Publications by authors named "Robert D Timmerman"

106 Publications

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

Int J Radiat Oncol Biol Phys 2021 Mar 19. Epub 2021 Mar 19.

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.

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 cm. 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.
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http://dx.doi.org/10.1016/j.ijrobp.2021.03.025DOI Listing
March 2021

Long-Term Results of a Phase 1 Dose-Escalation Trial and Subsequent Institutional Experience of Single-Fraction Stereotactic Ablative Radiation Therapy for Liver Metastases.

Int J Radiat Oncol Biol Phys 2021 Apr 16;109(5):1387-1395. Epub 2020 Dec 16.

Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas.

Purpose: We report long-term outcomes from our phase 1 dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR pooled with our subsequent single institutional experience with patients treated postprotocol at the highest dose level (40 Gy) established from the phase 1 study.

Methods And Materials: Patients with liver metastases from solid tumors located outside of the central liver zone were treated with single-fraction SABR on a phase 1 dose escalation trial. At least 700 cc of normal liver had to receive <9.1 Gy. Seven patients with 10 liver metastases received the initial prescription dose of 35 Gy, and dose was then escalated to 40 Gy for 7 more patients with 7 liver metastases. An additional 19 postprotocol patients with 22 liver metastases were treated to 40 Gy in a single fraction. Patients were followed for toxicity and underwent serial imaging to assess local control.

Results: Median imaging follow-up for the combined cohort (n = 33, 39 lesions) was 25.9 months; 38.9 months for protocol patients and 20.2 months for postprotocol patients. Median lesion size was 2.0 cm (range, 0.5-5.0 cm). There were no dose-limiting toxicities observed for protocol patients, and only 3 grade 2 toxicities were observed in the entire cohort, with no grade ≥3 toxicities attributable to treatment. Four-year actuarial local control of irradiated lesions in the entire cohort was 96.6%, 100% in the protocol group and 92.9% in the subsequent patients. Two-year overall survival for all treated patients was 82.0%.

Conclusions: For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy was safe and well-tolerated, and shows excellent local control with long-term follow-up; results in subsequent patients treated with single-fraction SABR doses of 40 Gy confirmed our earlier results.
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http://dx.doi.org/10.1016/j.ijrobp.2020.12.012DOI Listing
April 2021

Systematic Review and Meta-Analysis on the Use of Photon-based Stereotactic Radiosurgery Versus Fractionated Stereotactic Radiotherapy for the Treatment of Uveal Melanoma.

Am J Clin Oncol 2021 01;44(1):32-42

University of Washington School of Medicine.

Purpose: The purpose of this report is to assess the efficacy and adverse event profile of photon-based stereotactic radiosurgery (SRS) compared with fractionated stereotactic radiotherapy (fSRT) for the treatment of uveal melanoma. Primary outcomes include incidence proportions of local control, enucleation, metastatic progression, disease-specific, and overall mortality. Treatment-related toxicities such as incidence proportions of radiation retinopathy, neovascular glaucoma, optic neuropathy, and cataract formation were examined as secondary outcomes. Five-year survival and 5-year local control rates were also assessed.

Materials And Methods: PubMed, Embase, Web of Science, Scopus, and 2 Cochrane databases were searched up to December 31, 2018. Random effects models were used to calculate pooled incidence proportions of outcome measures. Meta-regression was carried out to explore the potential impact of dose per fraction on local control.

Results: Twenty-four articles with a total of 1745 patients were included in the meta-analysis. There were no statistically significant differences between photon-based fSRT and SRS for all primary, secondary and 5-year outcome measures, including local control (P=0.28), enucleation (P=0.51), and neovascular glaucoma (P=0.40). The 5-year local control rate was 90% (95% confidence interval: 76%, 96%) for fSRT and 89% (70%, 97%) for SRS.

Conclusions: Our meta-analysis showed no difference in tumor control, survival and toxicities, as defined in this paper, between SRS and fSRT for uveal melanoma. Confounding biases remain an expected limitation in this study of novel treatment modalities deployed in rare tumors. Further investigation is needed to validate outcomes and compare stereotactic treatment techniques.
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http://dx.doi.org/10.1097/COC.0000000000000775DOI Listing
January 2021

Fundamentals of Radiation Oncology for Neurologic Imaging.

Radiographics 2020 May-Jun;40(3):827-858. Epub 2020 Mar 27.

From the Departments of Radiation Oncology (J.T.M., P.T.L., R.D.T., L.A.N.) and Radiology (A.W.J., F.F.Y., L.C.M., B.R.S., A.A., K.M.R.), The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390.

Although the physical and biologic principles of radiation therapy have remained relatively unchanged, a technologic renaissance has led to continuous and ever-changing growth in the field of radiation oncology. As a result, medical devices, techniques, and indications have changed considerably during the past 20-30 years. For example, advances in CT and MRI have revolutionized the treatment planning process for a variety of central nervous system diseases, including primary and metastatic tumors, vascular malformations, and inflammatory diseases. The resultant improved ability to delineate normal from abnormal tissue has enabled radiation oncologists to achieve more precise targeting and helped to mitigate treatment-related complications. Nevertheless, posttreatment complications still occur and can pose a diagnostic challenge for radiologists. These complications can be divided into acute, early-delayed, and late-delayed complications on the basis of the time that they manifest after radiation therapy and include leukoencephalopathy, vascular complications, and secondary neoplasms. The different irradiation technologies and applications of these technologies in the brain, current concepts used in treatment planning, and essential roles of the radiation oncologist in the setting of brain disease are reviewed. In addition, relevant imaging findings that can be used to delineate the extent of disease before treatment, and the expected posttreatment imaging changes are described. Common and uncommon complications related to radiation therapy and the associated imaging manifestations also are discussed. Familiarity with these entities may aid the radiologist in making the diagnosis and help guide appropriate management. RSNA, 2020.
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http://dx.doi.org/10.1148/rg.2020190138DOI Listing
April 2021

In Reply to Mendenhall et al.

