Radiation necrosis after a combination of external beam radiotherapy and iodine-125 brachytherapy in gliomas.

PURPOSE: Frequency and risk profile of radiation necrosis (RN) in patients with glioma undergoing either upfront stereotactic brachytherapy (SBT) and additional salvage external beam radiotherapy (EBRT) after tumor recurrence or vice versa remains unknown. METHODS: Patients with glioma treated with low-activity temporary iodine-125 SBT at the University of Munich between 1999 and 2016 who had either additional upfront or salvage EBRT were included. Biologically effective doses (BED) were calculated. RN was diagnosed using stereotactic biopsy and/or metabolic imaging. The rate of RN was estimated with the Kaplan Meier method. Risk factors were obtained from logistic regression models. RESULTS: Eighty-six patients (49 male, 37 female, median age 47 years) were included. 38 patients suffered from low-grade and 48 from high-grade glioma. Median follow-up was 15 months after second treatment. Fifty-eight patients received upfront EBRT (median total dose: 60 Gy), and 28 upfront SBT (median reference dose: 54 Gy, median dose rate: 10.0 cGy/h). Median time interval between treatments was 19 months. RN was diagnosed in 8/75 patients. The 1- and 2-year risk of RN was 5.1% and 11.7%, respectively. Tumor volume and irradiation time of SBT, number of implanted seeds, and salvage EBRT were risk factors for RN. Neither of the BED values nor the time interval between both treatments gained prognostic influence. CONCLUSION: The combination of upfront EBRT and salvage SBT or vice versa is feasible for glioma patients. The risk of RN is mainly determined by the treatment volume but not by the interval between therapies.

Long-term outcome of stereotactic brachytherapy with temporary Iodine-125 seeds in patients with WHO grade II gliomas.

BACKGROUND: This long-term retrospective analysis aimed to investigate the outcome and toxicity profile of stereotactic brachytherapy (SBT) in selected low-grade gliomas WHO grade II (LGGII) in a large patient series. METHODS: This analysis comprised 106 consecutive patients who received SBT with temporary Iodine-125 seeds for histologically verified LGGII at the University of Munich between March 1997 and July 2011. Investigation included clinical characteristics, technical aspects of SBT, the application of other treatments, outcome analyses including malignization rates, and prognostic factors with special focus on molecular biomarkers. RESULTS: For the entire study population, the 5- and 10-years overall survival (OS) rates were 79% and 62%, respectively, with a median follow-up of 115.9 months. No prognostic factors could be identified. Interstitial radiotherapy was applied in 51 cases as first-line treatment with a median number of two seeds (range 1-5), and a median total implanted activity of 21.8 mCi (range 4.2-43.4). The reference dose average was 54.0 Gy. Five- and ten-years OS and progression-free survival rates after SBT were 72% and 43%, and 40% and 23%, respectively, with a median follow-up of 86.7 months. The procedure-related mortality rate was zero, although an overall complication rate of 16% was registered. Patients with complications had a significantly larger tumor volume (p = 0.029). CONCLUSION: SBT is a minimally invasive treatment modality with a favorable outcome and toxicity profile. It is both an alternative primary treatment method as well as an adjunct to open tumor resection in selected low-grade gliomas.

Stereotactic radiosurgery combined with targeted/ immunotherapy in patients with melanoma brain metastasis.

