Considering Lumpectomy Cavity PTV Expansions: Characterization of Intrafraction Lumpectomy Cavity Motion.

PURPOSE: Accelerated partial breast irradiation and lumpectomy cavity boost radiation therapy plans generally use volumetric expansions from the lumpectomy cavity clinical target volume to the planning target volume (PTV) of 1 to 1.5 cm, substantially increasing the volume of irradiated breast tissue. The purpose of this study was to quantify intrafraction lumpectomy cavity motion during external beam radiation therapy to inform the indicated clinical target volume to PTV expansion. METHODS AND MATERIALS: Forty-four patients were treated with a whole breast irradiation using traditional linear accelerator-based radiation therapy followed by lumpectomy cavity boost using magnetic resonance (MR)-guided radiation therapy on a prospective registry study. Two-dimensional cine-MR images through the center of the surgical cavity were acquired during each boost treatment to define the treatment position of the lumpectomy cavity. This was compared with the reference position to quantify intrafraction cavity motion. Free-breathing technique was used during treatment. Clinical outcomes including toxicity, cosmesis, and rates of local control were additionally analyzed. RESULTS: The mean maximum displacement per fraction in the anterior-posterior (AP) direction was 1.4 mm. Per frame, AP motion was <5 mm in 92% of frames. The mean maximum displacement per fraction in the superior-inferior (SI) direction was 1.2 mm. Per frame, SI motion was <5 mm in 94% of frames. Composite motion was <5 mm in 89% of frames. Three-year local control was 97%. Eight women (18%) developed acute G2 radiation dermatitis. With a median follow-up of 32.4 months, cosmetic outcomes were excellent (22/44, 50%), good (19/44, 43%), and fair (2/44, 5%). CONCLUSIONS: In approximately 90% of analyzed frames, intrafraction displacement of the lumpectomy cavity was <5 mm, with even less motion expected with deep inspiratory breath hold. Our results suggest reduced PTV expansions of 5 mm would be sufficient to account for lumpectomy cavity position, which may accordingly reduce late toxicity and improve cosmetic outcomes.

Unsealed Source: Scope of Practice for Radiopharmaceuticals Among United States Radiation Oncologists.

Purpose: Our purpose was to determine the utilization of and barriers to implementation of radiopharmaceutical therapy (RPT) among U.S. radiation oncologists. Methods and Materials: An anonymous, voluntary 21-item survey directed toward attending radiation oncologists was distributed via social media platforms (Twitter, LinkedIn, Facebook, Student Doctor Network). Questions assessed practice characteristics, specific RPT prescribing patterns, RPT prescribing interest, and perceived barriers to RPT implementation. Nonparametric χ2 test was used for correlation statistics. Results: Of the 142 respondents, 131 (92.3%) practiced in the United States and were included for this analysis. Respondents were well balanced in terms of practicing region, population size served, practice setting, and years in practice. Forty-eight percent (n = 63) reported prescribing at least 1 RPT. An additional 7% (n = 8) participate in RPT administration without billing themselves. Among those that actively prescribed RPT, the mean cumulative cases per month was 4.2 (range, 1-5). The most commonly prescribed radionuclides were radium-223 (40%; mean 2.8 cases/mo), iodine-131 (18%; mean 2.3 cases/mo), yttrium-90 (13%; mean 3.4 cases/mo), "other" (8%), samarium-153 (6%; mean 1.0 cases/mo), and strontrium-89 and phosphorous-32 (2% each; mean 1.8 and 0.4 cases/mo, respectively). Of those who answered "other," lutetium-177 dotatate was most commonly prescribed (8%). No significant (P < .05) association was noted between practice type, practice location, years of practice, or practice volume with utilization of any RPTs. Most radiation oncologists (56%, n = 74) responded they would like to actively prescribe more RPT, although 27% (n = 35) were indifferent, and 17% (n = 22) said they would not like to prescribe more RPT. Perceived barriers to implementation were varied but broadly categorized into treatment infrastructure (44%, n = 57), interspecialty relations (41%, n = 53), lack of training (23%, n = 30), and financial considerations (16%, n = 21). Conclusions: Among surveyed U.S. radiation oncologists, a significant number reported prescribing at least 1 RPT. The majority expressed interest in prescribing additional RPT. Wide-ranging barriers to implementation exist, most commonly interspecialty relations, treatment infrastructure, lack of training, and financial considerations.

