies exploring the clinical benefit and predictive biomarkers of combined multisite SBRT and PD-1–directed immunotherapy are warranted.

TPS1117 Background: This is a randomized Phase II/III trial to evaluate if stereotactic body radiotherapy (SBRT) and/or surgical resection (SR) of all metastatic sites in newly oligo-metastatic breast cancer who have received up to 12 months of first line systemic therapy without progression will significantly improve median progression free survival (PFS). If this aim is met the trial continues as a phase III to evaluate if SBRT/SR improves 5 year overall survival. Secondary aims include local control in the metastatic site, new distant metastatic rate, and technical quality. Translational primary endpoint is to determine whether < 5 CTCs is an independent prognostic marker for improved PFS and OS. Methods: Women with pathologically confirmed metastatic breast cancer to ≤ 4 sites who have been diagnosed within 365 days with metastatic disease and the primary tumor site disease is controlled. CNS metastases are ineligible. ER/PR and HER-2 neu status is required. Site radiation credentialing with a facility questionnaire and pre-treatment review of first case is required. Randomization is to standard systemic therapy with local radiotherapy/ surgery for palliation when necessary versus ablative therapy of all metastases with SBRT and/or SR. For the phase IIR portion to detect a signal for improved median PFS from 10.5 months to 19 months with 95% power and a 1-sided alpha of 0.15 and accounting for ineligible/lost patients, 128 patients will be required. For the Phase III, an additional 232 patients will be required to definitively determine if ablative therapy improves 5-year overall survival from 28% to 42.5% (HR=0.67), with 85% power and a one-sided type I error of 0.025. For the translational research assuming a two-sided probability of type I error of 0.05, the number of patients accrued in the Phase II-R and Phase III portions will provide sufficient power of at least 91% and 93% to detect whether < 5 CTC’s is prognostic for PFS and OS, respectively. Present accrual (1-31-2019): 105. Contact Information: Protocol: CTSU member web site https://www.ctsu.org . Enrollment: OPEN at https://open.ctsu.org . Support: This project is supported by NRG Oncology grants U10CA180868 and U10CA180822 from the National Cancer Institute (NCI). Translational science is supported by the Ludwig Foundation for Cancer Research. Clinical trial information: NCT02364557.

Purpose The NRG-BR001 trial is the first National Cancer Institute–sponsored trial to treat multiple (range 2-4) extracranial metastases with stereotactic body radiation therapy. Benchmark credentialing is required to ensure adherence to this complex protocol, in particular, for metastases in close proximity. The present report summarizes the dosimetric results and approval rates. Methods and Materials The benchmark used anonymized data from a patient with bilateral adrenal metastases, separated by Results Of 63 benchmarks submitted through October 2015, 94% were approved, with 51% approved at the first attempt. Most used volumetric arc therapy (VMAT) (78%), a single plan for both PTVs (90%), and prioritized the PTV over the stomach (75%). The median dose to 95% of the volume was 44.8 ± 1.0 Gy and 44.9 ± 1.0 Gy for the right and left PTV, respectively. The median dose to 0.03 cm 3 was 14.2 ± 2.2 Gy to the spinal cord and 46.5 ± 3.1 Gy to the stomach. Plans that spared the stomach significantly reduced the dose to the left PTV and stomach. Conformity metrics were significantly better for single plans that simultaneously treated both PTVs with VMAT, intensity modulated radiation therapy, or 3-dimensional conformal radiation therapy compared with separate plans. No significant differences existed in the dose at 2 cm from the PTVs. Conclusions Although most plans used VMAT, the range of conformity and dose falloff was large. The decision to prioritize either OARs or PTV coverage varied considerably, suggesting that the toxicity outcomes in the trial could be affected. Several benchmarks met the dose-volume histogram metrics but produced unacceptable plans owing to low conformity. Dissemination of a frequently-asked-questions document improved the approval rate at the first attempt. Benchmark credentialing was found to be a valuable tool for educating institutions about the protocol requirements.

