Outcomes of whole-brain radiation with simultaneous in-field boost (SIB) for the treatment of brain metastases.

PURPOSE: Prospective studies have demonstrated increased local control with the addition of a radiosurgery (SRS) boost to whole-brain irradiation (WBRT) in patients with brain metastases. However, the clinical application of SRS boost can be limited by several factors, including tumor size, numbers of lesions, and high cost of care. Here, we investigate the use of WBRT with a simultaneous integrated boost (SIB) to visible lesions in patients with brain metastases. MATERIALS: From 2011 to 2016, patients were prospectively enrolled and prescribed a dose of 25 or 37.5 Gray (Gy) WBRT with a SIB dose of 45 or 52.5 Gy to the gross lesions in 10 or 15 fractions, respectively. All plans were optimized for dose coverage of the whole brain and lesions using volumetric arc therapy (VMAT). Comprehensive neurocognitive and quality of life assessments were conducted at baseline and at follow-up. RESULTS: Thirteen patients were treated on this protocol. The 1-year local control rates were 92% at the patient level, and 98.6% at the lesion level. The overall 1-year intracranial control was 46%. Patients had no significant declines in Mini-Mental State Examination (MMSE), Hopkins Verbal Learning Test-Revised (HVLT-R), and Medical Outcomes Study (MOS) Cognitive Functional status scores pre- and post-treatment. CONCLUSION: WBRT with SIB to gross lesions using VMAT planning appears to be safe and effective in the treatment of brain metastases without significant cognitive decline. This treatment strategy should be considered in those patients with a high number of metastases or ones not amenable for radiosurgery. CLINICAL TRIAL REGISTRATION CODE: NCT01218542.

GammaKnife versus VMAT radiosurgery plan quality for many brain metastases.

The purpose of this work was to compare dose distributions between two radiosurgery modalities, single-isocenter volumetric modulated arc therapy (VMAT), and GammaKnife Perfexion (GK), in the treatment of a large number (≥7) of brain metastases. Twelve patients with 103 brain metastases were analyzed. The median number of targets per patient was 8 (range: 7-14). GK plans were compared to noncoplanar VMAT plans using both 6-MV flattening filter-free (FFF) and 10-MV FFF modes. Parameters analyzed included radiation therapy oncology group conformity index (CI), 12, 6, and 3 Gy isodose volumes (V12 Gy, V6 Gy, V3 Gy), mean and maximum hippocampal dose, and maximum skin dose. There were statistically significant differences in CI (2.5 ± 1.6 vs 1.6 ± 0.8 and 1.7 ± 0.9, P < 0.001, P < 0.001), V12 Gy (2.8 ± 6.1 cc vs 3.0 ± 5.2 cc and 3.1 ± 5.4 cc, P = 0.003, P < 0.001), and V3 Gy (323.0 ± 294.8 cc vs, 880.1 ± 369.1 cc and 937.9 ±  vs 361.9 cc, P = 0.005, P = 0.001) between GK versus both 6-MV FFF and 10-MV FFF. No significant differences existed for maximum hippocampal or skin doses. In conclusion, highly optimized VMAT produced improved conformity at the expense of a higher V12 Gy and V3 Gy volume when compared with highly optimized GK.

Simulating the Effect of Spectroscopic MRI as a Metric for Radiation Therapy Planning in Patients with Glioblastoma.

Due to glioblastoma's infiltrative nature, an optimal radiation therapy (RT) plan requires targeting infiltration not identified by anatomical magnetic resonance imaging (MRI). Here, high-resolution, whole-brain spectroscopic MRI (sMRI) is used to describe tumor infiltration alongside anatomical MRI and simulate the degree to which it modifies RT target planning. In 11 patients with glioblastoma, data from preRT sMRI scans were processed to give high-resolution, whole-brain metabolite maps normalized by contralateral white matter. Maps depicting choline to N-Acetylaspartate (Cho/NAA) ratios were registered to contrast-enhanced T1-weighted RT planning MRI for each patient. Volumes depicting metabolic abnormalities (1.5-, 1.75-, and 2.0-fold increases in Cho/NAA ratios) were compared with conventional target volumes and contrast-enhancing tumor at recurrence. sMRI-modified RT plans were generated to evaluate target volume coverage and organ-at-risk dose constraints. Conventional clinical target volumes and Cho/NAA abnormalities identified significantly different regions of microscopic infiltration with substantial Cho/NAA abnormalities falling outside of the conventional 60 Gy isodose line (41.1, 22.2, and 12.7 cm3, respectively). Clinical target volumes using Cho/NAA thresholds exhibited significantly higher coverage of contrast enhancement at recurrence on average (92.4%, 90.5%, and 88.6%, respectively) than conventional plans (82.5%). sMRI-based plans targeting tumor infiltration met planning objectives in all cases with no significant change in target coverage. In 2 cases, the sMRI-modified plan exhibited better coverage of contrast-enhancing tumor at recurrence than the original plan. Integration of the high-resolution, whole-brain sMRI into RT planning is feasible, resulting in RT target volumes that can effectively target tumor infiltration while adhering to conventional constraints.