BACKGROUND: There is limited data on the use of targeted or immunotherapy (TT/IT) in combination with single fraction stereotactic radiosurgery (SRS) in patients with melanoma brain metastasis (MBM). Therefore, we analyzed the outcome and toxicity of SRS alone compared to SRS in combination with TT/IT. METHODS: Patients with MBM treated with single session SRS at our department between 2014 and 2017 with a minimum follow-up of 3 months after first SRS were included. The primary endpoint of this study was local control (LC). Secondary endpoints were distant intracranial control, radiation necrosis-free survival (RNFS), and overall survival (OS). The local/ distant intracranial control rates, RNFS and OS were analyzed using the Kaplan-Meier method. The log-rank test was used to test differences between groups. Cox proportional hazard model was performed for univariate continuous variables and multivariate analyses. RESULTS: Twenty-eight patients (17 male and 11 female) with 52 SRS-lesions were included. The median follow-up was 19 months (range 14-24 months) after first SRS. Thirty-six lesions (69.2%) were treated with TT/IT simultaneously (4 weeks before and 4 weeks after SRS), while 16 lesions (30.8%) were treated with SRS alone or with sequential TT/IT. The 1-year local control rate was 100 and 83.3% for SRS with TT/IT and SRS alone (p = 0.023), respectively. The estimated 1-year RNFS was 90.0 and 82.1% for SRS in combination with TT/IT and SRS alone (p = 0.935). The distant intracranial control rate after 1 year was 47.7 and 50% for SRS in combination with TT/IT and SRS alone (p = 0.933). On univariate analysis, the diagnosis-specific Graded Prognostic Assessment including the BRAF status (Melanoma-molGPA) was associated with a significantly improved LC. Neither gender nor SRS-PTV margin had a prognostic impact on LC. V10 and V12 were significantly associated with RNFS (p < 0.001 and p = 0.004). CONCLUSION: SRS with simultaneous TT/IT significantly improved LC with no significant difference in radiation necrosis rate. The therapy combination appears to be effective and safe. However, prospective studies on SRS with simultaneous TT/IT are necessary and ongoing. TRIAL REGISTRATION: The institutional review board approved this analysis on 10th of February 2015 and all patients signed informed consent (UE nr. 128-14).

Brachytherapy of Intracranial Gliomas.

Interstitial implantation of radioactive materials (brachytherapy [BT]) has been designed to protractedly deliver a high radiation dose to a well-defined target volume, while minimizing irradiation of the adjacent normal tissues. Even though promising results have been reported over time, the role of this treatment modality in the management of brain tumors is still poorly defined, and only a few centers worldwide apply it in clinical practice. Nevertheless, temporary or permanent interstitial implantation of low activity (<20 mCi) and low dose rate (≤10 cGy/h) iodine-125 (125I) seeds as possible therapy of intracranial gliomas is currently undergoing a definite revival, and several indications for its use have been identified. Generally, 125I-BT may be considered a reasonable option in cases of unresectable, well-circumscribed, either newly diagnosed or recurrent tumors with a diameter of ≤4 cm, virtually in any location within the brain. Importantly, this treatment does not narrow down the spectrum of the possible subsequent salvage therapeutic options, since neither repeated interstitial nor additional external beam irradiation at the time of tumor progression after BT is associated with a significantly increased risk of radiogenic complications. Using correct patient selection criteria, appropriate surgical technique, and established treatment parameters, would make BT a truly minimally invasive procedure with a low risk of complications and reasonable efficacy.

Medulloblastoma in adults : A retrospective single institution analysis.

PURPOSE: Adult medulloblastoma is a rare disease treated according to the current pediatric treatment guidelines. This retrospective analysis investigated the clinical outcomes and prognostic factors of adult medulloblastoma patients, who received multimodal therapy at our institution. METHODS: Treatment charts of all patients over the age of 15 years of age with de novo medulloblastoma, who had been treated at our institution between 2001 and 2014, were retrospectively analyzed. Patients' demographic parameters, initial symptoms, treatment modalities, toxicities, and survival outcomes were investigated. RESULTS: In all, 21 patients with a median age of 30.2 years were identified. The most frequent histologies were desmoplastic and classic, and the most common molecular subtype was sonic hedgehog (SHH). After tumor resection, all patients received craniospinal irradiation (median dose 35.2 Gy) and a boost to the posterior fossa (median dose 19.8 Gy). Simultaneous chemotherapy with vincristine was given to 20 patients and sequential chemotherapy to 15 patients. The most common side effects were hematological toxicities. Median overall survival (OS) has not been reached after a median follow-up of 92 months. Estimated 5­ and 10-year OS was 89 and 80%, respectively. Estimated 5­ and 10-year progression-free survival (PFS) was 89 and 81%, respectively. In univariate analysis, a shorter interval between tumor resection and end of irradiation was significantly associated with improved OS and PFS, anaplastic histology with worse OS and PFS. CONCLUSIONS: The combined modality treatment showed a good outcome in adults with medulloblastoma. Treatment time was revealed to be prognostic and should be kept as short as possible.