Int J Radiat Oncol Biol Phys 2020 01;106(1):221

Department of Otolaryngology-Head & Neck Surgery, UT Southwestern Medical Center, Dallas, Texas.

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http://dx.doi.org/10.1016/j.ijrobp.2019.09.043DOI Listing
January 2020

Reply to T. Sio et al.

J Clin Oncol 2019 10 29;37(29):2699-2700. Epub 2019 Aug 29.

Andrea Bezjak, MD, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Rebecca Paulus, NRG Oncology, Philadelphia, PA; Laurie E. Gaspar, MD, University of Colorado Denver, Denver, CO; Robert D. Timmerman, MD, University of Texas Southwestern Medical Center, Dallas, TX; and Jeffrey D. Bradley, MD, Washington University in St Louis School of Medicine, St Louis, MO.

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http://dx.doi.org/10.1200/JCO.19.01663DOI Listing
October 2019

Addition of Iodinated Contrast to Rectal Hydrogel Spacer to Facilitate MRI-Independent Target Delineation and Treatment Planning for Prostate Cancer.

Pract Radiat Oncol 2019 Nov 4;9(6):e528-e533. Epub 2019 Jun 4.

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Purpose: Hydrogel spacers reduce rectal dose toxicity during prostate cancer radiation therapy. Current products require magnetic resonance imaging (MRI) for visualization during treatment planning, but MRI incompatibility and cost have prompted alternatives using computed tomography (CT). This case series evaluates the addition of iodinated contrast to hydrogel as such an alternative.

Methods And Materials: Three patients underwent rectal hydrogel spacer placement with iodinated contrast modification. CT was performed within 1 hour of injection and again 1 week later. MRI was obtained at the time of the second CT. Hydrogel delineation was compared between CT and MRI and between paired CT scans.

Results: Spacer enhancement was visible on CT immediately after hydrogel placement (mean Hounsfield units, 122; range, 52-193) but not at the second CT 1 week later (mean Hounsfield units, 8; range, -8 to 29). Delineated spacer volume did not significantly differ between immediate postprocedure CT and MRI ≥1 week later in 2 patients (patient 1: 16.6 vs 15.5 cm; patient 2: 12.6 vs 14.7 cm; paired t-test, P = .81).

Conclusions: CT visualization of rectal hydrogel admixed with contrast is feasible and allows delineation of interface with rectum/prostate.
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http://dx.doi.org/10.1016/j.prro.2019.05.013DOI Listing
November 2019

Safety and Efficacy of a Five-Fraction Stereotactic Body Radiotherapy Schedule for Centrally Located Non-Small-Cell Lung Cancer: NRG Oncology/RTOG 0813 Trial.

J Clin Oncol 2019 05 3;37(15):1316-1325. Epub 2019 Apr 3.

4 The University of Texas Southwestern, Dallas, TX.

Purpose: Patients with centrally located early-stage non-small-cell lung cancer (NSCLC) are at a higher risk of toxicity from high-dose ablative radiotherapy. NRG Oncology/RTOG 0813 was a phase I/II study designed to determine the maximum tolerated dose (MTD), efficacy, and toxicity of stereotactic body radiotherapy (SBRT) for centrally located NSCLC.

Materials And Methods: Medically inoperable patients with biopsy-proven, positron emission tomography-staged T1 to 2 (≤ 5 cm) N0M0 centrally located NSCLC were accrued into a dose-escalating, five-fraction SBRT schedule that ranged from 10 to 12 Gy/fraction (fx) delivered over 1.5 to 2 weeks. Dose-limiting toxicity (DLT) was defined as any treatment-related grade 3 or worse predefined toxicity that occurred within the first year. MTD was defined as the SBRT dose at which the probability of DLT was closest to 20% without exceeding it.

Results: One hundred twenty patients were accrued between February 2009 and September 2013. Patients were elderly, there were slightly more females, and the majority had a performance status of 0 to 1. Most cancers were T1 (65%) and squamous cell (45%). Organs closest to planning target volume/most at risk were the main bronchus and large vessels. Median follow-up was 37.9 months. Five patients experienced DLTs; MTD was 12.0 Gy/fx, which had a probability of a DLT of 7.2% (95% CI, 2.8% to 14.5%). Two-year rates for the 71 evaluable patients in the 11.5 and 12.0 Gy/fx cohorts were local control, 89.4% (90% CI, 81.6% to 97.4%) and 87.9% (90% CI, 78.8% to 97.0%); overall survival, 67.9% (95% CI, 50.4% to 80.3%) and 72.7% (95% CI, 54.1% to 84.8%); and progression-free survival, 52.2% (95% CI, 35.3% to 66.6%) and 54.5% (95% CI, 36.3% to 69.6%), respectively.

Conclusion: The MTD for this study was 12.0 Gy/fx; it was associated with 7.2% DLTs and high rates of tumor control. Outcomes in this medically inoperable group of mostly elderly patients with comorbidities were comparable with that of patients with peripheral early-stage tumors.
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http://dx.doi.org/10.1200/JCO.18.00622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524984PMC
May 2019

Phase 1 Fractional Dose-Escalation Study of Equipotent Stereotactic Radiation Therapy Regimens for Early-Stage Glottic Larynx Cancer.

