Enhancing Precision in Radiation Therapy for Locally Advanced Lung Cancer: A Case Study of Cone-Beam Computed Tomography (CBCT)-Based Online Adaptive Techniques and the Promise of HyperSight™ Iterative CBCT.

This study explores the dosimetric benefits of cone-beam computed tomography (CBCT)-based online adaptive radiation therapy (oART) for a non-small-cell lung cancer (NSCLC) patient exhibiting significant tumor shrinkage during ChemoRT. The patient was prescribed 60 Gray (Gy) in 30 fractions and was initially treated with conventional RT. After the delivery of the first four treatment fractions, the patient's treatment course was converted to oART due to tumor shrinkage seen on CBCT. Current oART dose calculations use a synthetic CT (sCT) image derived from deformable image registration (DIR) of the planning CT to the daily CBCT, and, as the tumor regressed, the discrepancy between the CBCT and the sCT increased, leading to a re-simulation after the delivery of the ninth fraction. In this case report, we first investigated dosimetric differences leveraged by converting this patient from conventional RT to oART. With oART using sCT, the patient's target coverage remained consistent with the reference plan while simultaneously changing lung V20 by 7.8 ± 1.4% and heart mean by 3.4 ± 1.5 Gy. Then, using this new simulation CT and comparing it with iterative CBCT (iCBCT) images acquired with the new HyperSight™ (HS) (Varian Medical Systems, Inc., Palo Alto, CA, USA) imaging system on the Ethos, we investigated the impact of direct dose calculation on HS-iCBCT as compared to sCT. The HS-iCBCT generated a dose distribution similar to the CT reference, achieving a 96.01% gamma passing rate using Task Group-218 (TG-218) criteria. Results indicate that HS-iCBCT has the potential to better reflect daily anatomical changes, resulting in improved dosimetric accuracy. This study highlights the advantages of oART in the presence of tumor response to therapy and underscores HS-iCBCT's potential to provide CT-level dose calculation accuracy in oART for NSCLC patients.

Improved Dosimetry and Plan Quality for Accelerated Partial Breast Irradiation Using Online Adaptive Radiation Therapy: A Single Institutional Study.

Purpose: Accelerated partial breast irradiation (APBI) is an attractive treatment modality for eligible patients as it has been shown to result in similar local control and improved cosmetic outcomes compared with whole breast radiation therapy. The use of online adaptive radiation therapy (OART) for APBI is promising as it allows for a reduction of planning target volume margins because breast motion and lumpectomy cavity volume changes are accounted for in daily imaging. Here we present a retrospective, single-institution evaluation on the adequacy of kV-cone beam computed tomography (CBCT) OART for APBI treatments. Methods and Materials: Nineteen patients (21 treatment sites) were treated to 30 Gy in 5 fractions between January of 2022 and May of 2023. Time between simulation and treatment, change in gross tumor (ie, lumpectomy cavity) volume, and differences in dose volume histogram metrics with adaption were analyzed. The Wilcoxon paired, nonparametric test was used to test for dose volume histogram metric differences between the scheduled plans (initial plans recalculated on daily CBCT anatomy) and delivered plans, either the scheduled or adapted plan, which was reoptimized using daily anatomy. Results: Median (interquartile range) time from simulation to first treatment was 26 days (21-32 days). During this same time, median gross tumor volume reduction was 16.0% (7.3%-23.9%) relative to simulation volume. Adaptive treatments took 31.3 minutes (27.4-36.6 minutes) from start of CBCT to treatment session end. At treatment, the adaptive plan was selected for 86% (89/103) of evaluable fractions. In evaluating plan quality, 78% of delivered plans met all target, organs at risk, and conformity metrics evaluated, compared with 34% of scheduled plans. Conclusions: Use of OART for stereotactic linac-based APBI allowed for safe, high-quality treatments in this cohort of 21 treatment courses. Although treatment delivery times were longer than traditional stereotactic body treatments, there were notable improvements in plan quality for APBI using OART.

A roadmap for implementation of kV-CBCT online adaptive radiation therapy and initial first year experiences.

