Green cocoon-derived sericin reduces cellular damage caused by radiation in human keratinocytes.

Radiation therapy used in the treatment of cancer causes skin damage, and no method of care has been established thus far. Recently, it has become clear that sericin derived from silkworm cocoons has moisturizing and antioxidant functions. In addition, green cocoon-derived sericin, which is rich in flavonoids, may have enhanced functions. However, whether this green cocoon-derived sericin can reduce radiotherapy-induced skin damage is unclear. In the present study, we aimed at establishing care methods to reduce skin cell damage caused by X-irradiation using green cocoon-derived sericin. We investigated its effect on human keratinocytes using lactate dehydrogenase activity to indicate damage reduction. Our results showed that green cocoon-derived sericin reduced cell damage caused by X-irradiation. However, this effect was not observed when cells were treated before X-irradiation or with a sericin derived from white cocoons. In addition, green cocoon-derived sericin decreased the levels of reactive oxygen species and lipid peroxidation. Our results suggest that green cocoon sericin mitigates the damaging effect of X-irradiation on cells, hence presenting potential usefulness in reducing skin damage from radiation therapy and opening new avenues in the care of cancer patients.

Clinical, imaging, and molecular features of radiation-induced glioblastomas developing more than 20 years after radiation therapy for intracranial germinomatous germ cell tumor: illustrative cases.

BACKGROUND: Germinomatous germ cell tumor is highly sensitive to chemoradiotherapy; patients are expected to survive for decades. Many radiation-induced malignant gliomas (RIMGs) occur >10 years after radiotherapy. Standard therapy for RIMGs has not been established because of the lesion's rarity, the patient's shorter survival period, and the risk of radiation necrosis by repeat radiation. OBSERVATIONS: Two patients, a 32-year-old man and a 50-year-old man, developed glioblastomas more than 20 years after radiation monotherapy for germinoma with or without mature teratoma. The first patient showed a tumor in the left frontotemporal region with disseminated lesions and died 2 months after partial resection of the tumor without responding to the chemotherapy with temozolomide and bevacizumab. Methylation classifier analysis classified the pathology as closest to diffuse pediatric-type high-grade glioma, Rtk1 subtype. The second patient showed a tumor mass in the brainstem and left cerebellar peduncle, which worsened progressively during chemotherapy with temozolomide and bevacizumab. The tumor transiently responded to stereotactic radiotherapy with the CyberKnife. However, the patient died of RIMG recurrence-related aspiration pneumonia 11 months after the biopsy. Methylation classifier analysis classified the pathology as closest to infratentorial pilocytic astrocytoma. LESSONS: Chemoradiotherapy may improve the survival of patients with RIMGs. Furthermore, molecular features may influence the clinical, locoregional, and pathological features of RIMG.

Verification of Qfix Encompass™ couch modeling using the Acuros XB algorithm and HypeArc™ using a high-spatial-resolution two-dimensional diode array.

We modeled the Qfix Encompass™ immobilization system and further verified the calculated dose distribution of the AcurosXB (AXB) dose calculation algorithm using SRS MapCHECKⓇ (SRSMC) in the HyperArc™ (HA) clinical plan. An Encompass system with a StereoPHAN™ QA phantom was scanned by SOMATOM go.Sim and imported to an Eclipse™ treatment planning system to create a treatment plan for Encompass modeling. The Encompass modeling was performed in the StereoPHAN with a pinpoint ion chamber for 6 MV and 6 MV flattening filter free (6 MV FFF), and 2 × 2 cm2, 4 × 4 cm2, and 6 × 6 cm2 irradiation field sizes. The dose calculation algorithm used was AXB ver. 15.5 with a 1.0 mm calculation grid size. The Hounsfield unit (HU) values of the Encompass modeling were set to 400, -100, -200, and -300 for Encompass, and -400, -600, -700, and -800 for the Encompass base. We evaluated the dose distribution after Encompass modeling by SRSMC using gamma analysis in 12 patients. We adopted HU values of -200 for Encompass, -800 for Encompass base for 6 MV, and -200 for Encompass and -700 for Encompass. Base for 6 MV FFF was adopted as the HU values for the Encompass modeling based on the measurement results. The proposed Encompass modeling resulted in a mean pass rate evaluation >98% for both 6 MV and 6 MV FFF when the 1%/1 mm criterion was used, demonstrating that the proposed HU value can be adopted to calculate more accurate dose distributions.