Comparing Preoperative With Postoperative Stereotactic Radiosurgery for Resectable Brain Metastases: A Multi-institutional Analysis.

BACKGROUND: Stereotactic radiosurgery (SRS) is an increasingly common modality used with surgery for resectable brain metastases (BM). OBJECTIVE: To present a multi-institutional retrospective comparison of outcomes and toxicities of preoperative SRS (Pre-SRS) and postoperative SRS (Post-SRS). METHODS: We reviewed the records of patients who underwent resection of BM and either Pre-SRS or Post-SRS alone between 2005 and 2013 at 2 institutions. Pre-SRS used a dose-reduction strategy based on tumor size, with planned resection within 48 hours. Cumulative incidence with competing risks was used to determine estimated rates. RESULTS: A total of 180 patients underwent surgical resection for 189 BM: 66 (36.7%) underwent Pre-SRS and 114 (63.3%) underwent Post-SRS. Baseline patient characteristics were balanced except for higher rates of performance status 0 (62.1% vs 28.9%, P < .001) and primary breast cancer (27.2% vs 10.5%, P = .010) for Pre-SRS. Pre-SRS had lower median planning target volume margin (0 mm vs 2 mm) and peripheral dose (14.5 Gy vs 18 Gy), but similar gross tumor volume (8.3 mL vs 9.2 mL, P = .85). The median imaging follow-up period was 24.6 months for alive patients. Multivariable analyses revealed no difference between groups for overall survival (P = .1), local recurrence (P = .24), and distant brain recurrence (P = .75). Post-SRS was associated with significantly higher rates of leptomeningeal disease (2 years: 16.6% vs 3.2%, P = .010) and symptomatic radiation necrosis (2 years: 16.4% vs 4.9%, P = .010). CONCLUSION: Pre-SRS and Post-SRS for resected BM provide similarly favorable rates of local recurrence, distant brain recurrence, and overall survival, but with significantly lower rates of symptomatic radiation necrosis and leptomeningeal disease in the Pre-SRS cohort. A prospective clinical trial comparing these treatment approaches is warranted. ABBREVIATIONS: BM, brain metastasesCI, confidence intervalCTV, clinical target volumeDBR, distant brain recurrenceGTV, gross tumor volumeLC, local controlLMD, leptomeningeal diseaseLR, local recurrenceMVA, multivariable analysisOS, overall survivalPost-SRS, postoperative stereotactic radiosurgeryPre-SRS, preoperative stereotactic radiosurgeryPTV, planning target volumeRN, radiation necrosisSRN, symptomatic radiation necrosisSRS, stereotactic radiosurgeryWBRT, whole-brain radiation therapy.

Novel risk stratification score for predicting early distant brain failure and salvage whole-brain radiotherapy after stereotactic radiosurgery for brain metastases.