Purpose To determine the feasibility of and acute toxicity associated with hypofractionated whole breast radiation (HypoRT) after breast-conserving surgery in patients excluded from or underrepresented in randomized trials comparing HypoRT with conventional fractionation schedules. Methods and Materials A review was conducted of all patients consecutively treated with HypoRT at the University of Chicago. All patients were treated to 42.56 Gy in 2.66 Gy daily fractions in either the prone or supine position. Planning was performed in most cases using wedges and large segments or a “field-in-field” technique. Breast volume was estimated using volumetric measurements of the planning target volume (PTV). Dosimetric parameters of heterogeneity (V105, V107, V110, and maximum dose) were recorded for each treatment plan. Acute toxicity was scored for each treated breast. Results Between 2006 and 2010, 78 patients were treated to 80 breasts using HypoRT. Most women were overweight or obese (78.7%), with a median body mass index of 29.2 kg/m 2 . Median breast volume was 1,351 mL. Of the 80 treated breasts, the maximum acute skin toxicity was mild erythema or hyperpigmentation in 70.0% (56/80), dry desquamation in 21.25% (17/80), and focal moist desquamation in 8.75% (7/80). Maximum acute toxicity occurred after the completion of radiation in 31.9% of patients. Separation >25 cm was not associated with increased toxicity. Breast volume was the only patient factor significantly associated with moist desquamation on multivariable analysis ( p = 0.01). Patients with breast volume >2,500 mL experienced focal moist desquamation in 27.2% of cases compared with 6.34% in patients with breast volume p = 0.03). Conclusions HypoRT is feasible and safe in patients with separation >25 cm and in patients with large breast volume when employing modern planning and positioning techniques. We recommend counseling regarding expected increases in skin toxicity in women with a PTV volume >2,500 mL.

TPS9599Background: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy associated with ultraviolet light exposure, advanced age and infection with the Merkel cell polyomavirus (MCP). Histori...

20 Background: Clinical responses to PD1 blockade have been linked to IFN-γ associated gene expression in the tumor microenvironment. Stereotactic body radiotherapy (SBRT) can stimulate innate and adaptive immunity to potentially augment immunotherapy. Anti-PD1 treatment outcomes are improved with lower disease burden and multi-site radiation is an emerging paradigm for eradicating metastatic disease. Methods: We conducted a phase I study for patients with metastatic solid tumors who progressed on standard treatment. The primary aim was to evaluate the safety of pembrolizumab Immunotherapy with Multi-Organ Site Ablative stereotactic body Radiation Therapy (iMOSART). Two to four metastases were chosen for each patient and not all sites of disease were targeted with SBRT. Metastases > 65cc were partially irradiated. Pembrolizumab was initiated within 7 days after the final SBRT treatment. Results: 79 patients were enrolled, three patients did not receive any treatment and three patients only received SBRT. The 73 patients included in the analysis were treated with SBRT and at least 1 cycle of pembrolizumab. 94.5% of patients had two lesions treated with SBRT. Median follow-up for toxicity was 5.5 months (IQR 3.3-8.1). Six patients experienced dose-limiting toxicity (DLT) with no radiation dose reductions. RECIST overall objective response rate was 13.5% in the 68 patients with imaging follow-up. Superior control of irradiated lesions was observed compared to non-irradiated target lesions for the 52 patients with paired data (p = 0·0005) with a mean percent tumor burden change -21·7% (SD 24·3%) for irradiated lesions vs. 1·7% (SD 46·3%) for non-irradiated lesions (p = 0·0008). While abscopal response defined by 30% reduction in any single non-irradiated measurable lesion was present in 26·9% of patients, abscopal response was 13·2% when defined by 30% reduction in aggregate diameter of non-irradiated measurable lesions. Conclusions: iMOSART was well tolerated with acceptable toxicity. Further randomized studies are warranted to investigate the potential clinical benefit of this combination approach. Clinical trial information: NCT02608385.