Temozolomide during radiotherapy of glioblastoma multiforme : Daily administration improves survival.

BACKGROUND: Temozolomide-(TMZ)-based chemoradiotherapy defines the current gold standard for the treatment of newly diagnosed glioblastoma. Data regarding the influence of TMZ dose density during chemoradiotherapy are currently not available. We retrospectively compared outcomes in patients receiving no TMZ, TMZ during radiotherapy on radiotherapy days only, and TMZ constantly 7 days a week. PATIENTS AND METHODS: From 2002-2012, a total of 432 patients with newly diagnosed glioblastoma received radiotherapy in our department: 118 patients had radiotherapy alone, 210 had chemoradiotherapy with TMZ (75 mg/m2) daily (7/7), and 104 with TMZ only on radiotherapy days (5/7). Radiotherapy was applied to a total dose of 60 Gy. RESULTS: Median survival after radiotherapy alone was 9.1 months, compared to 12.6 months with 5/7-TMZ and to 15.7 months with 7/7-TMZ. The 1­year survival rates were 33, 52, and 64%, respectively. Kaplan-Meier analysis showed a significant improvement of TMZ-7/7 vs. 5/7 (p = 0.01 by the log-rank test), while 5/7-TMZ was still superior to no TMZ at all (p = 0.02). Multivariate Cox regression showed a significant influence of TMZ regimen (p = 0.009) on hazard rate (+58% between groups) even in the presence of confounding factors age, sex, resection status, and radiotherapy dose concept. CONCLUSION: Our results confirm the findings of the EORTC/NCIC trial. It seems that also a reduced TMZ scheme can at first prolong the survival of glioblastoma patients, but not as much as the daily administration.

Suspected recurrence of brain metastases after focused high dose radiotherapy: can [18F]FET- PET overcome diagnostic uncertainties?

BACKGROUND: After focused high dose radiotherapy of brain metastases, differentiation between tumor recurrence and radiation-induced lesions by conventional MRI is challenging. This study investigates the usefulness of dynamic O-(2-18F-Fluoroethyl)-L-Tyrosine positron emission tomography (18F-FET PET) in patients with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy of brain metastases. METHODS: Twenty-two patients with 34 brain metastases (median age 61.9 years) were included. Due to follow-up scan evaluations after repeated treatment in a subset of patients, a total of 50 lesions with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy could be evaluated. 18F-FET PET analysis included the assessment of maximum and mean tumor-to-background ratio (TBRmax and TBRmean) and analysis of time-activity-curves (TAC; increasing vs. decreasing) including minimal time-to-peak (TTPmin). PET parameters were correlated with histological findings and radiological-clinical follow-up evaluation. RESULTS: Tumor recurrence was found in 21/50 cases (15/21 verified by histology, 6/21 by radiological-clinical follow-up) and radiation-induced changes in 29/50 cases (5/29 verified by histology, 24/29 by radiological-clinical follow-up). Median clinical-radiological follow-up was 28.3 months (range 4.2-99.1 months). 18F-FET uptake was higher in tumor recurrence compared to radiation-induced changes (TBRmax 2.9 vs. 2.0, p < 0.001; TBRmean 2.2 vs. 1.7, p < 0.001). Receiver-operating-characteristic (ROC) curve analysis revealed optimal cut-off values of 2.15 for TBRmax and 1.95 for TBRmean (sensitivity 86 %, specificity 79 %). Increasing TACs and long TTPmin were associated with radiation-induced changes, decreasing TACs with tumor recurrence (p = 0.01). By combination of TBR and TACs, sensitivity and specificity could be increased to 93 and 84 %. CONCLUSIONS: In patients with MRI-suspected tumor recurrence after focused high dose radiotherapy, 18F-FET PET has a high sensitivity and specificity for the differentiation of vital tumor tissue and radiation-induced lesions.