Int J Radiat Oncol Biol Phys 2019 09 14;105(1):110-118. Epub 2019 Mar 14.

Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.

Purpose: Early-stage glottic larynx squamous cell carcinoma (GLC) is a relatively common disease with excellent oncologic control, but treatment is associated with acute dysphagia and long-term voice quality changes. This phase 1 study of hypofractionated radiation therapy for early-stage GLC increased the fraction size while reducing the number of fractions until 5-fraction stereotactic ablative radiation therapy (SABR) was delivered.

Methods And Materials: Eligible patients had received a diagnosis of stage Tis to T2 GLC. Patients who had undergone prior curative-intent surgery were excluded. The equipotent dose levels were as follows: (1) level 0, 50 Gy in 15 fractions (n = 4); (2) level 1, 45 Gy in 10 fractions (n = 13); and (3) level 2, 42.5 Gy in 5 fractions (SABR level, n = 12). Grade 3 or 4 laryngeal edema, voice, dyspnea, stridor, or cough were the predefined dose-limiting toxicities.

Results: Twenty-nine patients were enrolled from November 2013 to March 2017. The median and minimum follow-up times were 39.2 and 13 months, respectively. Two actively smoking patients, 1 treated in level 1 (grade 4 laryngeal edema, grade 3 dysphagia) and 1 treated in level 2 (grade 3 laryngeal necrosis, dysphagia), developed dose-limiting toxicities. The former patient soon developed a local recurrence, and the latter patient recovered. There were a total of 5 local recurrences: 2 in level 0 and 3 in level 1. The Voice Handicap Index results showed robust long-term voice quality with median values of 7 and 0 at 6 and 12 months, respectively.

Conclusions: Given the tolerability, excellent voice outcomes, and preliminary efficacy data of 5-fraction glottic larynx SABR, this regimen warrants further study.
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http://dx.doi.org/10.1016/j.ijrobp.2019.03.010DOI Listing
September 2019

Long-term Follow-up on NRG Oncology RTOG 0915 (NCCTG N0927): A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys 2019 04 1;103(5):1077-1084. Epub 2018 Dec 1.

Washington University, St. Louis, Missouri.

Purpose: To present long-term results of RTOG 0915/NCCTG N0927, a randomized lung stereotactic body radiation therapy trial of 34 Gy in 1 fraction versus 48 Gy in 4 fractions.

Methods And Materials: This was a phase 2 multicenter study of patients with medically inoperable non-small cell lung cancer with biopsy-proven peripheral T1 or T2 N0M0 tumors, with 1-year toxicity rates as the primary endpoint and selected failure and survival outcomes as secondary endpoints. The study opened in September 2009 and closed in March 2011. Final data were analyzed through May 17, 2018.

Results: Eighty-four of 94 patients accrued were eligible for analysis: 39 in arm 1 and 45 in arm 2. Median follow-up time was 4.0 years for all patients and 6.0 years for those alive at analysis. Rates of grade 3 and higher toxicity were 2.6% in arm 1 and 11.1% in arm 2. Median survival times (in years) for 34 Gy and 48 Gy were 4.1 versus 4.6, respectively. Five-year outcomes (95% confidence interval) for 34 Gy and 48 Gy were a primary tumor failure rate of 10.6% (3.3%-23.1%) versus 6.8% (1.7%-16.9%); overall survival of 29.6% (16.2%-44.4%) versus 41.1% (26.6%-55.1%); and progression-free survival of 19.1% (8.5%-33.0%) versus 33.3% (20.2%-47.0%). Distant failure as the sole failure or a component of first failure occurred in 6 patients (37.5%) in the 34 Gy arm and in 7 (41.2%) in the 48 Gy arm.

Conclusions: No excess in late-appearing toxicity was seen in either arm. Primary tumor control rates at 5 years were similar by arm. A median survival time of 4 years for each arm suggests similar efficacy, pending any larger studies appropriately powered to detect survival differences.
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http://dx.doi.org/10.1016/j.ijrobp.2018.11.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454873PMC
April 2019

Stereotactic Body Radiation Therapy for Operable Early-Stage Lung Cancer: Findings From the NRG Oncology RTOG 0618 Trial.

JAMA Oncol 2018 09;4(9):1263-1266

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas.

Importance: Stereotactic body radiation therapy (SBRT) has become a standard treatment for patients with medically inoperable early-stage lung cancer. However, its effectiveness in patients medically suitable for surgery is unclear.

Objective: To evaluate whether noninvasive SBRT delivered on an outpatient basis can safely eradicate lung cancer and cure selected patients with operable lung cancer, obviating the need for surgical resection.

Design, Setting, And Participants: Single-arm phase 2 NRG Oncology Radiation Therapy Oncology Group 0618 study enrolled patients from December 2007 to May 2010 with median follow-up of 48.1 months (range, 15.4-73.7 months). The setting was a multicenter North American academic and community practice cancer center consortium. Patients had operable biopsy-proven peripheral T1 to T2, N0, M0 non-small cell tumors no more than 5 cm in diameter, forced expiratory volume in 1 second (FEV1) and diffusing capacity greater than 35% predicted, arterial oxygen tension greater than 60 mm Hg, arterial carbon dioxide tension less than 50 mm Hg, and no severe medical problems. The data analysis was performed in October 2014.

Interventions: The SBRT prescription dose was 54 Gy delivered in 3 18-Gy fractions over 1.5 to 2.0 weeks.