Purpose To assess the relationship between radiation dose and change in a set of mathematical intensity- and texture-based features and to determine the ability of texture analysis to identify patients who develop radiation pneumonitis (RP). Methods and Materials A total of 106 patients who received radiation therapy (RT) for esophageal cancer were retrospectively identified under institutional review board approval. For each patient, diagnostic computed tomography (CT) scans were acquired before (0-168 days) and after (5-120 days) RT, and a treatment planning CT scan with an associated dose map was obtained. 32- × 32-pixel regions of interest (ROIs) were randomly identified in the lungs of each pre-RT scan. ROIs were subsequently mapped to the post-RT scan and the planning scan dose map by using deformable image registration. The changes in 20 feature values (ΔFV) between pre- and post-RT scan ROIs were calculated. Regression modeling and analysis of variance were used to test the relationships between ΔFV, mean ROI dose, and development of grade ≥2 RP. Area under the receiver operating characteristic curve (AUC) was calculated to determine each feature's ability to distinguish between patients with and those without RP. A classifier was constructed to determine whether 2- or 3-feature combinations could improve RP distinction. Results For all 20 features, a significant ΔFV was observed with increasing radiation dose. Twelve features changed significantly for patients with RP. Individual texture features could discriminate between patients with and those without RP with moderate performance (AUCs from 0.49 to 0.78). Using multiple features in a classifier, AUC increased significantly (0.59-0.84). Conclusions A relationship between dose and change in a set of image-based features was observed. For 12 features, ΔFV was significantly related to RP development. This study demonstrated the ability of radiomics to provide a quantitative, individualized measurement of patient lung tissue reaction to RT and assess RP development.

Purpose: Blood oxygen level dependent (BOLD) contrast in magnetic resonance imaging (MRI) has been widely used for noninvasive evaluation of the effects of tumor-oxygenating agents. However, there have been few tests of the validity of this method. The goal of the present work was to use the T 1 of fluorine-19 in perfluorocarbon (PFC) emulsions as a "gold standard" for comparison with BOLD MRI. Methods and Materials: Rats bearing R3230AC tumors implanted in the hind limb were injected with an emulsion of perfluoro-15-crown-5-ether for 2–3 days before experiments, which ensured that the PFC emulsion concentrated in the tumors. We correlated changes in tumor oxygenation caused by carbogen inhalation measured by 1 H BOLD MRI with quantitative 19 F measurements. The 19 F spin-lattice relaxation rate R 1 (= 1/T 1 ) was measured to determine initial oxygen tension (pO 2 ) in each image pixel containing the PFC, and changes in pO 2 during carbogen (95% O 2 , 5% CO 2 ) breathing. In a second carbogen breathing period, changes in water signal linewidth were measured using high spectral and spatial resolution imaging. 19 F and 1 H measurements were used to classify pixels as responders to carbogen (pixels where oxygen increased significantly) or nonresponders (no significant change in tumor oxygenation). Results: The 19 F and 1 H measurements agreed in 65% ± 11% of pixels ( n = 14). Agreement was even stronger among pixels where 1 H showed increased oxygenation; 19 F measurements agreed with 1 H measurements in over 79% ± 11% of these pixels. Similarly, there was strong agreement between the two modalities in pixels where 19 F reported no change in pO 2 ; 1 H also showed no changes in 76% ± 18% of these pixels. Quantitative correlation of changes T 2 ∗ (ΔT 2 ∗) in 1 H and changes R 1 (ΔR 1 ) in 19 F was weak during carbogen breathing, and averaged over the whole tumor was ∼0.40 for 14 experiments. However, the spatial patterns of 1 H and 19 F changes were qualitatively very similar. In hypoxic regions that were identified based on long 19 F T 1 (>2.53 s), 19 F and 1 H MRI agreed that carbogen had relatively weak effects. Conclusions: These results suggest that 1 H BOLD MRI reliably identifies increases in tumor pO 2 . In hypoxic regions where increases in pO 2 are most desirable, carbogen was ineffective. The data suggest that 19 F and 1 H MRI can be used individually or in combination to guide the design of improved tumor-oxygenating agents.