PURPOSE: Online Adaptive Radiation Therapy (oART) follows a different treatment paradigm than conventional radiotherapy, and because of this, the resources, implementation, and workflows needed are unique. The purpose of this report is to outline our institution's experience establishing, organizing, and implementing an oART program using the Ethos therapy system. METHODS: We include resources used, operational models utilized, program creation timelines, and our institutional experiences with the implementation and operation of an oART program. Additionally, we provide a detailed summary of our first year's clinical experience where we delivered over 1000 daily adaptive fractions. For all treatments, the different stages of online adaption, primary patient set-up, initial kV-CBCT acquisition, contouring review and edit of influencer structures, target review and edits, plan evaluation and selection, Mobius3D 2nd check and adaptive QA, 2nd kV-CBCT for positional verification, treatment delivery, and patient leaving the room, were analyzed. RESULTS: We retrospectively analyzed data from 97 patients treated from August 2021-August 2022. One thousand six hundred seventy seven individual fractions were treated and analyzed, 632(38%) were non-adaptive and 1045(62%) were adaptive. Seventy four of the 97 patients (76%) were treated with standard fractionation and 23 (24%) received stereotactic treatments. For the adaptive treatments, the generated adaptive plan was selected in 92% of treatments. On average(±std), adaptive sessions took 34.52 ± 11.42 min from start to finish. The entire adaptive process (from start of contour generation to verification CBCT), performed by the physicist (and physician on select days), was 19.84 ± 8.21 min. CONCLUSION: We present our institution's experience commissioning an oART program using the Ethos therapy system. It took us 12 months from project inception to the treatment of our first patient and 12 months to treat 1000 adaptive fractions. Retrospective analysis of delivered fractions showed that the average overall treatment time was approximately 35 min and the average time for the adaptive component of treatment was approximately 20 min.

Leveraging intelligent optimization for automated, cardiac-sparing accelerated partial breast treatment planning.

Background: Accelerated partial breast irradiation (APBI) yields similar rates of recurrence and cosmetic outcomes as compared to whole breast radiation therapy (RT) when patients and treatment techniques are appropriately selected. APBI combined with stereotactic body radiation therapy (SBRT) is a promising technique for precisely delivering high levels of radiation while avoiding uninvolved breast tissue. Here we investigate the feasibility of automatically generating high quality APBI plans in the Ethos adaptive workspace with a specific emphasis on sparing the heart. Methods: Nine patients (10 target volumes) were utilized to iteratively tune an Ethos APBI planning template for automatic plan generation. Twenty patients previously treated on a TrueBeam Edge accelerator were then automatically replanned using this template without manual intervention or reoptimization. The unbiased validation cohort Ethos plans were benchmarked via adherence to planning objectives, a comparison of DVH and quality indices against the clinical Edge plans, and qualitative reviews by two board-certified radiation oncologists. Results: 85% (17/20) of automated validation cohort plans met all planning objectives; three plans did not achieve the contralateral lung V1.5Gy objective, but all other objectives were achieved. Compared to the Eclipse generated plans, the proposed Ethos template generated plans with greater evaluation planning target volume (PTV_Eval) V100% coverage (p = 0.01), significantly decreased heart V1.5Gy (p< 0.001), and increased contralateral breast V5Gy, skin D0.01cc, and RTOG conformity index (p = 0.03, p = 0.03, and p = 0.01, respectively). However, only the reduction in heart dose was significant after correcting for multiple testing. Physicist-selected plans were deemed clinically acceptable without modification for 75% and 90% of plans by physicians A and B, respectively. Physicians A and B scored at least one automatically generated plan as clinically acceptable for 100% and 95% of planning intents, respectively. Conclusions: Standard left- and right-sided planning templates automatically generated APBI plans of comparable quality to manually generated plans treated on a stereotactic linear accelerator, with a significant reduction in heart dose compared to Eclipse generated plans. The methods presented in this work elucidate an approach for generating automated, cardiac-sparing APBI treatment plans for daily adaptive RT with high efficiency.

Feasibility and Short-Term Toxicity of a Consecutively Delivered Five Fraction Stereotactic Body Radiation Therapy Regimen in Early-Stage Breast Cancer Patients Receiving Partial Breast Irradiation.