BACKGROUND: The purpose of this study was to evaluate predictors of early distant brain failure (DBF) and salvage whole-brain radiotherapy (WBRT) after treatment with stereotactic radiosurgery (SRS) for brain metastases and create a clinically relevant risk score to stratify patients' risk for these events. METHODS: The records of 270 patients with brain metastases who were treated with SRS between 2003 and 2012 were reviewed. Pretreatment patient and tumor characteristics were analyzed with univariate and multivariate analyses. The cumulative incidences of first DBF and salvage WBRT were calculated. Significant factors were used to create a score for stratifying early (6-month) DBF risk. RESULTS: No prior WBRT, a total lesion volume < 1.3 cm(3), primary breast cancer or malignant melanoma histology, and multiple metastases (≥2) were found to be significant predictors of early DBF. Each factor was ascribed 1 point because of similar hazard ratios. Scores of 0 to 1, 2, and 3 to 4 were considered to indicate low, intermediate, and high risk, respectively. This correlated with 6-month cumulative incidences of DBF of 16.6%, 28.8%, and 54.4%, respectively (P < .001). For patients without prior WBRT, the 6-month cumulative incidence of salvage WBRT was 2%, 17.7%, and 25.7%, respectively (P < .001). CONCLUSIONS: Early DBF after SRS requiring salvage WBRT remains a significant clinical problem. Patient stratification for early DBF can better inform the decision for the initial treatment strategy for brain metastases. The provided risk score may help to predict early DBF and subsequent salvage WBRT if SRS is initially used. External validation is needed before clinical implementation.

Locoregional Recurrence Risk in Breast Cancer Patients with Estrogen Receptor Positive Tumors and Residual Nodal Disease following Neoadjuvant Chemotherapy and Mastectomy without Radiation Therapy.

Among breast cancer patients treated with neoadjuvant chemotherapy (NAC) and mastectomy, locoregional recurrence (LRR) rates are unclear in women with ER+ tumors treated with adjuvant endocrine therapy without postmastectomy radiation (PMRT). To determine if PMRT is needed in these patients, we compared LRR rates of patients with ER+ tumors (treated with adjuvant endocrine therapy) with women who have non-ER+ tumors. 85 consecutive breast cancer patients (87 breast tumors) treated with NAC and mastectomy without PMRT were reviewed. Patients were divided by residual nodal disease (ypN) status (ypN+ versus ypN0) and then stratified by receptor subtype. Among ypN+ patients (n = 35), five-year LRR risk in patients with ER+, Her2+, and triple negative tumors was 5%, 33%, and 37%, respectively (p = 0.02). Among ypN+/ER+ patients, lymphovascular invasion and grade three disease increased the five-year LRR risk to 13% and 11%, respectively. Among ypN0 patients (n = 52), five-year LRR risk in patients with ER+, Her2+, and triple negative tumors was 7%, 22%, and 6%, respectively (p = 0.71). In women with ER+ tumors and residual nodal disease, endocrine therapy may be sufficient adjuvant treatment, except in patients with lymphovascular invasion or grade three tumors where PMRT may still be indicated.

Hypofractionated radiosurgery has a better safety profile than single fraction radiosurgery for large resected brain metastases.

The purpose of this study is to compare the safety and efficacy of single fraction radiosurgery (SFR) with hypofractionated radiosurgery (HR) for the adjuvant treatment of large, surgically resected brain metastases. Seventy-five patients with 76 resection cavities ≥ 3 cm received 15 Gray (Gy) × 1 SFR (n = 40) or 5-8 Gy × 3-5 HR (n = 36). Cumulative incidence of local failure (LF) and radiation necrosis (RN) was estimated accounting for death as a competing risk and compared with Gray's test. The effect of multiple covariates was evaluated with the Fine-Gray proportional hazards model. The most common HR dose-fractionation schedules were 6 Gy × 5 (44%), 7-8 Gy × 3 (36%), and 6 Gy × 4 (8%). The median follow-up was 11 months (range 2-71). HR patients had larger median resection cavity volumes (24.0 vs. 13.3 cc, p < 0.001), planning target volumes (PTV) (37.7 vs. 20.5 cc, p < 0.001), and cavity to PTV expansion margins (2 vs. 1.5 mm, p = 0.002) than SFR patients. Cumulative incidence of LF (95% CI) at 6 and 12-months for HR versus SFR was 18.9% (0.07-0.34) versus 15.9% (0.06-0.29), and 25.6% (0.12-0.42) versus 27.2% (0.14-0.42), p = 0.80. Cumulative incidence of RN (95% CI) at 6 and 12 months for HR vs. SFR was 3.3% (0.00-0.15) versus 10.7% (0.03-0.23), and 10.3% (0.02-0.25) versus 19.2% (0.08-0.34), p = 0.28. On multivariable analysis, SFR was significantly associated with an increased risk of RN, with a HR of 3.81 (95% CI 1.04-13.93, p = 0.043). Hypofractionated radiosurgery may be the more favorable treatment approach for radiosurgery of cavities 3-4 cm in size and greater.