Targeting the GTV in medically inoperable endometrial cancer using brachytherapy.

PURPOSE: We aimed to determine the relationship between gross tumor volume (GTV) dose and tumor control in women with medically inoperable endometrial cancer, and to demonstrate the feasibility of targeting a GTV-focused volume using imaged-guided brachytherapy. METHODS AND MATERIALS: An endometrial cancer database was used to identify patients. Treatment plans were reviewed to determine doses to GTV, clinical target volume (CTV), and OARs. Uterine recurrence-free survival was evaluated as a function of CTV and GTV doses. Brachytherapy was replanned with a goal of GTV D98 EQD2 ≥ 80 Gy, without regard for coverage of the uninvolved uterus and while respecting OAR dose constraints. RESULTS: Fifty-four patients were identified. In the delivered plans, GTV D90 EQD2 ≥ 80 Gy was achieved in 36 (81.8%) patients. Uterine recurrence-free survival was 100% in patients with GTV D90 EQD2 ≥ 80 Gy and 66.7% in patients with EQD2 < 80 Gy (p = 0.001). On GTV-only replans, GTV D98 EQD2 ≥ 80 Gy was achieved in 39 (88.6%) patients. Mean D2cc was lower for bladder (47.1 Gy vs. 73.0 Gy, p < 0.001), and sigmoid (47.0 Gy vs. 58.0 Gy, p = 0.007) on GTV-only replans compared to delivered plans. Bladder D2cc was ≥ 80 Gy in 11 (25.0%) delivered plans and four (9.1%) GTV-only replans (p = 0.043). Sigmoid D2cc was ≥ 65 Gy in 20 (45.4%) delivered plans and 10 (22.7%) GTV-only replans (p = 0.021). CONCLUSIONS: OAR dose constraints should be prioritized over CTV coverage if GTV coverage is sufficient. Prospective evaluation of image-guided brachytherapy to a reduced, GTV-focused volume is warranted.

Concurrent Radiation and Modern Systemic Therapies for Breast Cancer: An Ever-Expanding Frontier.

Radiotherapy is a critical tool for reducing locoregional recurrence, extending survival, and palliating symptoms in patients with breast cancer. With an ever-expanding armamentarium of systemic agents available, and an increasing trend toward the use of hypofractionated radiation regimens, it can be difficult to determine the safety of concurrent therapy. In particular, new targeted agents in both the adjuvant and metastatic setting have limited prospective or long-term data demonstrating safety when delivered concurrently with radiotherapy. Other systemic agents, including chemotherapy and endocrine therapy, are also important components of the overall treatment strategy for localized and metastatic breast cancer, and are often delivered concurrently with radiation in certain clinical scenarios. This review explores the safety, efficacy, and pitfalls of delivering radiation in conjunction with systemic therapies for breast cancer.

Reduction of cardiac dose using respiratory-gated MR-linac plans for gastro-esophageal junction cancer.

Treatment of locally advanced adenocarcinoma of the gastroesophageal junction (GEJ) with chemoradiation may be associated with high rates of symptomatic cardiac toxicity. Large margins are typically required to ensure coverage of GEJ tumors with free-breathing volumetric modulated arc therapy (VMAT) radiotherapy. The purpose of this study is to determine whether treatment with tighter margins enabled by maximum-inhalation breath hold (MIBH)-gated intensity modulated radiation therapy (IMRT) on an integrated MRI-linear accelerator system (MR-linac) can decrease radiation doses to the heart and cardiac substructures. Ten patients with locally advanced GEJ adenocarcinoma underwent both free breathing 4-dimensional computed tomography (4DCT) and MIBH MRI simulation scans. MR-linac IMRT plans were created with a 3 mm clinical target volume (CTV) to planning target volume (PTV) isotropic margin and 4DCT VMAT plans were created with a 11, 13, and 9 mm CTV to PTV anisotropic margins in the left-right, cranial-caudal, and anterior-posterior directions according to GEJ-specific PTV expansion recommendations by Voncken et al. Prescription dose to PTV was 50.4 Gy in 28 fractions. Dosimetry to the heart and cardiac substructures was compared with paired t test; p < 0.05 was considered significant. Mean PTV on the MR-linac IMRT plans was significantly smaller compared to the 4DCT VMAT plans (689 cm3vs 1275 cm3, p < 0.01). Mean dose to the heart and all cardiac substructures was significantly lower in the MR-linac IMRT plans compared to the 4DCT VMAT plans: heart 20.9 Gy vs 27.8 Gy, left atrium 29.6 Gy vs 39.4 Gy, right atrium 20.5 Gy vs 25.6 Gy, left ventricle 21.6 Gy vs 29.6 Gy, and right ventricle 18.7 Gy vs 25.2 Gy (all p values <0.05). MIBH-gated MR-linac IMRT treatment of locally advanced GEJ adenocarcinoma can significantly decrease doses to the heart and cardiac substructures and this may translate to reduced rates of cardiac toxicity.