Background: For appropriately selected patients with early-stage breast cancer (ESBC), accelerated partial breast irradiation (APBI) yields equivalent rates of ipsilateral breast tumor recurrence with mixed results in patient-rated cosmesis compared with whole-breast radiotherapy depending on the technique utilized. When utilizing external beam radiotherapy for APBI, techniques to reduce target margins and overall treatment volume are potentially important to decrease rates of long-term adverse cosmesis. Stereotactic body radiotherapy (SBRT) is a promising technique to deliver APBI because of its increased accuracy and sparing of uninvolved breast tissue. We report the initial results of a prospective clinical trial investigating feasibility, safety, and cosmetic outcomes of a daily five-fraction SBRT regimen for APBI. Methods: Twenty-three patients with ESBC after lumpectomy who met APBI suitability were enrolled. During lumpectomy, a bioabsorbable three-dimensional fixed array tissue marker (BioZorb™, Hologic, Marlborough, MA) was placed for enhanced visualization of the cavity boundaries. Clinical target volume (CTV) was defined as the delineable cavity plus a 1-cm isotropic expansion followed by a 3-mm isotropic planning target volume (PTV) expansion. Patients received 30 Gy delivered in five planned consecutive daily fractions in either prone or supine positioning depending on individual anatomy. Two patients completed the five-fraction treatments in 9-day interval and 11-day interval due to external circumstances. A maximum PTV of 124cc was allowed to minimize incidence of fat necrosis. Plans utilized 10-MV flattening filter-free beams delivered on a Varian Edge linear accelerator. Local control, toxicity, and nurse/patient-scored cosmesis at pre-treatment baseline, 1 month post-treatment, and at subsequent 6-month intervals were recorded. Results: Twenty-three patients were accrued at the time of submission with median follow-up of 6 months. No patients experienced grade ≥3 acute toxicity. Of the 10 events reported probably related to SBRT, nine were grade 1 (n = 9/10, 90%). There was no evidence of difference, deterioration, or change in patient or nurse-scored cosmesis from baseline to 1 and 6 months post-treatment. One patient developed nodal failure shortly after APBI. Conclusions: Although longer follow-up is needed to assess long-term toxicity and local control, this study demonstrated a five-fraction SBRT regimen delivered over consecutive days is a safe, efficient, well-tolerated, and cosmetically favorable means of delivering APBI in suitable women. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03643861, NCT03643861.

Graded Prognostic Assessment (GPA) for Patients With Lung Cancer and Brain Metastases: Initial Report of the Small Cell Lung Cancer GPA and Update of the Non-Small Cell Lung Cancer GPA Including the Effect of Programmed Death Ligand 1 and Other Prognostic Factors.

PURPOSE: Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly. METHODS AND MATERIALS: A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA. RESULTS: Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P < .01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies. CONCLUSIONS: Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.

Factors associated with loss to follow-up after radiation therapy for head and neck cancer.

OBJECTIVES: Head and neck cancer (HNC) patients are at high risk for late occurring radiation-related morbidity and recurrence, necessitating close long-term medical surveillance. This study identified factors associated with becoming lost to follow-up (LTFU) at a comprehensive cancer center. MATERIALS AND METHODS: Patients were drawn from survivors who received radiation for HNC at a single institution between 2001 and 2018. LTFU was defined as living patients without a clinical encounter within 2 years of the data query. RESULTS: In total, 537 patients met the inclusion criteria and 57 (10.6%) were identified as LTFU. Individual comparisons identified time since completing radiation, non-White race and being unmarried as associated with LTFU. Multiple regression identified time since treatment and being unmarried as factors associated with LTFU. A decision tree correctly sorted 89.4% using time, distance, and marital status. CONCLUSION: Time since radiation, distance to clinic, and being unmarried were factors associated with becoming LTFU.

Clinical Trial Eligibility Criteria and Recently Approved Cancer Therapies for Patients With Brain Metastases.

Brain metastases cause significant morbidity and mortality in patients with advanced cancer. In the era of precision oncology and immunotherapy, there are rapidly evolving systemic treatment options. These novel therapies may have variable intracranial efficacy, and patients with brain metastases remain a population of special interest. Typically, only patients with stable, asymptomatic and/or treated brain metastases are enrolled in clinical trials, or may be excluded altogether, particularly in the setting of leptomeningeal carcinomatosis. Consequently, this leads to significant concerns on the external validity of clinical trial evidence to real-world clinical practice. Here we describe the current trends in cancer clinical trial eligibility for patients with brain metastases in both early and late phase trials, with a focus on targeted and immunotherapies. We evaluate recent newly FDA approved therapies and the clinical trial evidence base leading to approval. This includes analysis of inclusion and exclusion criteria, requirements for baseline screening for brain metastases, surveillance cerebral imaging and incorporation of trial endpoints for patients with brain metastases. Finally, the use of alternative sources of data such as real-world evidence with registries and collaborative studies will be discussed.

Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma Growth.

Novel targeted agents to inhibit DNA repair pathways to sensitize tumors to irradiation (IR) are being investigated as an alternative to chemoradiation for locally advanced human papilloma virus negative (HPV-negative) head and neck squamous cell carcinoma (HNSCC). Two well-characterized targets that, when inhibited, exhibit potent IR sensitization are PARP1 and DNA-PKcs. However, their cooperation in sensitizing HPV-negative HNSCC to IR remains to be explored given that PARP1 and DNA-Pk CS bind to unresected stalled DNA replication forks and cooperate to recruit XRCC1 to facilitate double-strand break repair. Here, we show that the combination of the DNA-PK inhibitor NU7441 and the PARP inhibitor olaparib significantly decrease proliferation (61-78%) compared to no reduction with either agent alone (p < 0.001) in both SCC1 and SCC6 cell lines. Adding IR to the combination further decreased cell proliferation (91-92%, p < 0.001) in SCC1 and SCC6. Similar results were observed using long-term colony formation assays [dose enhancement ratio (DER) 2.3-3.2 at 4Gy, p < 0.05]. Reduced cell survival was attributed to increased apoptosis and G2/M cell cycle arrest. Kinomic analysis using tyrosine (PTK) and serine/threonine (STK) arrays reveals that combination treatment results in the most potent inhibition of kinases involved in the CDK and ERK pathways compared to either agent alone. In vivo, a significant delay of tumor growth was observed in UM-SCC1 xenografts receiving IR with olaparib and/or NU7441, which was similar to the cisplatin-IR group. Both regimens were less toxic than cisplatin-IR as assessed by loss of mouse body weight. Taken together, these results demonstrate that the combination of NU7441 and olaparib with IR enhances HPV-negative HNSCC inhibition in both cell culture and in mice, suggesting a potential innovative combination for effectively treating patients with HPV-negative HNSCC.

Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient.

PURPOSE: Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS: A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS: Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation (P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non-small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION: Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

Reduced Margin Stereotactic Body Radiation Therapy for Early Stage Non-Small Cell Lung Cancers.

Purpose Our study reports the clinical outcomes of patients treated with 5-mm isotropic margin, fiducial-guided stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC). We also sought to assess the effect of histological subtype on local control. Methods We retrospectively reviewed the charts of all patients treated with SBRT for NSCLC between 2007 and 2017 at our institution. All patients who had implanted fiducial markers, planning target volume (PTV) margins of 5 mm or less, early stage disease (T1-T2, N0), and at least one follow-up CT were included in this analysis. Estimates of local control were generated using the Kaplan-Meier method, and differences between survival curves were assessed using the log-rank test. Results A total of 152 patients met the inclusion criteria for this analysis, with a median follow-up of 27.9 months. Patients received 54 Gy in three fractions for peripheral tumors and 48-52.5 Gy in four to five fractions for central tumors. NSCLC histology was adenocarcinoma in 69 (45.4%) cases, squamous cell carcinoma in 65 (42.8%) cases, and other or non-subtyped in 18 (11.8%) cases. Across the entire cohort, the two-year estimate of local control was 95.1%. When histology was considered, the two-year estimate of local control among patients with adenocarcinoma was 95.6% as compared with 85.0% for patients with other subtypes (p=0.044). Conclusions Fiducial-guided, isotropic 5-mm PTV margin for thoracic SBRT did not compromise local control compared with historical standards. In this series, patients with adenocarcinoma experienced improved local control compared with squamous cell carcinoma.

Estrogen/progesterone receptor and HER2 discordance between primary tumor and brain metastases in breast cancer and its effect on treatment and survival.

BACKGROUND: Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). METHODS: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. RESULTS: The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08). CONCLUSIONS: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. KEY POINTS: 1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

Beyond an Updated Graded Prognostic Assessment (Breast GPA): A Prognostic Index and Trends in Treatment and Survival in Breast Cancer Brain Metastases From 1985 to Today.

PURPOSE: Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts. METHODS AND MATERIALS: A multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively. RESULTS: Median survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01). CONCLUSIONS: MS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.