Outcomes After Radiation Therapy to Metastatic Sites in Patients With Stage 4 Neuroblastoma.

In patients with high-risk metastatic neuroblastoma, the benefit of radiation therapy (RT) to metastatic sites as part of primary treatment has not been fully investigated. The purpose of this single-institution study was to evaluate local control of irradiated metastatic sites, and characterize metastatic disease burden and anatomic distribution in patients with high-risk metastatic neuroblastoma. The records of all patients diagnosed with stage 4 neuroblastoma between August 2000 and January 2010 were reviewed. Exclusion criteria included: bone-marrow only metastatic site, total body irradiation, or no imaging follow-up. A total of 37 patients met eligibility criteria. Median follow-up period for patients without relapse was 61 months. Five-year overall survival for all patients was 67%. Thirteen patients (35%) received RT to a metastatic site as part of their primary treatment. Among these patients, in-field recurrence occurred in three patients (23%), including two of three treated calvarial sites. In patients treated with or without RT to a metastatic site, respectively, there was no significant difference in 5-year overall survival (73% vs. 63%, P=0.84) or relapse-free survival (46% and 55%, P=0.48). Current metastatic site RT dose may be suboptimal, and certain locations may predict for a poor response. Further studies are necessary to elucidate the optimal role of RT to metastatic sites.

Reassessing dose constraints of organs at risk in children with abdominal neuroblastoma treated with definitive radiation therapy: a correlation with late toxicity.

BACKGROUND: In children treated with definitive radiation therapy (RT) for abdominal neuroblastoma, normal tissue constraints for organs at risk (OARs) are not well-standardized or evidence-based. In this study, we analyze dosimetric data of principal abdominal OARs, reassess existing RT planning constraints, and examine corresponding acute and late toxicity to OARs. PROCEDURE: The treatment plans of 30 consecutive children who underwent definitive RT for high-risk abdominal neuroblastoma were reviewed. Dose-volume histogram (DVH) statistics were recorded for the ipsilateral kidney (if unresected), contralateral kidney, and liver. DVH data were analyzed to determine if OAR constraints from recent protocols were met and correlated with the development of toxicity. RESULTS: The median follow-up period was 53.0 months. Ten, thirteen, and ten percent of patients' RT plans did not meet OAR DVH constraints for the liver, ipsilateral kidney, and contralateral kidney, respectively. Of the three patients whose plans did not achieve ipsilateral kidney DVH constraint(s), two developed evidence of late ipsilateral kidney hypoplasia, but maintained normal laboratory kidney function. No patient experienced late toxicity of the contralateral kidney nor developed RT-related late hepatic complications. CONCLUSIONS: In children treated for abdominal neuroblastoma, the risk of developing clinically significant RT-related late toxicity of the kidney and liver is not appreciable, even when current DVH parameters for OARs are not achieved in planning. Toxicity outcomes did not necessarily correlate with present-day OAR dose constraints. Currently utilized DVH constraints are highly variable, and must be further studied and supported by toxicity outcomes to more accurately characterize risk of complications.

Intracranial control and radiographic changes with adjuvant radiation therapy for resected brain metastases: whole brain radiotherapy versus stereotactic radiosurgery alone.

The aim of this study was to compare outcomes of postoperative whole brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) alone in patients with resected brain metastases (BM). We reviewed records of patients who underwent surgical resection of BM followed by WBRT or SRS alone between 2003 and 2013. Local control (LC) of the treated resected cavity, distant brain control (DBC), leptomeningeal disease (LMD), overall survival (OS), and radiographic leukoencephalopathy rates were estimated by the Kaplan-Meier method. One-hundred thirty-two patients underwent surgical resection for 141 intracranial metastases: 36 (27 %) patients received adjuvant WBRT and 96 (73 %) received SRS alone to the resection cavity. One-year OS (56 vs. 55 %, p = 0.64) and LC (83 vs. 74 %, p = 0.31) were similar between patients receiving WBRT and SRS. After controlling for number of BM, WBRT was associated with higher 1-year DBC compared with SRS (70 vs. 48 %, p = 0.03); single metastasis and WBRT were the only significant predictors for reduced distant brain recurrence in multi-variate analysis. Freedom from LMD was higher with WBRT at 18 months (87 vs. 69 %, p = 0.045), while incidence of radiographic leukoencephalopathy was higher with WBRT at 12 months (47 vs. 7 %, p = 0.001). One-year freedom from WBRT in the SRS alone group was 86 %. Compared with WBRT for patients with resected BM, SRS alone demonstrated similar LC, higher rates of LMD and inferior DBC, after controlling for the number of BM. However, OS was similar between groups. The results of ongoing clinical trials are needed to confirm these findings.