A Phase 1 Dose Escalation Study of Neoadjuvant SBRT Plus Elective Nodal Radiation with Concurrent Capecitabine for Resectable Pancreatic Cancer.

PURPOSE: The role of neoadjuvant radiation for resectable pancreatic adenocarcinoma is controversial. We performed a prospective dose-escalation study of neoadjuvant stereotactic body radiation therapy (SBRT) with concurrent capecitabine and elective nodal irradiation (ENI) followed by surgical resection to explore the toxicity and feasibility of this approach. METHODS AND MATERIALS: Patients with biopsy proven, resectable cancers of the pancreatic head were enrolled. A 4 + 4 dose-escalation design was employed delivering 5 fractions of 5 to 7 Gy to primary tumor with concurrent capecitabine. The maximum tolerated dose level was expanded for an additional 4 patients. Patients at all dose levels were treated with ENI delivering 25 Gy in 5 fractions. Dose-limiting toxicity was defined as any grade ≥3 nonhematologic toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0) attributable to chemoradiation occurring within 90 days of SBRT. RESULTS: A total of 17 patients were enrolled with 16 patients evaluable and 13 patients ultimately proceeding to surgery. The most common toxicity was nausea (56%). There were no dose-limiting toxicities, and SBRT was maximally dose escalated to 35 Gy in 5 fractions for 8 patients. All patients completing surgery had R0 resections. Seven patients (54%) had moderate treatment effect identified in pathologic specimens. Three patients (23%) developed locoregional recurrences, with 2 (15%) partially included within the treated volume. CONCLUSIONS: SBRT was safely dose escalated to 35 Gy in 5 fractions along with concurrent capecitabine and ENI. This regimen will be used in a future expansion cohort.

Combined Immunotherapy and Stereotactic Radiotherapy Improves Neurologic Outcomes in Patients with Non-small-cell Lung Cancer Brain Metastases.

BACKGROUND: The purpose of this study was to compare the outcomes of patients with non-small cell lung cancer (NSCLC) brain metastases treated with stereotactic radiotherapy (SRT) alone versus SRT and immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: Patients treated for their first diagnosis of intracranial metastases with SRT or SRT plus ICI were retrospectively identified. Overall survival (OS), local control (LC), distant brain failure (DBF), neurologic death, and rates of radiation necrosis were calculated. Univariate (UVA) and multivariable (MVA) analyses with competing risk analysis were performed. RESULTS: Seventy-seven patients with 132 lesions were analyzed, including 44 patients with 68 lesions in the SRT group and 33 patients with 64 lesions in the SRT plus ICI group. There were no differences in baseline factors between groups. Use of ICI predicted for decreased DBF (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.84; P = .01), decreased rates of neurologic death (HR, 0.29; 95% CI, 0.10-0.85; P = .02), and better OS (HR, 0.46; 95% CI, 0.23-0.91; P = .03). Two-year LC was 97% for the SRT + ICI group, and 86% for the SRT-alone group (P = .046). Actuarial 2-year DBF was 39% for the SRT + ICI group and 66% for the SRT alone group (P = .016). On MVA, ICI use persisted in predicting lower incidence of neurologic death (HR, 0.25; 95% CI, 0.09-0.72; P = .01) and DBF (HR, 0.47; 95% CI, 0.25-0.85; P = .01) when adjusted for competing risk of death. CONCLUSION: In this cohort of patients with NSCLC brain metastases, ICI use combined with SRT predicted for improved LC and OS and decreased DBF and risk of neurologic death.