Main Outcomes And Measures: Primary end point was primary tumor control, with survival, adverse events, and the incidence and outcome of surgical salvage as secondary end points.

Results: Of 33 patients accrued, 26 were evaluable (23 T1 and 3 T2 tumors; 15 [58%] male; median age, 72.5 [range, 54-88] years). Median FEV1 and diffusing capacity of the lung for carbon monoxide at enrollment were 72.5% (range, 38%-136%) and 68% (range, 22%-96%) of predicted, respectively. Only 1 patient had a primary tumor recurrence. Involved lobe failure, the other component defining local failure, did not occur in any patient, so the estimated 4-year primary tumor control and local control rate were both 96% (95% CI, 83%-100%). As per protocol guidelines, the single patient with local recurrence underwent salvage lobectomy 1.2 years after SBRT, complicated by a grade 4 cardiac arrhythmia. The 4-year estimates of disease-free and overall survival were 57% (95% CI, 36%-74%) and 56% (95% CI, 35%-73%), respectively. Median overall survival was 55.2 months (95% CI, 37.7 months to not reached). Protocol-specified treatment-related grade 3, 4, and 5 adverse events were reported in 2 (8%; 95% CI, 0.1%-25%), 0, and 0 patients, respectively.

Conclusions And Relevance: As given, SBRT appears to be associated with a high rate of primary tumor control, low treatment-related morbidity, and infrequent need for surgical salvage in patients with operable early-stage lung cancer.

Trial Registration: ClinicalTrials.gov Identifier: NCT00551369.
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http://dx.doi.org/10.1001/jamaoncol.2018.1251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117102PMC
September 2018

Cyberknife stereotactic radiosurgery and radiation therapy treatment planning system.

Med Dosim 2018 Summer;43(2):129-140. Epub 2018 Mar 28.

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX USA.

CyberKnife is an image-guided stereotactical dose delivery system designed for both focal irradiation and radiation therapy (SRT). Focal irradiation refers the use of many small beams to deliver highly focus dose to a small target region in a few fractions. The system consists of a 6-MV linac mounted to a robotic arm, coupled with a digital x-ray imaging system. The radiation dose is delivered using many beams oriented at a number of defined or nodal positions around the patients. The CyberKnife can be used for both intracranial and extracranial treaments unlike the Gamma Knife which is limited to intracranial cases. Multiplan (Accuray Inc., Sunnyvale, CA) is the treatment planning system developed to cooperate with this accurate and versatile SRS and SRT system, and exploit the full function of Cyberknife in high-precision radiosurgery and therapy. Optimized inverse treatment plan can be achieved by fine-tuning contours and planning parameters. Precision is the newest version of Cyberknife treatment planning system (TPS) and an upgrade to Multiplan. It offers several new features such as Monte Carlo for multileaf collimator (MLC) and retreatment for other modalities that added more support for the Cyberknife system. The Cybeknife TPS is an easy-to-use and versatile inverse planning platform, suitable for stereotactic radiosurgery and radiation therapy. The knowledge and experience of the planner in this TPS is essential to improve the quality of patient care.
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http://dx.doi.org/10.1016/j.meddos.2018.02.006DOI Listing
October 2018

Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

JAMA Oncol 2018 Jan 11;4(1):e173501. Epub 2018 Jan 11.

Departments of Radiation Oncology, Harold C. Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center, Dallas.

Importance: Patterns-of-failure studies suggest that in metastatic non-small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited.

Objective: To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy in patients with non-progressive limited metastatic NSCLC after induction therapy led to significant improvements in progression-free survival (PFS).

Design, Setting, And Participants: This is a single-institution randomized phase 2 study of maintenance chemotherapy alone vs SAbR followed by maintenance chemotherapy for patients with limited metastatic NSCLC (primary plus up to 5 metastatic sites) whose tumors did not possess EGFR-targetable or ALK-targetable mutations but did achieve a partial response or stable disease after induction chemotherapy.

Interventions: Maintenance chemotherapy or SAbR to all sites of gross disease (including SAbR or hypofractionated radiation to the primary) followed by maintenance chemotherapy.

Main Outcomes And Measures: The primary end point was PFS; secondary end points included toxic effects, local and distant tumor control, patterns of failure, and overall survival.

Results: A total of 29 patients (9 women and 20 men) were enrolled; 14 patients (median [range] age, 63.5 [51.0-78.0] years) were allocated to the SAbR-plus-maintenance chemotherapy arm, and 15 patients (median [range] age, 70.0 [51.0-79.0] years) were allocated to the maintenance chemotherapy-alone arm. The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy-alone arm (P = .01). Toxic effects were similar in both arms. There were no in-field failures with fewer overall recurrences in the SAbR arm while those patients receiving maintenance therapy alone had progression at existing sites of disease and distantly.

Conclusions And Relevance: Consolidative SAbR prior to maintenance chemotherapy appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local therapy in limited metastatic settings.

Trial Registration: clinicaltrials.gov Identifier: NCT02045446.
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http://dx.doi.org/10.1001/jamaoncol.2017.3501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833648PMC
January 2018

Emphasis on Repair, Not Just Avoidance of Injury, Facilitates Prudent Stereotactic Ablative Radiotherapy.