Patterns of presentation and failure in patients with gliomatosis cerebri treated with partial-brain radiation therapy.

BACKGROUND: The patterns of lobar involvement, optimal treatment, and disease course among patients with gliomatosis cerebri (GC) have not been fully characterized. The current study evaluates the clinical presentations and outcomes for patients with GC treated with radiation therapy (RT) at our institution. METHODS: A total of 26 patients (25 with follow-up) with GC were diagnosed and treated between January 2004 and June 2012. Inclusion criteria consisted of brain magnetic resonance imaging and neuroradiology confirmation of contiguous involvement of ≥ 3 lobes/lobar equivalents with preservation of neural architecture. Patients were treated with either partial-brain RT to involved tumor (25 patients) or whole-brain RT (1 patient). The median RT dose was 54.0 Gray. The median follow-up was 17.3 months. RESULTS: The median age of the patients at the time of diagnosis was 57 years. Twenty-one patients (81%) and 5 patients (19%) had 3 to 6 and ≥ 7 involved lobes/lobar equivalents, respectively. The median progression-free survival and overall survival were 7.4 months and 14.9 months, respectively. Fifteen patients experienced radiographic disease progression after partial-brain RT, 14 of whom (93%) developed infield disease recurrence. On univariate analysis, higher tumor grade and type II GC (with focal mass) were associated with a poorer progression-free survival. The extent of lobar involvement and chemotherapy were not associated with overall survival. CONCLUSIONS: Even with partial-brain RT, nearly all disease recurrences were infield and clinical outcomes were similar to previous GC series, thereby suggesting that whole-brain RT is not necessary for this patient population. A greater number of involved lobes did not correlate with inferior outcomes. Further studies are necessary to establish more uniform and optimal treatments for this rare disease.

Spot-scanning beam proton therapy vs intensity-modulated radiation therapy for ipsilateral head and neck malignancies: a treatment planning comparison.

Radiation therapy for head and neck malignancies can have side effects that impede quality of life. Theoretically, proton therapy can reduce treatment-related morbidity by minimizing the dose to critical normal tissues. We evaluated the feasibility of spot-scanning proton therapy for head and neck malignancies and compared dosimetry between those plans and intensity-modulated radiation therapy (IMRT) plans. Plans from 5 patients who had undergone IMRT for primary tumors of the head and neck were used for planning proton therapy. Both sets of plans were prepared using computed tomography (CT) scans with the goals of achieving 100% of the prescribed dose to the clinical target volume (CTV) and 95% to the planning TV (PTV) while maximizing conformity to the PTV. Dose-volume histograms were generated and compared, as were conformity indexes (CIs) to the PTVs and mean doses to the organs at risk (OARs). Both modalities in all cases achieved 100% of the dose to the CTV and 95% to the PTV. Mean PTV CIs were comparable (0.371 IMRT, 0.374 protons, p = 0.953). Mean doses were significantly lower in the proton plans to the contralateral submandibular (638.7 cGy IMRT, 4.3 cGy protons, p = 0.002) and parotid (533.3 cGy IMRT, 48.5 cGy protons, p = 0.003) glands; oral cavity (1760.4 cGy IMRT, 458.9 cGy protons, p = 0.003); spinal cord (2112.4 cGy IMRT, 249.2 cGy protons, p = 0.002); and brainstem (1553.52 cGy IMRT, 166.2 cGy protons, p = 0.005). Proton plans also produced lower maximum doses to the spinal cord (3692.1 cGy IMRT, 2014.8 cGy protons, p = 0.034) and brainstem (3412.1 cGy IMRT, 1387.6 cGy protons, p = 0.005). Normal tissue V10, V30, and V50 values were also significantly lower in the proton plans. We conclude that spot-scanning proton therapy can significantly reduce the integral dose to head and neck critical structures. Prospective studies are underway to determine if this reduced dose translates to improved quality of life.