Modeling the Impact of Cardiopulmonary Irradiation on Overall Survival in NRG Oncology Trial RTOG 0617.

PURPOSE: To quantitatively predict the impact of cardiopulmonary dose on overall survival (OS) after radiotherapy for locally advanced non-small cell lung cancer. EXPERIMENTAL DESIGN: We used the NRG Oncology/RTOG 0617 dataset. The model building procedure was preregistered on a public website. Patients were split between a training and a set-aside validation subset (N = 306/131). The 191 candidate variables covered disease, patient, treatment, and dose-volume characteristics from multiple cardiopulmonary substructures (atria, lung, pericardium, and ventricles), including the minimum dose to the hottest x% volume (Dx%[Gy]), mean dose of the hottest x% (MOHx%[Gy]), and minimum, mean (Mean[Gy]), and maximum dose. The model building was based on Cox regression and given 191 candidate variables; a Bonferroni-corrected P value threshold of 0.0003 was used to identify predictors. To reduce overreliance on the most highly correlated variables, stepwise multivariable analysis (MVA) was repeated on 1000 bootstrapped replicates. Multivariate sets selected in ≥10% of replicates were fit to the training subset and then averaged to generate a final model. In the validation subset, discrimination was assessed using Harrell c-index, and calibration was tested using risk group stratification. RESULTS: Four MVA models were identified on bootstrap. The averaged model included atria D45%[Gy], lung Mean[Gy], pericardium MOH55%[Gy], and ventricles MOH5%[Gy]. This model had excellent performance predicting OS in the validation subset (c = 0.89). CONCLUSIONS: The risk of death due to cardiopulmonary irradiation was accurately modeled, as demonstrated by predictions on the validation subset, and provides guidance on the delivery of safe thoracic radiotherapy.

MRI-guided adaptive radiotherapy for liver tumours: visualising the future.

MRI-guided radiotherapy is a novel and rapidly evolving technology that might enhance the risk-benefit ratio. Through direct visualisation of the tumour and the nearby healthy tissues, the radiation oncologist can deliver highly accurate treatment even to mobile targets. Each individual treatment can be customised to changing anatomy, potentially reducing the risk of radiation-related toxicities while simultaneously increasing the dose delivered to the tumour. MRI-guided radiotherapy offers a new tool for the radiation oncologist, and creates an opportunity to achieve durable local control of liver tumours that might not otherwise be possible. Future work will allow us to expand the population eligible for curative-intent radiotherapy, optimise and customise radiation doses to specific tumours, and hopefully create opportunities for improving outcomes through machine learning and radiomics-based approaches. This Review outlines the current and future applications for MRI-guided radiotherapy with respect to metastatic and primary liver cancers.

Impact of adjuvant fractionated stereotactic radiotherapy dose on local control of brain metastases.

PURPOSE: The aim of this study was to determine whether a higher biological effective dose (BED) would result in improved local control in patients treated with fractionated stereotactic radiotherapy (FSRT) for their resected brain metastases. METHODS: Patients with newly diagnosed brain metastases without previous brain radiotherapy were retrospectively reviewed. Patients underwent surgical resection of at least one brain metastasis and were treated with adjuvant FSRT, delivering 25-36 Gy in 5-6 fractions. Outcomes were computed using Kaplan-Meier survival analysis and univariate analysis. RESULTS: Fifty-four patients with 63 post-operative cavities were included. Median follow-up was 16 months (3-60). Median metastasis size at diagnosis was 2.9 cm (0.6-8.1) and median planning target volume was 19.7 cm3 (6.3-68.1). Two-year local control (LC) was 83%. When stratified by dose, 2 years LC rate was 95.1% in those treated with 30-36 Gy in 5-6 fractions (BED10 of 48-57.6 Gy10) versus 59.1% lesions treated with 25 Gy in 5 fractions (BED10 of 37.5 Gy10) (p < 0.001). LC was not associated with resection cavity size. One year overall survival was 68.7%, and was independent of BED10. Symptomatic radiation necrosis occurred in 7.9% of patients and was not associated with dose. CONCLUSION: In the post-operative setting, high-dose FSRT (BED10 > 37.5 Gy10) were associated with a significantly higher rate of LC compared to lower BED regimens. Overall, 25 Gy in 5 fractions is not an adequate dose to control microscopic disease. If selecting a 5-fraction regimen, 30 Gy in five fractions appears to provide excellent tumor bed control.