Purpose To calculate planning target volume (PTV) margins for chest wall and regional nodal targets using daily orthogonal kilovolt (kV) imaging and to study residual setup error after kV alignment using volumetric cone-beam computed tomography (CBCT). Methods and Materials Twenty-one postmastectomy patients were treated with intensity modulated radiation therapy with 7-mm PTV margins. Population-based PTV margins were calculated from translational shifts after daily kV positioning and/or weekly CBCT data for each of 8 patients, whose surgical clips were used as surrogates for target volumes. Errors from kV and CBCT data were mathematically combined to generate PTV margins for 3 simulated alignment workflows: ( 1 ) skin marks alone; ( 2 ) weekly kV imaging; and ( 3 ) daily kV imaging. Results The kV data from 613 treatment fractions indicated that a 7-mm uniform margin would account for 95% of daily shifts if patients were positioned using only skin marks. Total setup errors incorporating both kV and CBCT data were larger than those from kV alone, yielding PTV expansions of 7 mm anterior–posterior, 9 mm left–right, and 9 mm superior–inferior. Required PTV margins after weekly kV imaging were similar in magnitude as alignment to skin marks, but rotational adjustments of patients were required in 32% ± 17% of treatments. These rotations would have remained uncorrected without the use of daily kV imaging. Despite the use of daily kV imaging, CBCT data taken at the treatment position indicate that an anisotropic PTV margin of 6 mm anterior–posterior, 4 mm left–right, and 8 mm superior–inferior must be retained to account for residual errors. Conclusions Cone-beam CT provides additional information on 3-dimensional reproducibility of treatment setup for chest wall targets. Three-dimensional data indicate that a uniform 7-mm PTV margin is insufficient in the absence of daily IGRT. Interfraction movement is greater than suggested by 2-dimensional imaging, thus a margin of at least 4 to 8 mm must be retained despite the use of daily IGRT.

TPS1098Background: This randomized Phase II trial evaluates if stereotactic body radiotherapy (SBRT) and/or surgical resection (SR) of all metastatic sites in newly oligo-metastatic breast cancer who have received, or planned to receive, up to 12 months of first line systemic therapy without progression will significantly improve median progression free survival (PFS). If this aim is met, a phase III component evaluates if SBRT/SR improves 5 year OS. Secondary aims include local control in the metastases, new metastases, and technical quality. Translational primary endpoint is to determine whether < 5 CTCs is an independent prognostic marker for improved PFS and OS. Methods: A 2016 amendment expanded eligibility criteria to pathologically confirmed metastatic breast cancer to ≤ 2 sites and < 12 months of standard first line systemic therapy. Registration must occur