Semin Radiat Oncol 2017 10;27(4):378-392

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address:

Stereotactic ablative radiotherapy (SAbR) is a potent, hypofractionated treatment against cancer which puts adjacent normal tissue in potential peril. Accurate delineation of normal tissue injury risks from SAbR has been challenging, and lack of clear understanding of SAbR tolerance continues to limit its potential. In this review, we contend that SAbR effects on normal tissue could be akin to a surgical "wound," and that adequate wound repair of organs at risk is an essential component of effective SAbR therapy. To mitigate risks of clinical relevance from an SAbR wound, in addition to the traditional views on architectural organization and functional organization of an organ at risk, one should also consider the organ's predominant wound healing tendencies. We also propose that avoidance of SAbR injury to organs at risk must involve careful thought to minimize risk factors that could further impair wound healing. It is imperative that efforts aimed at determining appropriate dose constraints based on predicted SAbR wound injury repair mechanisms for a particular organ to be studied as a critically important step to furthering our understanding of SAbR-related normal tissue tolerances. This can be best achieved through thoughtful design of prospective phase I dose-escalation studies.
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http://dx.doi.org/10.1016/j.semradonc.2017.04.007DOI Listing
October 2017

Dosimetric comparison of rectal-sparing capabilities of rectal balloon vs injectable spacer gel in stereotactic body radiation therapy for prostate cancer: lessons learned from prospective trials.

Med Dosim 2017 Winter;42(4):341-347. Epub 2017 Jul 31.

Department of Radiation Oncology, Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address:

This study aimed to compare the rectal-sparing capabilities of rectal balloons vs absorbable injectable spacer gel in stereotactic body radiation therapy (SBRT) for prostate cancer. Patient samples included in this analysis were obtained from 2 multi-institutional prospective trials of SBRT for prostate cancer using a rectal balloon (n = 36 patients) and injectable spacer gel (n = 36). Treatment prescription dose was 45 Gy in 5 fractions in 42 patients; for equal comparison, the remaining 30 patients were rescaled to 45 Gy from 47.5 Gy prescription (n = 6) and 50 Gy prescription (n = 24). The median prostate volumes and body mass index in the 2 patient samples were not statistically significantly different (p= 0.67 and 0.45, respectively), supporting anatomic similarity between cohorts. The injectable spacer gel achieved dosimetric superiority over the rectal balloon with respect to the maximum dose to the rectum (42.3 vs 46.2 Gy, p < 0.001), dose delivered to 33% of the rectal circumference (28 vs 35.1 Gy, p < 0.001), and absolute volume of rectum receiving 45 Gy (V45), V40, and V30 (0.3 vs 1.7 cc, 1 vs 5.4 cc, and 4.1 vs 9.6 cc, respectively; p < 0.001 in all cases). There was no difference between the 2 groups with respect to the V50 of the rectum or the dose to 50% of the rectal circumference (p= 0.29 and 0.06, respectively). The V18.3 of the bladder was significantly larger with the rectal balloon (19.9 vs 14.5 cc, p= 0.003). In this analysis of patients enrolled on 2 consecutive multi-institutional prospective trials of SBRT for prostate cancer, the injectable spacer gel outperformed the rectal balloon in the majority of the examined and relevant dosimetric rectal-sparing parameters. The rectal balloon did not outperform the injectable spacer gel in any measured rectal dose parameter.
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http://dx.doi.org/10.1016/j.meddos.2017.07.002DOI Listing
August 2018

Multistage stereotactic radiosurgery for large cerebral arteriovenous malformations using the Gamma Knife platform.

Med Phys 2017 Oct 12;44(10):5010-5019. Epub 2017 Aug 12.

Radiation Oncology Department, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Purpose: Radiosurgery is an established technique to treat cerebral arteriovenous malformations (AVMs). Obliteration of larger AVMs (> 10-15 cm or diameter > 3 cm) in a single session is challenging with current radiosurgery platforms due to toxicity. We present a novel technique of multistage stereotactic radiosurgery (SRS) for large intracranial arteriovenous malformations (AVM) using the Gamma Knife system.

Materials/methods: Eighteen patients with large (> 10-15 cm or diameter > 3 cm) AVMs, which were previously treated using a staged SRS technique on the Cyberknife platform, were retrospectively selected for this study. The AVMs were contoured and divided into 3-8 subtargets to be treated sequentially in a staged approach at half to 4 week intervals. The prescription dose ranged from 15 Gy to 20 Gy, depending on the subtarget number, volume, and location. Gamma Knife plans using multiple collimator settings were generated and optimized. The coordinates of each shot from the initial plan covering the total AVM target were extracted based on their relative positions within the frame system. The shots were regrouped based on their location with respect to the subtarget contours to generate subplans for each stage. The delivery time of each shot for a subtarget was decay corrected with Co for staging the treatment course to generate the same dose distribution as that planned for the total AVM target. Conformality indices and dose-volume analysis were performed to evaluate treatment plans.

Results: With the shot redistribution technique, the composite dose for the multistaged treatment of multiple subtargets is equivalent to the initial plan for total AVM target. Gamma Knife plans resulted in an average PTV coverage of 96.3 ± 0.9% and a PITV of 1.23 ± 0.1. The resulting Conformality indices, V and R dose spillage values were 0.76 ± 0.05, 3.4 ± 1.8, and 3.1 ± 0.5 respectively.

Conclusion: The Gamma Knife system can deliver a multistaged conformal dose to treat large AVMs when correcting for translational setup errors of each shot at each staged treatment.
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http://dx.doi.org/10.1002/mp.12455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646226PMC
October 2017

Application of Critical Volume-Dose Constraints for Stereotactic Body Radiation Therapy in NRG Radiation Therapy Trials.

Int J Radiat Oncol Biol Phys 2017 05;98(1):34-36

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; NRG Radiation Oncology Committee and/or NRG Medical Physics Subcommittee.