Dosimetric study for spine stereotactic body radiation therapy: magnetic resonance guided linear accelerator versus volumetric modulated arc therapy.

Background Stereotactic body radiation therapy (SBRT) given in 1-5 fractions is an effective treatment for vertebral metastases. Real-time magnetic resonance-guided radiotherapy (MRgRT) improves soft tissue contrast, which translates into accurate delivery of spine SBRT. Here we report on clinical implementation of MRgRT for spine SBRT, the quality of MRgRT plans compared to TrueBeam based volumetric modulated arc therapy (VMAT) plans in the treatment of spine metastases and benefits of MRgRT MR scan. Patients and methods Ten metastatic lesions were included in this study for plan comparison. Lesions were spread across thoracic spine and lumbosacral spine. Three fraction spine SBRT plans: 27Gy to planning target volume (PTV) and 30Gy to gross tumor volume (GTV) were generated on the ViewRay MRIdian Linac system and compared to TrueBeamTM STx based VMAT plans. Plans were compared using metrics such as minimum dose, maximum dose, mean dose, ratio of the dose to 50% of the volume (R50), conformity index, homogeneity index and dose to the spinal cord. Results MRIdian plans achieved equivalent target coverage and spinal cord dose compared to VMAT plans. The maximum and minimum PTV doses and homogeneity index were equivalent for both planning systems. R50 was lower for MRIdian plans compared to VMAT plans, indicating a lower spread of intermediate doses with MRIdian system (5.16 vs. 6.11, p = 0.03). Conclusions MRgRT can deliver high-quality spine SBRT plans comparable to TrueBeam volumetric modulated arc therapy (VMAT) plans.

Cardiac Toxicity in Operable Esophageal Cancer Patients Treated With or Without Chemoradiation.

PURPOSE: The purpose of this study was to evaluate predictors of cardiac events in esophageal cancer patients treated with neoadjuvant chemoradiotherapy (NA CRT) followed by surgery compared with surgery alone. MATERIALS AND METHODS: We retrospectively identified patients treated for esophageal cancer between 2006 and 2016. A total of 123 patients were identified; 70 were treated with surgery alone, and 53 were treated with NA CRT. Cardiac events were scored based on Common Terminology Criteria for Adverse Events (version 4.03), and dosimetric data was compiled for all patients who received radiation. Univariate analysis and multivariable analysis (MVA) were performed to identify predictors of cardiac events. Competing risk of death regression was performed to a model the cumulative incidence of cardiac events. RESULTS: The overall rates of grade ≥3 cardiac events were 24.5% in the NA CRT group versus 10% in the surgery group (P=0.04). On MVA, use of NA CRT (P<0.01, hazard ratio [HR]: 3.45, 95% confidence interval [CI]: 1.35-9.09) predicted for grade ≥3 cardiac events, though no dosimetric variable predicted for grade ≥3 cardiac events or overall survival. On MVA, NA CRT predicted for pericardial effusions of any grade (P<0.01, HR: 3.70, 95% CI: 1.67-8.33). The V45 Gy was the most significant predictor of pericardial effusions (P=0.012, HR: 1.03, 95% CI: 1.01-1.06) CONCLUSIONS:: NA CRT significantly increased the rate of grade ≥3 cardiac events compared with patients treated with surgery alone. Although no dosimetric parameter predicted for grade ≥3 cardiac events or survival, the V45 Gy predicted for pericardial effusions.

Low cardiac and left anterior descending coronary artery dose achieved with left-sided multicatheter interstitial-accelerated partial breast irradiation.