Background: The current standard of care for metastatic breast cancer patients (pts) is to deliver palliative chemotherapy, biologic &/or hormonal therapy when appropriate, with radiation &/or surgery reserved for the management of symptomatic or non-responsive (mets). For selected pts with limited metastatic (met) disease, mets-directed ablative therapy, with either surgical resection or high dose conformal radiotherapy (in addition to standard systemic therapies) to lung, liver, CNS adrenal, & multiple organs has been shown to result in long-term disease control numerically superior to systemic therapy alone. NRG-BR002 is a randomized Phase II trial to evaluate stereotactic body radiotherapy (SBRT) &/or surgical resection (SR) of all met sites in newly oligometastatic breast cancer in addition to standard systemic therapy. Trial Design & Eligibility For the Ph IIR, eligible breast cancer pts who have received up to 6 months of first line systemic therapy without progression will be randomized to receive either standard systemic therapy with mets directed therapy as needed ( control arm) versus ablative therapy of all met sites with either body SBRT &/or surgical resection (SR) ( per the treating physician discretion) to determine if there is an improvement median progression free survival (PFS). If this aim is met the trial continues as a Ph III to evaluate if SBRT/SR improves 5 year overall survival. Secondary aims include local control in the met site, new distant met rate, & technical quality. The primary translational endpoint tests whether < 5 CTCs (per 7.5ml of blood) is an independent prognostic (outcome) marker for improved PFS & OS in oligometastatic breast cancer. Women with pathologically confirmed met breast cancer to < /= 2 sites, with up to 6 months of standard first line systemic therapy & the primary site disease is controlled. CNS mets are ineligible. ER/PR & HER-2 neu are required on either the primary or met site. Site radiation credentialing & a facility questionnaire are required. Randomization is to standard systemic therapy with local radiotherapy/ surgery for palliation when necessary vs ablative therapy of all mets with SBRT &/or SR. Statistics: For the Ph IIR portion to detect a signal for improved median PFS from 10.5 months to 19 months with 95% power & accounting for ineligible/lost pts, 146 pts will be required. For the Ph III, an additional 246, for a total of 402 pts will be required to definitively determine if ablative therapy improves 5-year overall survival from 28% to 42.5% (HR=0.67), with 85% power & a 1-sided type I error of 0.025. For the translational research, the number of pts accrued in the Ph IIR & Ph III portions will provide sufficient power ≥ 91% to detect whether < 5 CTC's is a prognostic marker for improved PFS & OS. Present Accrual & Target Accrual NRG BR002 activated 12/24/2014 with a target accrual of 146 pts for the Ph II component & 256 additional for the Ph III. Contact Information: Protocol: CTSU member web site https://www.ctsu.org. Enrollment: OPEN at https://open.ctsu.org. Support: Supported by NRG Oncology grants U10CA180868 & U10CA180822 from the National Cancer Institute (NCI). Citation Format: Chmura SJ, Winter KA, Salama JK, Woodward WA, Borges VF, Al-Hallaq H, Matuszak M, Jaskowiak NT, Milano MT, Bandos H, White JR. NRG-BR002: A phase IIR/III trial of standard of care therapy with or without stereotactic body radiotherapy (SBRT) &/or surgical ablation for newly oligometastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-03-04.

Intensity modulated radiation therapy (IMRT) has achieved widespread use for prostate cancer; however, in relation to this use, outcomes studies are still relatively sparse. We report a single-institutional experience in outcomes analysis with the use of IMRT for the primary management of prostate cancer. One hundred thirty consecutive patients with adenocarcinoma of the prostate were treated at a single institution using IMRT with curative intent. Thirty-six (28%) patients were classified as low-risk, 69 (53%) as intermediate-risk, and 25 (19%) as high-risk. The median dose prescription was 76 Gy to the planning target volume. Sixty-five (50%) patients received androgen deprivation therapy (ADT) for a median 4 months, starting 2 months prior to IMRT. Biochemical failure was defined as PSA > post-treatment nadir+2. Gastrointestinal (GI) and Genitourinary (GU) toxicity were defined by RTOG criteria. Median follow-up was 53 months. By NCCN risk category, 4-year biochemical control was 97%, 94%, and 87% for low, intermediate, and high-risk patients, respectively. Among disease factors, multivariable analysis demonstrated the strongest association between biochemical control and Gleason score ≤6 (p=0.0371). Therapy was well tolerated with no Grade 4 toxicity and limited grade 3 GI or GU toxicity. Acute Grade 3+ GI and GU toxicity rates were 0% and 2%, and maximal late Grade 3+ GI and GU toxicity rates were 5% and 6%, respectively. Late rectal toxicity was associated with higher volumes of RT to the rectum. By last follow-up late Grade 3+ toxicity was 2% for both GI and GU systems. In conclusion, patients treated with IMRT for prostate cancer have excellent rates of biochemical control and low rates of severe toxicity of treatment.