Multicomponent mathematical model for tumor volume calculation with setup error using single-isocenter stereotactic radiotherapy for multiple brain metastases.

We evaluated the tumor residual volumes considering six degrees-of-freedom (6DoF) patient setup errors in stereotactic radiotherapy (SRT) with multicomponent mathematical model using single-isocenter irradiation for brain metastases. Simulated spherical gross tumor volumes (GTVs) with 1.0 (GTV 1), 2.0 (GTV 2), and 3.0 (GTV 3)-cm diameters were used. The distance between the GTV center and isocenter (d) was set at 0-10 cm. The GTV was simultaneously translated within 0-1.0 mm (T) and rotated within 0°-1.0° (R) in the three axis directions using affine transformation. We optimized the tumor growth model parameters using measurements of non-small cell lung cancer cell lines' (A549 and NCI-H460) growth. We calculated the GTV residual volume at the irradiation's end using the physical dose to the GTV when the GTV size, d, and 6DoF setup error varied. The d-values that satisfy tolerance values (10%, 35%, and 50%) of the GTV residual volume rate based on the pre-irradiation GTV volume were determined. The larger the tolerance value set for both cell lines, the longer the distance to satisfy the tolerance value. In GTV residual volume evaluations based on the multicomponent mathematical model on SRT with single-isocenter irradiation, the smaller the GTV size and the larger the distance and 6DoF setup error, the shorter the distance that satisfies the tolerance value might need to be.

Epigenetic upregulation of Schlafen11 renders WNT- and SHH-activated medulloblastomas sensitive to cisplatin.

BACKGROUND: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. METHODS: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. RESULTS: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. CONCLUSIONS: High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.

Reduced-dose WBRT combined with SRS for 1-4 brain metastases aiming at minimizing neurocognitive function deterioration without compromising brain tumor control.

Background and purpose: To minimize cognitive decline without increasing brain tumor recurrence (BTR) by reduced-dose whole-brain radiotherapy (RD-WBRT) (25 Gy, 10 fractions) + stereotactic radiosurgery (SRS) in patients with ≤ 4 brain metastases. Materials and methods: Eligible patients with ≤ 4 brain metastases on contrast-enhanced MRI and Karnofsky Performance Status ≥ 70. The primary endpoint was the non-inferiority of BTR at distant sites in the brain (BTR-distant)-free survival at 6 months compared to that of the standard dose (SD)-WBRT (30 Gy, 10 fractions) + SRS arm in a randomized clinical trial (JROSG99-1) of SRS with/without SD-WBRT. Secondary endpoints included BTR at any brain sites (BTR-all) and neurocognitive function assessed by a six-test standardized battery. Results: Forty patients from seven institutions were enrolled (median age 69 years). The primary tumor site was a lung in 28 patients; 20 patients had a solitary brain metastasis. The median survival time was 19.0 months (95 %CI: 13.8 %-27.5 %). The BTR-distant-free survival at 6 months was 76.9 % (59.5 %-87.7 %), which is comparable to that of historical control although predetermined non-inferiority (>71 %) could not be confirmed (p = 0.16). The cumulative incidence of BTR-all at 6 months accounting for the competing risk of death was 23.0 % (11.4-37.1), which was not worse than that of historical control (p = 0.774). The frequency of the cumulative incidence of persistent cognitive decline at 6 months was 48.6 % under the [>2.0 SD in ≥ 1 test] definition. Conclusions: RD-WBRT may yield comparable intracranial tumor control when combined with SRS, and may reduce the risk of neurocognitive decline compared to that after SD-WBRT.

The impact of target positioning error and tumor size on radiobiological parameters in robotic stereotactic radiosurgery for metastatic brain tumors.