Stereotactic body radiotherapy in patients with stage I non-small-cell lung cancer aged 75 years and older: retrospective results from a multicenter consortium.

BACKGROUND: This study was a retrospective analysis of elderly patients treated with stereotactic body radiotherapy (SBRT) in the setting of a multi-institutional consortium. PATIENTS AND METHODS: Three institutions pooled data on patients aged ≥ 75 years who received SBRT for stage I non-small-cell lung cancer (NSCLC). Forty-seven tumors in 46 patients were analyzed in patients aged 75 to 92 years (median, 82 years). Treatment was delivered during 2007 to 2009, with a median follow-up of 12.4 months. All patients underwent staging positron emission tomography-computed tomography (PET-CT), and 87% of tumors were confirmed by biopsy results. Total doses were 35 to 60 Gy, mainly in 3 to 5 fractions. All tumors were treated using a linear accelerator, with 96% of patients receiving 3-dimensional (3D) conformal RT and 4% undergoing intensity modulated RT (IMRT). RESULTS: At the time of analysis, the local failure rate was 2% (1 of 47). The regional failure rate was 9% (4 of 47). The distant failure rate was 6% (3 of 47). The combined failure rate was 15% (7 of 47) because 1 patient experienced both regional and distant failure. Among 20 tumors with any acute toxicity, there were no ≥ grade 3 toxicities. Pneumonitis (n = 10) grades 1 (n = 3) and 2 (n = 2) was seen in 15% and 10% of patients, respectively; these data were missing for 25% of patients. CONCLUSION: SBRT in patients aged ≥ 75 years with stage I NSCLC proved tolerable, with toxicity rates comparable to those in younger patients. Excellent rates of local, regional, and distant control were achieved at a median follow-up of 12.4 months. This patient population represents a rapidly growing segment of the early lung cancer population, and SBRT appears to be a safe and effective treatment option for patients who are not optimal candidates for surgery.

Association of clinical response and long-term outcome among patients with biopsied orbital pseudotumor receiving modern radiation therapy.

PURPOSE: To retrospectively evaluate institutional outcomes for patients treated with modern radiation therapy (RT) for biopsied orbital pseudotumor (OP). METHODS AND MATERIALS: Twenty patients (26 affected orbits) with OP were treated with RT between January 2002 and December 2011. All patients underwent biopsy with histopathologic exclusion of other disease processes. Sixteen patients (80%) were treated with intensity modulated RT, 3 (15%) with opposed lateral beams, and 1 (5%) with electrons. Median RT dose was 27 Gy (range 25.2-30.6 Gy). Response to RT was evaluated at 4 months post-RT. Partial response (PR) was defined as improvement in orbital symptoms without an increase in steroid dose. Complete response (CR) 1 and CR 2 were defined as complete resolution of orbital symptoms with reduction in steroid dose (CR 1) or complete tapering of steroids (CR 2). The median follow-up period was 18.6 months (range 4-81.6 months). RESULTS: Seventeen patients (85%) demonstrated response to RT, with 7 (35%), 1 (5%), and 9 (45%) achieving a PR, CR 1, and CR 2, respectively. Of the 17 patients who had ≥ PR at 4 months post-RT, 6 (35%) experienced recurrence of symptoms. Age (>46 years vs ≤ 46 years, P=.04) and clinical response to RT (CR 2 vs CR 1/PR, P=.05) were significantly associated with pseudotumor recurrence. Long-term complications were seen in 7 patients (35%), including 4 with cataract formation, 1 with chronic dry eye, 1 with enophthalmos, and 1 with keratopathy. CONCLUSIONS: RT is an effective treatment for improving symptoms and tapering steroids in patients with a biopsy supported diagnosis of OP. Older age and complete response to RT were associated with a significantly reduced probability of symptom recurrence. The observed late complications may be related to RT, chronic use of steroids/immunosuppressants, medical comorbidities, or combination of factors.