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http://dx.doi.org/10.1016/j.ijrobp.2017.01.204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754194PMC
May 2017

Phantom-to-clinic development of hypofractionated stereotactic body radiotherapy for early-stage glottic laryngeal cancer.

Med Dosim 2017 Summer;42(2):90-96. Epub 2017 Apr 21.

Department of Radiation Oncology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address:

The purpose of this study was to commission and clinically test a robotic stereotactic delivery system (CyberKnife, Sunnyvale, CA) to treat early-stage glottic laryngeal cancer. We enrolled 15 patients with cTis-T2N0M0 carcinoma of the glottic larynx onto an institutional review board (IRB)-approved clinical trial. Stereotactic body radiotherapy (SBRT) plans prescribed 45 Gy/10 fractions to the involved hemilarynx. SBRT dosimetry was compared with (1) standard carotid-sparing laryngeal intensity-modulated radiation therapy (IMRT) and (2) selective hemilaryngeal IMRT. Our results demonstrate that SBRT plans improved sparing of the contralateral arytenoid (mean 20.0 Gy reduction, p <0.001), ipsilateral carotid D (mean 20.6 Gy reduction, p <0.001), contralateral carotid D (mean 28.1 Gy reduction, p <0.001), and thyroid D (mean 15.0 Gy reduction, p <0.001) relative to carotid-sparing IMRT. SBRT also modestly improved dose sparing to the contralateral arytenoid (mean 4.8 Gy reduction, p = 0.13) and spinal cord D (mean 4.9 Gy reduction, p = 0.015) relative to selective hemilaryngeal IMRT plans. This "phantom-to-clinic" feasibility study confirmed that hypofractionated SBRT treatment for early-stage laryngeal cancer can potentially spare dose to adjacent normal tissues relative to current IMRT standards. Clinical efficacy and toxicity correlates continue to be collected through an ongoing prospective trial.
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http://dx.doi.org/10.1016/j.meddos.2017.01.004DOI Listing
March 2018

Local Hypothermia as a Radioprotector of the Rectal Wall During Prostate Stereotactic Body Radiation Therapy.

Int J Radiat Oncol Biol Phys 2017 05 11;98(1):75-82. Epub 2017 Jan 11.

Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas.

Purpose: To compare the single-fraction dose-related incidence of rectal obstruction and/or bleeding in normothermic and hypothermic rectums of a rat model.

Methods And Materials: A 1.9-cm length of rectum was irradiated with a single fraction in 57 Sprague-Dawley rats using a dedicated image-guided small animal irradiator and Monte Carlo-based treatment planning system. All rats had a rectal temperature control apparatus placed during irradiation and were stratified to achieve either a normothermic (37°C) or hypothermic (15°C) rectal wall temperature. Radiation was delivered to a 1-cm-diameter cylindrical volume about the cooling device and rectal wall. The radiation dose was escalated from 16 Gy up to 37 Gy to assess the dose response in each arm. The primary endpoint of this study was rectal obstruction and/or bleeding during a follow-up of 180 to 186 days. Histologic scoring was performed on all study rats.

Results: Probit analysis showed a dose associated with a 50% incidence of rectal obstruction of 24.6 Gy and 40.8 Gy for normothermic and hypothermic arms, respectively. The occurrence of obstruction and/or bleeding correlated with the posttreatment histologic score for normothermic rats; however, there was no difference in histologic score between normothermic and hypothermic rats at the highest dose levels evaluated.

Conclusions: A significant radioprotective effect was observed using local hypothermia during a single large dose of radiation for the functional endpoint of rectal obstruction and/or bleeding. A confirmatory study in a large animal model with anatomic and physiologic similarities to humans is suggested.
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http://dx.doi.org/10.1016/j.ijrobp.2017.01.017DOI Listing
May 2017

SBRT for early-stage glottic larynx cancer-Initial clinical outcomes from a phase I clinical trial.

PLoS One 2017 2;12(3):e0172055. Epub 2017 Mar 2.

Department of Otolaryngology, Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

Purpose: To confirm safety and feasibility of hypofractionated SBRT for early-stage glottic laryngeal cancer.

Methods: Twenty consecutive patients with cTis-T2N0M0 carcinoma of glottic larynx were enrolled. Patients entered dose-fractionation cohorts of incrementally shorter bio-equivalent schedules starting with 50 Gy in 15 fractions (fx), followed by 45 Gy/10 fx and, finally, 42.5 Gy/5 fx. Maximum combined CTV-PTV expansion was limited to 5 mm. Patients were treated on a Model G5 Cyberknife (Accuray, Sunnyvale, CA).

Results: Median follow-up is 13.4 months (range: 5.6-24.6 months), with 12 patients followed for at least one year. Maximum acute toxicity consisted of grade 2 hoarseness and dysphagia. Maximum chronic toxicity was seen in one patient treated with 45 Gy/10 fx who continued to smoke >1 pack/day and ultimately required protective tracheostomy. At 1-year follow-up, estimated local disease free survival for the full cohort was 82%. Overall survival is 100% at last follow-up.

Conclusions: We were able to reduce equipotent total fractions of SBRT from 15 to 5 without exceeding protocol-defined acute/subacute toxicity limits. With limited follow-up, disease control appears comparable to standard treatment. We continue to enroll to the 42.5 Gy/5 fx cohort and follow patients for late toxicity.

Trial Registration: ClinicalTrials.gov NCT01984502.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172055PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333979PMC
August 2017

Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial.

J Clin Oncol 2017 Jan 31;35(1):56-62. Epub 2016 Oct 31.