This study aimed to evaluate the effect of target positioning error (TPE) on radiobiological parameters, such as tumor control probability (TCP) and normal tissue complication probability (NTCP), in stereotactic radiosurgery (SRS) for metastatic brain tumors of different sizes using CyberKnife. The reference SRS plans were created using the circular cone of the CyberKnife for each spherical gross tumor volume (GTV) with diameters (φ) of 5, 7.5, 10, 15, and 20 mm, contoured on computed tomography images of the head phantom. Subsequently, plans involving TPE were created by shifting the beam center by 0.1-2.0 mm in three dimensions relative to the reference plans using the same beam arrangements. Conformity index (CI), generalized equivalent uniform dose (gEUD)-based TCP, and NTCP of estimated brain necrosis were evaluated for each plan. When the gEUD parameter "a" was set to - 10, the CI and TCP for the reference plan at the φ5-mm GTV were 0.90 and 80.8%, respectively. The corresponding values for plans involving TPE of 0.5-mm, 1.0-mm, and 2.0-mm were 0.62 and 77.4%, 0.40 and 62.9%, and 0.12 and 7.2%, respectively. In contrast, the NTCP for all GTVs were the same. The TCP for the plans involving a TPE of 2-mm was 7.2% and 68.8% at the φ5-mm and φ20-mm GTV, respectively. The TPEs corresponding to a TCP reduction rate of 3% at the φ5-mm and φ20-mm GTV were 0.41 and 0.99 mm, respectively. TPE had a significant effect on TCP in SRS for metastatic brain tumors using CyberKnife, particularly for small GTVs.

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.

Calculated relative biological effectiveness (RBE) for initial DNA double-strand breaks (DSB) from flattening filter and flattening filter-free 6 MV X-ray fields.

OBJECTIVES: We evaluated the radiobiological effectiveness based on the yields of DNA double-strand breaks (DSBs) of field induction with flattening filter (FF) and FF-free (FFF) photon beams. METHODS: We used the particle and heavy ion transport system (PHITS) and a water equivalent phantom (30 × 30 × 30 cm3) to calculate the physical qualities of the dose-mean lineal energy (yD) with 6 MV FF and FFF. The relative biological effectiveness based on the yields of DNA-DSBs (RBEDSB) was calculated for standard radiation such as 220 kVp X-rays by using the estimating yields of SSBs and DSBs. The measurement points used to calculate the in-field yD and RBEDSB were located at a depth of 3, 5, and 10 cm in the water equivalent phantom on the central axis. Measurement points at 6, 8, and 10 cm in the lateral direction of each of the three depths from the central axis were set to calculate the out-of-field yD and RBEDSB. RESULTS: The RBEDSB of FFF in-field was 1.7% higher than FF at each measurement depth. The RBEDSB of FFF out-of-field was 1.9 to 6.4% higher than FF at each depth measurement point. As the distance to out-of-field increased, the RBEDSB of FFF rose higher than those of FF. FFF has a larger RBEDSB than FF based on the yields of DNA-DSBs as the distance to out-of-field increased. CONCLUSIONS: The out-of-field radiobiological effect of FFF could thus be greater than that of FF since the spreading of the radiation dose out-of-field with FFF could be a concern compared to the FF. ADVANCES IN KNOWLEDGE: The RBEDSB of FFF of out-of-field might be larger than FF.

Radiobiological evaluation considering setup error on single-isocenter irradiation in stereotactic radiosurgery.

