Primary radiation therapy in stage I/II indolent orbital lymphoma - a comprehensive retrospective recurrence and toxicity analysis.

PURPOSE OR OBJECTIVE: To provide a comprehensive recurrence and toxicity analysis of patients treated with radiotherapy alone for stage I/II (Ann-Arbor classification) indolent orbital lymphoma. MATERIAL AND METHODS: We retrospectively reviewed the medical charts of 46 patients (and 51 orbits) treated at our centre with radiotherapy between 1995 and 2012 for biopsy-proven stage I/IIE primary orbital lymphomas. We evaluated treatment response and performed a comprehensive toxicity analysis with correlation to delivered radiation dose. RESULTS: At diagnosis, the median age was 63.5 years (range: 20-92). At initial diagnosis 43 and 3 patients had unilateral, synchronous bilateral involvement while there were 2 cases of contralateral metachronous failure. The predominant histological subtype was extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in 42 (91.3%), follicular in 1 (2.2%), lymphoplasmacytic lymphoma in 1 (2.2%) and other indolent histology in 2 (4.3%) patients. Most lymphomas were located in the conjunctiva (18/35.3%) or eyelids (18/35.3%). Thirty-eight (82.6%) patients presented with stage I while 8/46 (17.4%) with stage II disease. The median radiation dose was 39.6 Gy (range: 21.6-48.6 Gy) delivered in 1.8-2 Gy single fractions. At a median follow-up of 83 months (range: 7-258 months), the complete remission rate was 98%. A local relapse was observed in 2/51 (3.9%) orbits and 4/46 (8.7%) patients had systemic relapse. The 5- and 10-year PFS rates were 79.2% (95% CI: 73.0%-85.4%) and 67.6% (95% CI: 59.4%-75.8%); 5- and 10-year OS was 83.6% (95% CI: 77.9%-89.3%) and 76.5% (95% CI: 69.4%-83.6%), respectively. In total, 66 acute toxicity events (all-grade) were observed: 5/51 (9.8%) ≥G2 acute conjunctivitis, 2/51 (3.9%) cases of G2 acute keratitis, 1/51 (2%) cases of ≥G2 ophthalmagia and 12/51 (23.5%) cases of ≥G2 xerophthalmia. Furthermore, 45 chronic adverse events were observed in 34/51 (66.7%) irradiated orbits with 30 late adverse events attributed to cataract. CONCLUSION: Our analysis confirms the role of radiotherapy alone at lower doses in the treatment of indolent orbital lymphomas. Further research is required to assess the efficacy of ultra-low-dose radiotherapy and anti-CD20 monoclonal antibodies to further mitigate long-term sequelae.

Quantification of cerebral blood flow, cerebral blood volume, and blood-brain-barrier leakage with DCE-MRI.

Dynamic susceptibility contrast MRI (DSC-MRI) is the current standard for the measurement of Cerebral Blood Flow (CBF) and Cerebral Blood Volume (CBV), but it is not suitable for the measurement of Extraction Flow (EF) and may not allow for absolute quantification. The objective of this study was to develop and evaluate a methodology to measure CBF, CBV, and EF from T1-weighted dynamic contrast-enhanced MRI (DCE-MRI). A two-compartment modeling approach was developed, which applies both to tissues with an intact and with a broken Blood-Brain-Barrier (BBB). The approach was evaluated using measurements in normal grey matter (GM) and white matter (WM) and in tumors of 15 patients. Accuracy and precision were estimated with simulations of normal brain tissue. All tumor and normal tissue curves were accurately fitted by the model. CBF (mL/100 mL/min) was 82 +/- 21 in GM and 23 +/- 14 in WM, CBV (mL/100 mL) was 2.6 +/- 0.8 in GM and 1.3 +/- 0.4 in WM. EF (mL/100 mL/min) was close to zero in GM (-0.009 +/- 0.05) and WM (-0.03 +/- 0.08). Simulations show an overlap between CBF values of WM and GM, which is eliminated when Contrast-to-Noise (CNR) is improved. The model provides a consistent description of tracer kinetics in all brain tissues, and an accurate assessment of perfusion and permeability in reference tissues. The measurement sequence requires optimization to improve CNR and the precision in the perfusion parameters. With this approach, DCE-MRI presents a promising alternative to DSC-MRI for quantitative bolus-tracking in the brain.

Radiologic findings in patients treated with boron neutron capture therapy for glioblastoma multiforme within EORTC trial 11961.