BACKGROUND. In this retrospective study, the authors hypothesized that magnetic resonance imaging (MRI) would alter partial breast irradiation (PBI) eligibility by identifying cancers outside the PBI volume compared with mammography alone. METHODS. Since 2002, MRI was used nonselectively at the authors' institution for the staging of patients with nonmetastatic breast cancer. Of 450 consecutive patients with invasive breast cancer, 110 patients who were eligible for PBI were identified by using criteria outlined by National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Oncology Group trial 0413 based on mammography, ultrasonography, and initial pathology. In that trial, patients were randomized (stage I/II invasive cancers that measured ≤3 cm and ≤3 positive lymph nodes) to receive either whole-breast radiotherapy or PBI. MRI reports were reviewed to determine whether MRI identified secondary lesions 1) within the same quadrant (multifocal), 2) in a different quadrant (multicentric), or 3) in the contralateral breast. These lesions were pathologically proven carcinoma and would have rendered the patient ineligible for PBI. RESULTS. MRI identified secondary lesions in 10% of patients (95% confidence interval [CI], 4.4%-15.6%). Multifocal disease was identified in 3.6% (95% CI, 1.4%-9%), multicentric disease was identified in 4.5% (95% CI, 2%-10.2%), and contralateral disease was identified in 1.8% (95% CI, 0.5%-6.4%). The proportion of patients with false-positive MRI findings was 4.5% (95% CI, 2%-10.2%). The positive predictive value of MRI was 72.2% (95% CI, 46.4%-89.3%). CONCLUSIONS. MRI identified frequent secondary cancers that would not be removed routinely by surgery or targeted in the radiation field if treated with PBI. The current data suggest that MRI should be considered to assess PBI eligibility to minimize potential local failures. Cancer 2008. © 2008 American Cancer Society.

We evaluate whether magnetic resonance imaging (MRI) with blood oxygenation level-dependent (BOLD) contrast correctly predicts the relative effects of tumor-oxygenating agents on hypoxic fraction in BA1112 rhabdomyosarcomas in WAG/Rij rats.The response of ten tumors to carbogen (95% O(2)/5% CO(2)), a perfluorocarbon emulsion (PFC), and the combination of PFC + carbogen was studied with high spectral and spatial resolution MR imaging of the water resonance at 4.7 Tesla. Decreases in MR signal linewidth indicate increases in tumor blood oxygen levels.Average MR signal linewidth was decreased 2.0% by carbogen, 2.5% by PFC + air, and 4.9% by PFC + carbogen. PFC + carbogen caused a larger linewidth decrease than either treatment alone (p0.04 by ANOVA). Maps of pixels responding to treatment indicate that combining PFC with carbogen significantly enlarges the area of the tumor in which oxygen levels are increased (p0.01 by ANOVA).MRI predicts that PFC + carbogen will increase radiosensitivity more than either treatment alone; this agrees with the known effects of these treatments on hypoxic fraction. Utilizing MRI to choose the treatment that maximizes the size and extent of increases in tumor oxygenation could reduce hypoxic fraction.

Purpose: To assess the 3D dose coverage of the supraclavicular fossa (SCF) and axillary apex (AA) following conventional dose prescription and blocking. Materials and Methods: 16 patients with breast cancer were evaluated using CT-based planning. The SCF, AA, and brachial plexus (BP) were outlined on the planning CT. Spinal cord and humeral head blocks were drawn on the 2D digitally-reconstructed radiograph without the targets displayed. The prescription point was placed 3cm deep, lateral to the sternocleidomastoid muscle, and superior to the medial third of the clavicle. From an oblique 6MV beam plan, dose-volume histograms were generated. Results: The fraction of SCF underdosed by 5% ranged from 2–85%. 2–5% of the SCF was underdosed in five patients, 13–20% in five, 24–30% in three and 68–85% in three. The portion of AA underdosed by 10% was 0–8% in five patients, 20–32% in four, 42–62% in three and 84–100% in five. The volume of BP receiving > 90% of the prescription dose varied from 7–93%. In 6/16 patients, >50% of the BP received >90% of the dose. 2D blocking was suboptimal for the SCF in 2 patients and for the AA in 6. Better target coverage and less volume above 100% of the dose was achieved with inverse planning. Conclusions: Although 2D SCF coverage was adequate in the majority of patients, the conventional field does not optimally cover the SCF in 3D. When the intention is to treat the AA, 3D planning may be required for adequate coverage. Intensity modulation may result in better coverage of the SCF and AA while reducing dose to the BP.