PURPOSE: We calculated the dosimetric indices and estimated the tumor control probability (TCP) considering six degree-of-freedom (6DoF) patient setup errors in stereotactic radiosurgery (SRS) using a single-isocenter technique. METHODS: We used simulated spherical gross tumor volumes (GTVs) with diameters of 1.0 cm (GTV 1), 2.0 cm (GTV 2), and 3.0 cm (GTV 3), and the distance (d) between the target center and isocenter was set to 0, 5, and 10 cm. We created the dose distribution by convolving the blur component to uniform dose distribution. The prescription dose was 20 Gy and the dose distribution was adjusted so that D95 (%) of each GTV was covered by 100% of the prescribed dose. The GTV was simultaneously rotated within 0°-1.0° (δR) around the x-, y-, and z-axes and then translated within 0-1.0 mm (δT) in the x-, y-, and z-axis directions. D95, conformity index (CI), and conformation number (CN) were evaluated by varying the distance from the isocenter. The TCP was estimated by translating the calculated dose distribution into a biological response. In addition, we derived the x-y-z coordinates with the smallest TCP reduction rate that minimize the sum of squares of the residuals as the optimal isocenter coordinates using the relationship between 6DoF setup error, distance from isocenter, and GTV size. RESULTS: D95, CI, and CN were decreased with increasing isocenter distance, decreasing GTV size, and increasing setup error. TCP of GTVs without 6DoF setup error was estimated to be 77.0%. TCP were 25.8% (GTV 1), 35.0% (GTV 2), and 53.0% (GTV 3) with (d, δT, δR) = (10 cm, 1.0 mm, 1.0°). The TCP was 52.3% (GTV 1), 54.9% (GTV 2), and 66.1% (GTV 3) with (d, δT, δR) = (10 cm, 1.0 mm, 1.0°) at the optimal isocenter position. CONCLUSION: The TCP in SRS for multiple brain metastases with a single-isocenter technique may decrease with increasing isocenter distance and decreasing GTV size when the 6DoF setup errors are exceeded (1.0 mm, 1.0°). Additionally, it might be possible to better maintain TCP for GTVs with 6DoF setup errors by using the optimal isocenter position.

A comparative study of high-dose-rate brachytherapy boost combined with external beam radiation therapy versus external beam radiation therapy alone for high-risk prostate cancer.

We aimed to compare the outcomes of high-dose-rate brachytherapy (HDR-BT) boost and external beam radiation therapy (EBRT) alone for high-risk prostate cancer. This was a single-center, retrospective and observational study. Consecutive patients who underwent initial radical treatment by HDR-BT boost or EBRT alone from June 2009 to May 2016 at the Niigata University Medical and Dental Hospital, Japan were included. A total of 96 patients underwent HDR-BT boost, and 61 underwent EBRT alone. The prescription dose of HDR-BT boost was set to 18 Gy twice a day with EBRT 39 Gy/13 fractions. The dose for EBRT alone was mostly 70 Gy/28 fractions. The high-risk group received >6 months of prior androgen deprivation therapy. Overall survival, biochemical-free survival, local control and distant metastasis-free survival rates at 5 years were analyzed. The incidence of urological and gastrointestinal late adverse events of Grade 2 and above was also summarized. In the National Comprehensive Cancer Network (NCCN) high-risk calssification, HDR-BT boost had a significantly higher biochemical-free survival rate at 5 years (98.9% versus 90.7%, P = 0.04). Urethral strictures were more common in the HDR-BT boost group. We will continuously observe the progress of the study patients and determine the longer term results.

Maximum distance in single-isocenter technique of stereotactic radiosurgery with rotational error using margin-based analysis.

Through geometrical simulation, we evaluated the effect of rotational error in patient setup on geometrical coverage and calculated the maximum distance between the isocenter and target, where the clinical PTV margin secures geometrical coverage with a single-isocenter technique. We used simulated spherical GTVs with diameters of 1.0 (GTV 1), 1.5 (GTV 2), 2.0 (GTV 3), and 3.0 cm (GTV 4). The location of the target center was set such that the distance between the target and isocenter ranged from 0 to 15 cm. We created geometrical coverage vectors so that each target was entirely covered by 100% of the prescribed dose. The vectors of the target positions were simultaneously rotated within a range of 0°-2.0° around the x-, y-, and z-axes. For each rotational error, the reduction in geometrical coverage of the targets was calculated and compared with that obtained for a rotational error of 0°. The tolerance value of the geometrical coverage reduction was defined as 5% of the GTV. The maximum distance that satisfied the 5% tolerance value for different values of rotational error at a clinical PTV margin of 0.1 cm was calculated. When the rotational errors were 0.5° for a 0.1 cm PTV margin, the maximum distances were as follows: GTV 1: 7.6 cm; GTV 2: 10.9 cm; GTV 3: 14.3 cm; and GTV 4: 21.4 cm. It might be advisable to exclude targets that are > 7.6 cm away from the isocenter with a single-isocenter technique to satisfy the tolerance value for all GTVs.