PURPOSE: To assess the occurrence and development of cerebral radiologic changes (cerebral atrophy and white matter lesions) in patients treated with boron neutron capture therapy (BNCT) for primary supratentorial glioblastoma multiforme within the European Organization for Research and Treatment of Cancer (EORTC) trial 11961. METHODS AND MATERIALS: Magnetic resonance imaging (MRI) scans were performed before and after surgery and at 1 week and 2, 4.5, 6, 9, 12, 15, and 18 months after BNCT. For the current study, MRI scans of all assessable patients were analyzed, with emphasis on cerebral atrophy and white matter abnormalities. RESULTS: Twenty-six patients had been treated with BNCT according to the EORTC trial 11961, of whom 24 were assessable for the current study. The development of possible BNCT-related cerebral changes was observed in 12 patients (50%), 10 of whom had cerebral atrophy (42%) and 10 white matter changes (42%) after a median interval of 7.5 and 4.5 months, respectively. CONCLUSION: In this study, cerebral radiologic changes appeared in 50% of patients within the first year after BNCT. Although a clear correlation between the BNCT dose and the development of cerebral changes could not be demonstrated, a relationship between the occurrence of these radiologic abnormalities and BNCT seems likely.

Optimized radiation of pelvic volumes in the clinical setting by using a novel bellyboard with integrated gonadal shielding.

The purpose of this study was to determine the feasibility of a custom-made, modified bellyboard to reduce radiotherapy side effects on small bowel, bladder, skin, and male gonads. Two groups of 10 consecutive patients each were treated from January 2003 through April 2003 with neoadjuvant (45 Gy) or adjuvant (54 Gy) radio(chemo)therapy in single fractions of 5 days a week 1.8 Gy for rectal carcinoma, using a photon energy of 15 MV. One group was positioned in a prone position without an immobilization device, the other group was positioned on our bellyboard. Treatment planning was calculated by using a 4- and a 3-field box technique. Differences in the dose of organs of risk were calculated. For 1 male patient, a gonadal shielding was developed and integrated. All patients examined with the bellyboard demonstrated an anterior and cranial dislocation of the small bowel. Using a 4-field box, the mean dose to the small bowel of patients treated on our bellyboard was 56.5% as compared to 63.1% when treated without the bellyboard. When a 3-field box was used, the mean dose to the small bowel was 52.4% when the bellyboard was used, as compared to a mean dose of 63.1% without the bellyboard. Regarding the dose volume effects to the bladder, the mean dose for patients treated with a 4-field box was about 14.5% higher as compared to patients treated with a 3-field box. The mean dose to the hip joints and skin also depended on the radiation technique. The patient who received gonadal shielding received a maximal total gonadal dose of about 75.0 cGy in single fractions of maximal 3.0 cGy (TL-dosimeters). Daily setup variations evaluated by a beam's-eye view were similar in both groups and ranged from 0.5 cm 1.0 cm. For daily use, our bellyboard appears to be an ideal compromise due to effectiveness, its easy handling, and reproductive positioning; moreover, it can also be used in combination with gonadal shielding.

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.

Irradiation and bevacizumab in high-grade glioma retreatment settings.

PURPOSE: Reirradiation is a treatment option for recurrent high-grade glioma with proven but limited effectiveness. Therapies directed against vascular endothelial growth factor have been shown to exert certain efficacy in combination with chemotherapy and have been safely tested in combination with radiotherapy in a small cohort of patients. To study the feasibility of reirradiation combined with bevacizumab treatment, the toxicity and treatment outcomes of this approach were analyzed retrospectively. PATIENTS AND METHODS: After previous treatment with standard radiotherapy (with or without temozolomide) patients with recurrent malignant glioma received bevacizumab (10 mg/kg intravenous) on Day 1 and Day 15 during radiotherapy. Maintenance therapy was selected based on individual considerations, and mainly bevacizumab-containing regimens were chosen. Patients received 36 Gy in 18 fractions. RESULTS: The data of the medical charts of the 30 patients were analyzed retrospectively. All were irradiated in a single institution and received either bevacizumab (n = 20), no additional substance (n = 7), or temozolomide (n = 3). Reirradiation was tolerated well, regardless of the added drug. In 1 patient treated with bevacizumab, a wound dehiscence occurred. Overall survival was significantly better in patients receiving bevacizumab (p = 0.03, log-rank test). In a multivariate proportional hazards Cox model, bevacizumab, Karnovsky performance status, and World Health Organization grade at relapse turned out to be the most important predictors for overall survival. CONCLUSION: Reirradiation with bevacizumab is a feasible and effective treatment for patients with recurrent high-grade gliomas. A randomized trial is warranted to finally answer the question whether bevacizumab adds substantial benefit to a radiotherapeutic retreatment setting.

Therapeutic options for recurrent malignant glioma.