Stephen G. Chun and Ritsuko U. Komaki, University of Texas MD Anderson Cancer Center, Houston; Hak Choy, Robert D. Timmerman, and Puneeth Iyengar, University of Texas Southwestern Medical Center, Dallas; Vivek S. Kavadi, Texas Oncology-Sugar Land, Sugar Land, TX; Chen Hu and Rebecca Paulus, NRG Oncology Statistics and Data Management Center; James M. Galvin, Imaging and Radiation Oncology Core, Philadelphia; Raymond B. Wynn, UPMC Cancer Center, Pittsburg, PA; Chen Hu, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; Steven E. Schild, Mayo Clinic, Scottsdale, AZ; Jeffrey A. Bogart, State University of New York Upstate Medical University, Syracuse, NY; Michael C. Dobelbower, University of Alabama at Birmingham, Birmingham, AL; Walter Bosch, Clifford G. Robinson, and Jeffrey D. Bradley, Washington University in Saint Louis, St Louis, MO; Samir Narayan, Michigan Cancer Research Consortium Community Clinical Oncology Program, Ann Arbor, MI; Adam Raben, Christiana Care Health Services Community Clinical Oncology Program, Newark, DE; Mark E. Augspurger, Florida Radiation Oncology Group; Baptist Health, Jacksonville, FL; and Robert M. MacRae, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada.

Purpose Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non-small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities. Results The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P = .005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distant metastasis-free survival were not different between IMRT and 3D-CRT. IMRT was associated with less ≥ grade 3 pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses ( P < .05), and the volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis ( P < .05). The lung V5 was not associated with any ≥ grade 3 toxicity, whereas the lung V20 was associated with increased ≥ grade 3 pneumonitis risk on multivariable analysis ( P = .026). Conclusion IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC.
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http://dx.doi.org/10.1200/JCO.2016.69.1378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455690PMC
January 2017

Stereotactic ablative body radiotherapy (SAbR) for oligometastatic cancer.

Br J Radiol 2017 Feb 23;90(1070):20160500. Epub 2016 Dec 23.

Department of Radiation Oncology, Southwestern Medical Center, University of Texas, Dallas, TX, USA.

The metastatic state of most solid cancers traditionally has been regarded as an incurable dissemination of disease, with treatment focused on delaying progression rather than eliminating all tumour burden. In this setting, local therapies including surgery and radiotherapy are directed at quality of life end points and not at improvement in survival. However, improvements in imaging and systemic therapy have highlighted populations of patients with lower burden of metastatic disease, termed "oligometastatic," who may present an exception. This condition is hypothesized to bridge the gap between incurable metastatic disease and locoregional disease, where miliary spread either has not occurred or remains eradicable. Consequently, elimination of such low-burden residual disease may "cure" some patients or delay further progression. Accordingly, use of local therapies with the intent of improving survival in oligometastatic disease has increased. Technological advances in radiation delivery with stereotactic ablative body radiotherapy (SAbR) in particular have provided a non-invasive and low-morbidity option. While observational studies have provided interesting preliminary data, significant work remains necessary to prove the merits of this treatment paradigm. This review discusses the data for the oligometastatic state and its treatment with SAbR, as well as challenges to its investigation.
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http://dx.doi.org/10.1259/bjr.20160500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685107PMC
February 2017

Stereotactic ablative body radiosurgery (SABR) or Stereotactic body radiation therapy (SBRT).

Adv Drug Deliv Rev 2017 01 5;109:3-14. Epub 2016 Dec 5.

Department of Radiation Oncology, University of Texas Southwestern Medical Center in Dallas, TX, USA; Department of Neurological Surgery, University of Texas Southwestern Medical Center in Dallas, TX, USA. Electronic address:

While conventional treatment relies on protracted courses of therapy using relatively small dose-per-fraction sizes of 1.8-2Gy, there is substantial evidence gathered over decades that this may not be the optimal approach for all targetable disease. Stereotactic ablative body radiosurgery (SABR) or stereotactic body radiation therapy (SBRT) is a technique which uses precise targeting to deliver high doses of radiation capable of ablating tumors directly. In this review, we will discuss the justification for and techniques used to deliver ablative doses to improve treatment outcomes, interactions with biological and immunologic therapy, and special procedures to spare normal tissue, which have facilitated the expanding role for these techniques in the management of a wide range of malignant histologies and disease states.
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http://dx.doi.org/10.1016/j.addr.2016.11.005DOI Listing
January 2017

In Regard to Valle et al.

Int J Radiat Oncol Biol Phys 2016 10;96(2):482-483

Miami Veterans Affairs Healthcare System and University of Miami, Miami, Florida.

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http://dx.doi.org/10.1016/j.ijrobp.2016.05.031DOI Listing
October 2016

Rationale of technical requirements for NRG-BR001: The first NCI-sponsored trial of SBRT for the treatment of multiple metastases.

Pract Radiat Oncol 2016 Nov - Dec;6(6):e291-e298. Epub 2016 May 20.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

Introduction: In 2014, the NRG Oncology Group initiated the first National Cancer Institute-sponsored, phase 1 clinical trial of stereotactic body radiation therapy (SBRT) for the treatment of multiple metastases in multiple organ sites (BR001; NCT02206334). The primary endpoint is to test the safety of SBRT for the treatment of 2 to 4 multiple lesions in several anatomic sites in a multi-institutional setting. Because of the technical challenges inherent to treating multiple lesions as their spatial separation decreases, we present the technical requirements for NRG-BR001 and the rationale for their selection.