Efficacy and Safety of the Radiotherapy for Liver Cancer: Assessment of Local Controllability and its Role in Multidisciplinary Therapy.

This study investigated the efficacy and safety of radiotherapy as part of multidisciplinary therapy for advanced hepatocellular carcinoma (HCC). Clinical data of 49 HCC patients treated with radiotherapy were assessed retrospectively. The efficacy of radiotherapy was assessed by progression-free survival, disease control rate, and overall survival. Safety was assessed by symptoms and hematological assay, and changes in hepatic reserve function were determined by Child-Pugh score and albumin-bilirubin (ALBI) score. Forty patients underwent curative radiotherapy, and nine patients with portal vein tumor thrombus (PVTT) underwent palliative radiotherapy as part of multidisciplinary therapy. Local disease control for curative therapy was 80.0% and stereotactic body radiotherapy was 86.7% which was greater than that of conventional radiotherapy (60.0%). Patients with PVTT had a median observation period of 651 days and 75% three-year survival when treated with multitherapy, including radiotherapy for palliative intent, transcatheter arterial chemoembolization, and administration of molecular targeted agents. No adverse events higher than grade 3 and no changes in the Child-Pugh score and ALBI score were seen. Radiotherapy is safe and effective for HCC treatment and can be a part of multidisciplinary therapy.

Effect of setup error in the single-isocenter technique on stereotactic radiosurgery for multiple brain metastases.

In conventional stereotactic radiosurgery (SRS), treatment of multiple brain metastases using multiple isocenters is time-consuming resulting in long dose delivery times for patients. A single-isocenter technique has been developed which enables the simultaneous irradiation of multiple targets at one isocenter. This technique requires accurate positioning of the patient to ensure optimal dose coverage. We evaluated the effect of six degrees of freedom (6DoF) setup errors in patient setups on SRS dose distributions for multiple brain metastases using a single-isocenter technique. We used simulated spherical gross tumor volumes (GTVs) with diameters ranging from 1.0 to 3.0 cm. The distance from the isocenter to the target's center was varied from 0 to 15 cm. We created dose distributions so that each target was entirely covered by 100% of the prescribed dose. The target's position vectors were rotated from 0°-2.0° and translated from 0-1.0 mm with respect to the three axes in space. The reduction in dose coverage for the targets for each setup error was calculated and compared with zero setup error. The calculated margins for the GTV necessary to satisfy the tolerance values for loss of GTV coverage of 3% to 10% were defined as coverage-based margins. In addition, the maximum isocenter to target distance for different 6DoF setup errors was calculated to satisfy the tolerance values. The dose coverage reduction and coverage-based margins increased as the target diameter decreased, and the distance and 6DoF setup error increased. An increase in setup error when a single-isocenter technique is used may increase the risk of missing the tumor; this risk increases with increasing distance from the isocenter and decreasing tumor size.

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).

Dosimetric comparison of analytic anisotropic algorithm and Acuros XB algorithm in VMAT plans for high-grade glioma.

PURPOSE: To investigate the dosimetric impact between the anisotropic analytical algorithm (AAA) and the Acuros XB (AXB) algorithm in volumetric-modulated arc therapy (VMAT) plans for high-grade glioma (HGG). METHODS: We used a heterogeneous phantom to quantify the agreement between the measured and calculated doses from the AAA and from the AXB. We then analyzed 14 patients with HGG treated by VMAT, using the AAA. We newly created AXB plans for each corresponding AAA plan under the following conditions: (1) re-calculation for the same number of monitor units with an identical beam and leaf setup, and (2) re-optimization under the same conditions of dose constraints. The dose coverage for the planning target volume (PTV) was evaluated by dividing the coverage into the skull, air, and soft-tissue regions. RESULTS: Compared to the results obtained with the AAA, the AXB results were in good agreement with the measured profiles. The dose differences in the PTV between the AAA and re-calculated AXB plans were large in the skull region contained in the target. The dose difference in the PTV in both types of plan was significantly correlated with the volume of the skull contained in the target (r = 0.71, p = 0.0042). A re-optimized AXB plan's dose difference was lower vs. the re-calculated AXB plan's. CONCLUSIONS: We observed dose differences between the AAA and AXB plans, in particular in the cases in which the skull region of the target was large. Considering the phantom measurement results, the AXB algorithm should be used in VMAT plans for HGG.