PURPOSE: Studies have shown that an additional mean dose of 1 Gy to the heart can increase the relative risk of cardiac events. The purpose of this study was to quantify the dose delivered to the heart and left anterior descending artery (LAD) in a series of patients with left-sided breast cancer (BC) or ductal carcinoma in situ treated with multicatheter-accelerated partial breast irradiation (MC-APBI) at a single institution. METHODS AND MATERIALS: Patients with left-sided BC or ductal carcinoma in situ treated consecutively from 2005 to 2011 with MC-APBI were retrospectively identified. Cardiac and LAD contours were generated for each patient. Cardiac dosimetry and distance to the planning target volume were recorded. Patient health records were reviewed and cardiac events were recorded based on Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Twenty consecutive patients with left-sided BC treated with MC-APBI were retrospectively identified. Median followup was 41.4 months. Mean equivalent dose in 2 Gy fractions delivered to the heart and LAD were 1.3 (standard deviation: 0.7, range: 0.2-2.9) and 3.8 (standard deviation: 3.0, range: 0.4-11.3) Gy, respectively. There was an inverse linear relationship (R2 = 0.52) between heart-to-lumpectomy cavity distance and mean heart equivalent dose in 2 Gy fractions. One patient (5%) experienced symptomatic cardiac toxicity. CONCLUSIONS: MC-APBI consistently delivers average doses to the heart and LAD that are similar to those achieved in most series with deep inspiration breath-hold and lower than free-breathing radiotherapy techniques. Distance from the heart to the lumpectomy cavity and the availability of other heart-sparing technologies should be considered to minimize the risk of cardiac toxicity.

Large volume re-irradiation for recurrent meningioma with pulsed reduced dose rate radiotherapy.

PURPOSE: Meningiomas comprise up to 30% of primary brain tumors. The majority of meningioma patients enjoy high rates of control after conventional therapies. However, patients with recurrent disease previously treated with radiotherapy have few options for salvage treatment, and systemic interventions have proven largely ineffective. The aim of this study was to determine whether pulsed reduced dose rate radiotherapy (PRDR) was well tolerated in a small cohort of patients with recurrent meningioma. METHODS: We retrospectively identified eight patients with recurrent intracranial meningioma treated with PRDR from April 2013 to August of 2017 at a single institution. All patients had radiographic and/or pathologic evidence of progression prior to treatment and had previously completed conventional radiotherapy. Acute and late toxicities were graded based on CTCAE 4.0. RESULTS: Of eight patients, six had histologically confirmed atypical meningiomas upon recurrence. All patients were re-treated with IMRT at an apparent dose rate of 0.0667 Gy/min. Median time between radiation courses was 7.7 years. Median PRDR dose was 54 Gy in 27 fractions to a median volume of 261.6 cm3. Two patients (25%) had in field failure with a median follow up of 23.3 months. PFS at 6 months was 100%. All but one (87.5%) patient was still alive at last follow up. No patient experienced grade ≥ 2 acute or late toxicities. CONCLUSIONS: PRDR re-irradiation was well tolerated and appeared effective for a small cohort of patients with recurrent meningioma previously treated with radiotherapy. A phase II trial to assess this prospectively is in development.

Geminin regulates the transcriptional and epigenetic status of neuronal fate-promoting genes during mammalian neurogenesis.

Regulating the transition from lineage-restricted progenitors to terminally differentiated cells is a central aspect of nervous system development. Here, we investigated the role of the nucleoprotein geminin in regulating neurogenesis at a mechanistic level during both Xenopus primary neurogenesis and mammalian neuronal differentiation in vitro. The latter work utilized neural cells derived from embryonic stem and embryonal carcinoma cells in vitro and neural stem cells from mouse forebrain. In all of these contexts, geminin antagonized the ability of neural basic helix-loop-helix (bHLH) transcription factors to activate transcriptional programs promoting neurogenesis. Furthermore, geminin promoted a bivalent chromatin state, characterized by the presence of both activating and repressive histone modifications, at genes encoding transcription factors that promote neurogenesis. This epigenetic state restrains the expression of genes that regulate commitment of undifferentiated stem and neuronal precursor cells to neuronal lineages. However, maintaining geminin at high levels was not sufficient to prevent terminal neuronal differentiation. Therefore, these data support a model whereby geminin promotes the neuronal precursor cell state by modulating both the epigenetic status and expression of genes encoding neurogenesis-promoting factors. Additional developmental signals acting in these cells can then control their transition toward terminal neuronal or glial differentiation during mammalian neurogenesis.