Iodine-125 brachytherapy as upfront and salvage treatment for brain metastases : A comparative analysis.

BACKGROUND: Outcome and toxicity profiles of salvage stereotactic ablative radiation strategies for recurrent pre-irradiated brain metastases are poorly defined. This study compared risk-benefit profiles of upfront and salvage iodine-125 brachytherapy (SBT) for small brain metastases. As the applied SBT treatment algorithm required histologic proof of metastatic brain disease in all patients, we additionally aimed to elucidate the value of biopsy before SBT. PATIENTS AND METHODS: Patients with small untreated (n = 20) or pre-irradiated (n =28) suspected metastases intended for upfront or salvage SBT, respectively, were consecutively included. Temporary iodine-125 implants were used (median reference dose: 50 Gy, median dose rate: 15 cGy/h). Cumulative biologically effective doses (BED) were calculated and used for risk assessment. Treatment toxicity was classified according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria. RESULTS: Upfront SBT was initiated in 20 patients and salvage SBT in 23. In 5 patients, salvage SBT was withheld because of proven radiation-induced lesions. Treatment groups exhibited similar epidemiologic data except for tumor size (which was slightly smaller in the salvage group). One-year local/distant tumor control rates after upfront and salvage SBT were similar (94 %/65 % vs. 87 %/57 %, p = 0.45, respectively). Grade I/II toxicity was suffered by 2 patients after salvage SBT (cumulative BED: 192.1 Gy3 and 249.6 Gy3). No toxicity-related risk factors were identified. CONCLUSION: SBT combines diagnostic yield with effective treatment in selected patients. The low toxicity rate in the salvage group points to protective radiobiologic characteristics of continuous low-dose rate irradiation. Upfront and salvage SBT are similarly effective and safe. Histologic reevaluation should be reconsidered after previous radiotherapy to avoid under- or overtreatment.

Outcome and toxicity profile of salvage low-dose-rate iodine-125 stereotactic brachytherapy in recurrent high-grade gliomas.

BACKGROUND: The aim of this study was to provide an outcome and toxicity profile of salvage low-dose-rate iodine-125 (I-125) stereotactic brachytherapy (SBT) in patients with small, circumscribed malignant glioma recurrences. METHODS: Patients with malignant glioma recurrences consecutively undergoing salvage SBT from 2003 to 2011 were identified from our prospective tumor database. SBT was considered a potentially suitable treatment strategy for adult mostly multimodally pretreated patients (Karnofsky score of ≥ 70) with biopsy-proven, circumscribed, small (diameter ≤ 3.5 cm) recurrences. Exclusively temporary I-125 seeds were used (reference dose: 50 Gy, dose rate: < 15 cGy/h). Study endpoints were time-to-treatment failure (TTF) after SBT, postrecurrence survival (PRS), and toxicity. Survival was assessed with the Kaplan-Meier method. Adverse events were categorized according to the RTOG/EORTC classification. Prognostic factors were obtained from proportional hazards models. RESULTS: Sixty-eight patients (28 WHO grade III, 40 WHO grade IV gliomas) were included. Fifty-nine patients had previously received external beam radiation. Median TTF and PRS were 8.3 months and 13.4 months, respectively. TTF and PRS were longer for grade III gliomas than for glioblastomas (15.0 vs. 6.2 months and 28.1 vs. 9.3 months, respectively). Patients with grade III tumors were younger (p = 0.002). Favorable factors for TTF and PRS were age ≤ 50 years and a methylated O(6)-methylguanine-DNA methyltransferase (MGMT)-promoter. Alternative models including tumor grade instead of age reached a similar good fit. Three patients suffered from grade I, one from grade II, and two from grade IV toxicity. CONCLUSIONS: Salvage SBT is feasible and safe even after previously performed external beam radiation. Favorable outcome measurements in particular for grade III recurrences deserve further prospective evaluation.

Excellent local control and survival after postoperative or definitive radiation therapy for sarcomas of the head and neck.