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.

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.

The neurocognitive function change criteria after whole-brain radiation therapy for brain metastasis, in reference to health-related quality of life changes: a prospective observation study.

BACKGROUND: We sought to construct the optimal neurocognitive function (NCF) change criteria sensitive to health-related quality of life (HR-QOL) in patients who have undergone whole-brain radiation therapy (WBRT) for brain metastasis. METHODS: We categorized the patients by the changes of NCF into groups of improvement versus deterioration if at least one domain showed changes that exceeded the cut-off while other domains remained stable. The remaining patients were categorized as stable, and the patients who showed both significant improvement and deterioration were categorized as 'both.' We examined the clinical meaning of NCF changes using the cut-off values 1.0, 1.5, and 2.0 SD based on the percentage of patients whose HR-QOL changes were ≥ 10 points. RESULTS: Baseline, 4-month and 8-month data were available in 78, 41 (compliance; 85%), and 29 (81%) patients, respectively. At 4 months, improvement/stable/deterioration/both was seen in 15%/12%/41%/32% of the patients when 1.0 SD was used; 19%/22%/37%/22% with 1.5 SD, and 17%/37%/37%/9% with 2.0 SD. The HR-QOL scores on the QLQ-C30 functional scale were significantly worse in the deterioration group versus the others with 1.0 SD (p = 0.013) and 1.5 SD (p = 0.015). With 1.5 SD, the HR-QOL scores on the QLQ-BN20 was significantly better in the improvement group versus the others (p = 0.033). However, when 'both' was included in 'improvement' or 'deterioration,' no significant difference in HR-QOL was detected. CONCLUSIONS: The NCF cut-off of 1.5 SD and the exclusion of 'both' patients from the 'deterioration' and 'improvement' groups best reflects HR-QOL changes.

The association between oral candidiasis and severity of chemoradiotherapy-induced dysphagia in head and neck cancer patients: A retrospective cohort study.

BACKGROUND AND PURPOSE: Concurrent chemoradiotherapy (CCRT) for head and neck cancer (HNC) is a risk factor for oral candidiasis (OC). As Candida spp. are highly virulent, we conducted a retrospective study to determine whether OC increases the severity of dysphagia related to mucositis in HNC patients. PATIENTS AND METHODS: We retrospectively analyzed the cases of consecutive patients with carcinomas of the oral cavity, pharynx, and larynx who underwent CCRT containing cisplatin (CDDP) at our hospital. The diagnosis of OC was based on gross mucosal appearance. We performed a multivariate analysis to determine whether OC was associated with the development of grade 3 dysphagia in the Radiation Therapy Oncology Group (RTOG) Acute Toxicity Criteria. The maximum of the daily opioid doses was compared between the patients with and without OC. RESULTS: We identified 138 HNC patients. OC was observed in 51 patients (37%). By the time of their OC diagnosis, 19 (37%) had already developed grade 3 dysphagia. Among the 30 patients receiving antifungal therapy, 12 (40%) showed clinical deterioration. In the multivariate analysis, OC was independently associated with grade 3 dysphagia (OR 2.75; 95%CI 1.22-6.23; p = 0.015). The patients with OC required significantly higher morphine-equivalent doses of opioids (45 vs. 30 mg/day; p = 0.029). CONCLUSION: Candida infection causes refractory dysphagia. It is worth investigating whether antifungal prophylaxis reduces severe dysphagia related to candidiasis.