Methods And Materials: Patients with controlled primary tumors of breast, non-small cell lung, or prostate are eligible if they have 2 to 4 metastases distributed among 7 extracranial anatomic locations throughout the body. Prescription and organ-at-risk doses were determined by expert consensus. Credentialing requirements include (1) irradiation of the Imaging and Radiation Oncology Core phantom with SBRT, (2) submitting image guided radiation therapy case studies, and (3) planning the benchmark. Guidelines for navigating challenging planning cases including assessing composite dose are discussed.

Results: Dosimetric planning to multiple lesions receiving differing doses (45-50 Gy) and fractionation (3-5) while irradiating the same organs at risk is discussed, particularly for metastases in close proximity (≤5 cm). The benchmark case was selected to demonstrate the planning tradeoffs required to satisfy protocol requirements for 2 nearby lesions. Examples of passing benchmark plans exhibited a large variability in plan conformity.

Discussion: NRG-BR001 was developed using expert consensus on multiple issues from the dose fractionation regimen to the minimum image guided radiation therapy guidelines. Credentialing was tied to the task rather than the anatomic site to reduce its burden. Every effort was made to include a variety of delivery methods to reflect current SBRT technology. Although some simplifications were adopted, the successful completion of this trial will inform future designs of both national and institutional trials and would allow immediate clinical adoption of SBRT trials for oligometastases.
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http://dx.doi.org/10.1016/j.prro.2016.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099083PMC
March 2017

Pre-treatment factors associated with detecting additional brain metastases at stereotactic radiosurgery.

J Neurooncol 2016 06 10;128(2):251-7. Epub 2016 Mar 10.

Department of Radiation Oncology, Inova Dwight and Martha Schar Cancer Institute, 3300 Gallows Road, Falls Church, VA, 22042, USA.

The number of brain metastases identified on diagnostic magnetic resonance imaging (MRI) is a key factor in consideration of stereotactic radiosurgery (SRS). However, additional lesions are often detected on high-resolution SRS-planning MRI. We investigated pre-treatment clinical characteristics that are associated with finding additional metastases at SRS. Patients treated with SRS for brain metastases between the years of 2009-2014 comprised the study cohort. All patients underwent frame-fixed, 1 mm thick MRI on the day of SRS. Patient, tumor, and treatment characteristics were analyzed for an association with increase in number of metastases identified on SRS-planning MRI. 289 consecutive SRS cases were analyzed. 725 metastases were identified on pre-treatment MRI and 1062 metastases were identified on SRS-planning MRI. An increase in the number of metastases occurred in 34 % of the cases. On univariate analysis, more than four metastases and the diameter of the largest lesion were significantly associated with an increase in number of metastases on SRS-planning MRI. When stratified by the diameter of the largest lesion into <2, 2-3, or ≥3 cm, additional metastases were identified in 37, 29, and 18 %, respectively. While this increase in the number of metastases is largely due to the difference in imaging technique, the number and size of the metastases were also associated with finding additional lesions. These clinical factors may be considered when determining treatment options for brain metastases.
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http://dx.doi.org/10.1007/s11060-016-2103-3DOI Listing
June 2016

From Patchell to Brown: An Evidence-Based Evolution of the Role of Radiotherapy on the Management of Brain Metastases.

World Neurosurg 2016 Jan 8;85:10-4. Epub 2015 Dec 8.

Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

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http://dx.doi.org/10.1016/j.wneu.2015.12.003DOI Listing
January 2016

A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer: NRG Oncology RTOG 0915 (NCCTG N0927).

Int J Radiat Oncol Biol Phys 2015 Nov 17;93(4):757-64. Epub 2015 Jul 17.

The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.

Purpose: To compare 2 stereotactic body radiation therapy (SBRT) schedules for medically inoperable early-stage lung cancer to determine which produces the lowest rate of grade ≥3 protocol-specified adverse events (psAEs) at 1 year.

Methods And Materials: Patients with biopsy-proven peripheral (≥2 cm from the central bronchial tree) T1 or T2, N0 (clinically node negative by positron emission tomography), M0 tumors were eligible. Patients were randomized to receive either 34 Gy in 1 fraction (arm 1) or 48 Gy in 4 consecutive daily fractions (arm 2). Rigorous central accreditation and quality assurance confirmed treatment per protocol guidelines. This study was designed to detect a psAEs rate >17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included rates of primary tumor control (PC), overall survival (OS), and disease-free survival (DFS) at 1 year. Designating the better of the 2 regimens was based on prespecified rules of psAEs and PC for each arm.

Results: Ninety-four patients were accrued between September 2009 and March 2011. The median follow-up time was 30.2 months. Of 84 analyzable patients, 39 were in arm 1 and 45 in arm 2. Patient and tumor characteristics were balanced between arms. Four (10.3%) patients on arm 1 (95% confidence interval [CI] 2.9%-24.2%) and 6 (13.3%) patients on arm 2 (95% CI 5.1%-26.8%) experienced psAEs. The 2-year OS rate was 61.3% (95% CI 44.2%-74.6%) for arm 1 patients and 77.7% (95% CI 62.5%-87.3%) for arm 2. The 2-year DFS was 56.4% (95% CI 39.6%-70.2%) for arm 1 and 71.1% (95% CI 55.5%-82.1%) for arm 2. The 1-year PC rate was 97.0% (95% CI 84.2%-99.9%) for arm 1 and 92.7% (95% CI 80.1%-98.5%) for arm 2.

Conclusions: 34 Gy in 1 fraction met the prespecified criteria and, of the 2 schedules, warrants further clinical research.
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http://dx.doi.org/10.1016/j.ijrobp.2015.07.2260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744654PMC
November 2015