BACKGROUND: To report our results with postoperative or definitive radiation therapy in head and neck sarcomas. METHODS: We performed a retrospective analysis of 26 patients suffering from head and neck sarcomas, who received postoperative or definitive radiation therapy between 2003 and 2012. Median age was 64 years (19-88) and 69 % were male. Tumor locations were skull (including skin) in 31 %, paranasal sinus/orbita in 27 % and neck (including pharynx/larynx) in 42 %. Median tumor size was 4.6 cm (1-12 cm). 22 patients (85 %) presented in primary situation. Stage at presentation (UICC 7(th) for soft tissue sarcomas) was as follows: Ia:4 %, IIa:50 %, IIb:15 %, III:31 %. All except one patient suffered from high grade lesions (G2/3 FNCLCC), predominantly angiosarcoma (35 %), MFH (19 %) and synovial sarcoma (15 %). Surgery was performed in 21 pts (81 %), resulting in free margins in 10 (38 %), microscopically positive margins in 6 (23 %) and gross residual disease in 5 (19 %). Median dose to the primary tumor region was 66Gy (45-72Gy) in conventional fractionation, using 3D-CRT in 65 %, IMRT in 27 % and electrons in 8 %. 50 % of the patients also received sequential chemotherapy. RESULTS: Median follow up was 39 months (8-136). We observed three local recurrences, transferring into estimated 3- and 5-year local control rates of 86 %. One additional patient failed distantly, resulting in 3- and 5-year freedom from treatment failure rates of 82 %. Four patients have deceased, transferring into 3- and 5-year overall survival rates of 88 % and 82 %, respectively. Only two of the four deaths were sarcoma related. Maximum acute toxicity (CTCAE 3.0) was grade 1 in 27 % of the patients, grade 2 in 50 % and grade 3 in 23 %. Severe acute toxicity was mainly represented by mucositis and dysphagia. Maximum late toxicity was grade 1 in 31 %, grade 2 in 15 % and grade 3 in 19 % of the patients. Severe late toxicity included skin ulceration (n = 1), dysphagia with persistent tube dependency (n = 1), persistent sinusitis (n = 1) and hearing loss (n = 2). CONCLUSION: Excellent local control and overall survival rates can be achieved with postoperative or definitive radiation therapy with acceptable acute and late toxicities in patients suffering from sarcomas of the head and neck region.

Prognostic factors for survival and radiation necrosis after stereotactic radiosurgery alone or in combination with whole brain radiation therapy for 1-3 cerebral metastases.

BACKGROUND: In the present study factors affecting survival and toxicity in cerebral metastasized patients treated with stereotactic radiosurgery (SRS) were analyzed with special focus on radiation necrosis. PATIENTS AND METHODS: 340 patients with 1-3 cerebral metastases having been treated with SRS were retrospectively analyzed. Radiation necrosis was diagnosed by MRI und PET imaging. Univariate and multivariate analysis using a Cox proportional hazards regression model and log-rank test were performed to determine the prognostic value of treatment-related and individual factors for outcome and SRS-related complications. RESULTS: Median overall survival was 282 days and median follow-up 721 days. 44% of patients received WBRT during the course of disease. Concerning univariate analysis a significant difference in overall survival was found for Karnofsky Performance Status (KPS ≤ 70: 122 days; KPS > 70: 342 days), for RPA (recursive partitioning analysis) class (RPA class I: 1800 days; RPA class II: 281 days; RPA class III: 130 days), irradiated volume (≤2.5 ml: 354 days; > 2.5 ml: 234 days), prescribed dose (≤18 Gy: 235 days; > 18 Gy: 351 days), gender (male: 235 days; female: 327 days) and whole brain radiotherapy (+WBRT: 341 days/-WBRT: 231 days). In multivariate analysis significance was confirmed for KPS, RPA class and gender. MRI and clinical symptoms suggested radiation necrosis in 21 patients after SRS +/- whole brain radiotherapy (WBRT). In five patients clinically relevant radiation necrosis was confirmed by PET imaging. CONCLUSIONS: SRS alone or in combination with WBRT represents a feasible option as initial treatment for patients with brain metastases; however a significant subset of patients may develop neurological complications. Performance status, RPA class and gender were identified to predict improved survival in cerebral metastasized patients.