Electromagnetic Transponder Based Tracking and Gating in the Radiotherapeutic Treatment of Thoracic Malignancies.

PURPOSE: This report details our institutional workflow and technique for use of the Calypso electromagnetic transponder system with respiratory gating for localization and tracking of lung tumors during stereotactic radiation therapy for early stage thoracic malignancies. METHODS AND MATERIALS: Sixteen patients underwent bronchoscopic fiducial placement of 3 transponders in small airways in proximity to the primary tumor. Transponders were placed <19 cm from the most anterior skin location of the patient for appropriate tracking functionality. Patients underwent simulation with 4-dimensional assessment and were treated with transponder based positional gating if tumors moved >5 mm in any direction. Tumor motion <5 mm was not gated and treated using an internal target volume approach. A 5 mm uniform planning target volume was used. Before treatment, fiducial placement and tumor location were verified by daily kilovoltage (kV) and cone beam computed tomography image guidance. Tracking limits were placed based on the movement of the transponders from the centroid of the structures on the maximum intensity projection image. The Calypso treatment system paused treatment automatically if beacons shifted beyond the predefined tracking limits. RESULTS: All 16 patients underwent successful implantation of the electromagnetic transponders. Eight patients exhibited tumor motion sufficient to require respiratory gating, and the other 8 patients were treated using a free breathing internal target volume technique. Difficulty with transponder sensing was experienced in 3 patients as a result of anatomic interference with the placement of the sensing arrays; each of these cases was successfully treated after making setup modifications. Triggered imaging of fiducials during treatment was consistent with real-time positioning determined by the Calypso tracking system. CONCLUSIONS: Respiratory gated electromagnetic based transponder guided stereotactic body radiation therapy using the workflow described is feasible and well tolerated in selected patients with early stage lung malignancies.

A competing risk nomogram to predict severe late toxicity after modern re-irradiation for squamous carcinoma of the head and neck.

PURPOSE: Severe late toxicity is common after re-irradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck. However, many patients experience complications from tumor progression before manifesting late effects. We constructed a nomogram to examine this relationship between late toxicity and competing risks. METHODS AND MATERIALS: Patients with RSP squamous carcinoma originating in a field previously irradiated to ≥40 Gy and treated with IMRT-based re-irradiation to ≥40 Gy were collected. Grade ≥3 late toxicity developing ≥90 days after re-irradiation was collected. A multivariable competing-risk model was fit to the actuarial risk of late toxicity with progression or death as the competing risk. The final bootstrap optimized model was converted into a nomogram. RESULTS: From 9 institutions, 505 patients were included. The 2-year incidence of grade ≥3 late toxicity was 16.7% (95% CI 13.2-20.2%) whereas progression or death was 64.2% (95% CI 59.7-68.8%). The median freedom from late toxicity, progression or death was 10.7, 5.5 and 3.2 months for RPA class I-III patients respectively, whereas the median OS was 44.9, 15.9 and 7.9 months, respectively. The final model included six clinical factors. Notably, dose, volume and fractionation did not significantly impact toxicity. CONCLUSIONS: After re-irradiation, the risk of progression or death is approximately four times the risk of radiation-related severe late toxicity. The risk of late toxicity may be more dependent on patient and disease factors than modifiable treatment factors. This model is useful for patient selection, pre-treatment consent and post-treatment survivorship following re-irradiation.

Prognostic models for patients with brain metastases after stereotactic radiosurgery with or without whole brain radiotherapy: a validation study.

PURPOSE/OBJECTIVE(S): To compare the performance of five prognostic models [RTOG recursive partitioning analysis (RPA), Score Index for Radiosurgery in Brain Metastases (SIR), Barnholtz-Sloan-Kattan nomogram (BSKN), diagnosis-specific Graded Prognostic Assessment (dsGPA), and Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA)] against actual survival in patients with brain metastases treated with SRS +/- WBRT. MATERIALS/METHODS: 100 consecutive patients treated with SRS +/- WBRT between January 2006 and July 2012 were retrospectively analyzed. Patients were binned according to 33 percentiles of the predicted survival distribution for the BSKN and dsGPA models to compare with LungmolGPA, RPA and SIR. Pearson's correlation coefficients between predicted and observed survival were estimated to quantify the proportion of variance in observed survival. RESULTS: Median survival for the entire cohort was 13.5 months, with predicted vs actual MS by BSKN, SIR, dsGPA, RPA, adenocarcinoma Lung-molGPA, and nonadenocarcinoma Lung-molGPA was 3.8 vs 15.6 months, 7 vs 13.5 months, 9.4 vs 13.5 months, 10.3 vs 13.5 months, 13.7 vs 13.7 months, and 9.8 vs 9.7 months, respectively. The BSKN model and adenocarcinoma LungmolGPA created three groups with a statistically significantly different MS (p = 0.002 and p = 0.01, respectively). CONCLUSION: All models under-predicted MS and only the BSKN and Lung-molGPA model stratified patients into three risk groups with statistically significant actual MS. The prognostic groupings of the adenocarcinoma Lung-molGPA group was the best predictor of MS, and showed that we are making improvements in our prognostic ability by utilizing molecular information that is much more widely available in the current treatment era.

