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.

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.

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.

Present clinical practices of stereotactic irradiation for metastatic brain tumors in Japan: results of questionnaire survey of the Japanese Radiation Oncology Study Group (JROSG) working subgroup for neurological tumors.

BACKGROUND: To determine the current practice of stereotactic irradiation (STI) for brain metastases in Japan by a questionnaire survey. METHODS: A questionnaire was distributed to 313 institutions performing STI with one of the following machines: Gamma Knife (GK), CyberKnife (CK), Novalis (Nov), or other linear accelerator (LINAC)-based systems (OLS). The participation was voluntary. RESULTS: There were 163 responding institutions. The total number of STI treatments between April 2013 and March 2014 was 10,684. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) were performed in 8624 (80.7%) and 2060 (19.3%) cases, respectively. Whole-brain radiation therapy (WBRT) was performed for a total of 3515 cases. For a case model of a 1.5-cm solitary brain metastasis in a non-eloquent area, the most common GTV-PTV margin was 2 mm (22 of 114 institutions), and an institutional standard fraction was 1 (75 of 114 institutions). The doses for the model case also varied from 13.0 to 26.0 Gy (Median 20 Gy) when converted to SRS (α/ß = 10). A prescription point was at the PTV margin the most. The median dose constraints which were converted to SRS (α/ß = 3) to organs at risk were 12.2, 12.7, and 13.7 Gy for optic nerves, cavernous sinus, and brainstem, respectively. CONCLUSIONS: STI for brain metastases in current practice varied significantly among institutions. These different strategies relied mostly on the type of treatment machine used. It is thus necessary to establish a common guideline to express dose prescriptions and plan qualities for different STI machines.

Factors Affecting the Baseline and Post-Treatment Scores on the Hopkins Verbal Learning Test-Revised Japanese Version before and after Whole-Brain Radiation Therapy.

Our objectives were to (1) investigate the feasibility of the use of the Japanese version of the Hopkins Verbal Learning Test-Revised (HVLT-R); (2) identify the clinical factors influencing the HVLT-R scores of patients undergoing whole-brain radiation therapy (WBRT); and (3) compare the neurocognitive function (NCF) after WBRT in different dose fractionation schedules. We administered the HVLT-R (Japanese version) before (baseline) and at four and eight months after WBRT in 45 patients who received either therapeutic (35Gy-in-14, n = 16; 30Gy-in-10, n = 18) or prophylactic (25Gy-in-10, n = 11) WBRT. Sixteen patients dropped out before the eight-month examination, due mostly to death from cancer. The Karnofsky Performance Status (KPS) 80-100 group had significantly higher baseline total recall (TR) scores (p = 0.0053), delayed recall (DR) scores (p = 0.012), and delayed recognition (DRecog) scores (p = 0.0078). The patients aged ≤65 years also had significantly higher TR scores (p = 0.030) and DRecog scores (p = 0.031). The patients who underwent two examinations (worse-prognosis group) had significantly decreased DR scores four months after WBRT compared to the baseline (p = 0.0073), and they were significantly more likely to have declined individual TR scores (p = 0.0017) and DR scores (p = 0.035) at four months. The eight-month HVLT-R scores did not significantly decline regardless of the WBRT dose fractionation. The baseline NCF was determined by age and KPS, and the early decline in NCF is characteristic of the worse-prognosis group.

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.

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.

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.

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.

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.