The Evolving Role of Postmastectomy Radiation Therapy.

Throughout various eras of breast cancer therapy, postmastectomy radiation therapy (PMRT) has played an important role in the treatment of locally advanced breast cancer. PMRT decreases locoregional recurrence and may improve overall survival in patients with tumors over 5 cm or positive lymph nodes. As novel cancer therapies improve survival in breast cancer, the role of radiation therapy is evolving. Individualized recommendations for PMRT dependent on pathologic response after neoadjuvant systemic therapy are under investigation. This review summarizes the role of PMRT during breast cancer therapy and discusses open questions that may change the landscape of future breast cancer treatment.

Postmastectomy Radiation Therapy: Are We Ready to Individualize Radiation?

Contemporary recommendations for postmastectomy radiation have undergone a shift in thinking away from simple stage based recommendations (one size fits all) to a system that considers both tumor biology and host factors. While surgical staging has traditionally dictated indications for postmastectomy radiation therapy (PMRT), our current understanding of tumor biology, host, immunoprofiles, and tumor microenvironment may direct a more personalized approach to radiation. Understanding the interaction of these variables may permit individualization of adjuvant therapy aimed at appropriate escalation and deescalation, including recommendations for PMRT. This article summarizes the current data regarding tumor and host molecular biomarkers in vitro and in vivo that support the individualization of PMRT and discusses open questions that may alter the future of breast cancer treatment.

Volume, Dose, and Fractionation Considerations for IMRT-based Reirradiation in Head and Neck Cancer: A Multi-institution Analysis.

PURPOSE: Limited data exist to guide the treatment technique for reirradiation of recurrent or second primary squamous carcinoma of the head and neck. We performed a multi-institution retrospective cohort study to investigate the effect of the elective treatment volume, dose, and fractionation on outcomes and toxicity. METHODS AND MATERIALS: Patients with recurrent or second primary squamous carcinoma originating in a previously irradiated field (≥40 Gy) who had undergone reirradiation with intensity modulated radiation therapy (IMRT); (≥40 Gy re-IMRT) were included. The effect of elective nodal treatment, dose, and fractionation on overall survival (OS), locoregional control, and acute and late toxicity were assessed. The Kaplan-Meier and Gray's competing risks methods were used for actuarial endpoints. RESULTS: From 8 institutions, 505 patients were included in the present updated analysis. The elective neck was not treated in 56.4% of patients. The median dose of re-IMRT was 60 Gy (range 39.6-79.2). Hyperfractionation was used in 20.2%. Systemic therapy was integrated for 77.4% of patients. Elective nodal radiation therapy did not appear to decrease the risk of locoregional failure (LRF) or improve the OS rate. Doses of ≥66 Gy were associated with improvements in both LRF and OS in the definitive re-IMRT setting. However, dose did not obviously affect LRF or OS in the postoperative re-IMRT setting. Hyperfractionation was not associated with improved LRF or OS. The rate of acute grade ≥3 toxicity was 22.1% overall. On multivariable logistic regression, elective neck irradiation was associated with increased acute toxicity in the postoperative setting. The rate of overall late grade ≥3 toxicity was 16.7%, with patients treated postoperatively with hyperfractionation experiencing the highest rates. CONCLUSIONS: Doses of ≥66 Gy might be associated with improved outcomes in high-performance patients undergoing definitive re-IMRT. Postoperatively, doses of 50 to 66 Gy appear adequate after removal of gross disease. Hyperfractionation and elective neck irradiation were not associated with an obvious benefit and might increase toxicity.