BACKGROUND AND PURPOSE: Despite the given advances in neuro-oncology most patients with high grade malignant glioma ultimately fail locally or locoregionally. In parallel with improvements of initial treatment options, several salvage strategies have been elucidated and already entered clinical practice. Aim of this article is to review the current status of salvage strategies in recurrent high grade glioma. MATERIAL AND METHODS: Using the following MESH headings and combinations of these terms the pubmed database was searched: "Glioma", "Recurrence", "Neoplasm Recurrence, Local", "Radiosurgery", "Brachytherapy", "Neurosurgical Procedures" and "Drug Therapy". For citation crosscheck the ISI web of science database was used employing the same search terms. In parallel, the abstracts of ASCO 2008-2009 were analyzed accordingly. RESULTS: Currently the following options for salvage entered clinical practice: re-resection, re-irradiation (stereotactic radiosurgery, (hypo-)fractionated (stereotactic) radiotherapy, interstitial brachytherapy) or single/poly-chemotherapy schedules including new dose-intensified or alternative treatment protocols employing targeted drugs. Re-operation is associated with high morbidity and mortality, however, is an option in a highly selected patient cohort. Since toxicity has been overestimated, re-irradiation is an increasingly used option with precise fractionated radiotherapy being the most optimal technique. On average, time to secondary progression is in the range of several months. Conventional chemotherapy regimens also improve time to secondary progression; however the efficacy is only modest and treatment-related toxicities like myelo-suppression occur very frequently. Molecular targeted agents/kinases are undergoing clinical testing; however no final recommendations can be made. CONCLUSIONS: Currently, several re-treatment options with only modest efficacy exist. The relative value of each approach compared to other options is unknown as well as it remains open which sequence of modalities should be chosen.

FET-PET for malignant glioma treatment planning.

BACKGROUND AND PURPOSE: The aim of this study was to compare MRI-based morphological gross tumour volumes (GTVs) to biological tumour volumes (BTVs), defined by the pathological radiotracer uptake in positron emission tomography (PET) imaging with (18)F-fluoroethyltyrosine (FET), subsequently clinical target volumes (CTVs) and finally planning target volumes (PTVs) for radiotherapy planning of glioblastoma. PATIENTS AND METHODS: Seventeen patients with glioblastoma were included into a retrospective protocol. Treatment-planning was performed using clinical target volume (CTV=BTV+20mm or CTV=GTV+20mm+inclusion of the edema) and planning target volume (PTV=CTV+5mm). Image fusion and target volume delineation were performed with OTP-Masterplan®. Initial gross tumour volume (GTV) definition was based on MRI data only or FET-PET data only (BTV), secondarily both data sets were used to define a common CTV. RESULTS: FET based BTVs (median 43.9 cm(3)) were larger than corresponding GTVs (median 34.1cm(3), p=0.028), in 11 of 17 cases there were major differences between GTV/BTV. To evaluate the conformity of both planning methods, the index (CTV(MRT)∩CTV(FET))/(CTV(MRT)∪CTV(FET)) was quantified which was significantly different from 1 (0.73 ± 0.03, p<0.001). CONCLUSION: With FET-PET-CT planning, the size and geometrical location of GTVs/BTVs differed in a majority of patients. It remains open whether FET-PET-based target definition has a relevant clinical impact for treatment planning.

Giant multilevel thoracic hemangioma with spinal cord compression in a patient with Klippel-Weber-Trenaunay syndrome: case report.

STUDY DESIGN: Case report and clinical discussion. OBJECTIVE: We intend to report a very rare case of a giant spinal hemangioma causing myelopathy. SUMMARY OF BACKGROUND DATA: Multilevel symptomatic spinal hemangiomas causing acute neurologic symptoms are rare disorders. We found only sporadic reports in English literature. METHODS: We describe a very rare case in which Klippel-Trenaunay-Weber syndrome is associated with a multisegmental vertebral hemangioma causing a rapidly progressing thoracic myelopathy. RESULTS: Because of the extension of the disease, surgical intervention was not feasible, the patient was treated by radiotherapy. The patient showed a complete regression of symptoms with stable condition after 3 months. CONCLUSIONS: In extensive spinal hemangiomas, radiotherapy may represent a safe treatment modality with rapid clinical improvement even in cases with spinal cord compression. This report contributes to a wide range of known vascular abnormalities in Klippel-Trenaunay-Weber syndrome and supports the need for a careful multisystemic evaluation of these patients.

Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial.

BACKGROUND: Is Gamma Knife surgery alone as effective as surgery plus whole brain irradiation (WBRT) for patients with a single, small-sized brain metastasis? METHODS: Patients aged between 18 and 80 years harboring a single, resectable metastasis < or =3 cm in diameter, a Karnofsky performance score (KPS) > or =70, and a stable systemic disease were randomly assigned to microsurgery plus WBRT or Gamma Knife surgery alone. The primary end point was length of survival, secondary end points were recurrence of tumor in the brain, health related quality of life, and treatment related toxicity. RESULTS: Due to poor patient accrual, the study was stopped prematurely. The final analysis was based on 33 patients in the surgery and 31 patients in the radiosurgery group. Treatment results did not differ in terms of survival (P = 0.8), neurological death rates (P = 0.3), and freedom from local recurrence (P = 0.06). Patients of the radiosurgery group experienced more often distant recurrences (P = 0.04); after adjustment for the effects of salvage radiosurgery this difference was lost (P = 0.4). Radiosurgery was associated with a shorter hospital stay, less frequent and shorter timed steroid application (P < or = 0.001), and lower frequency of grade 1/2 toxicities (according to the RTOG/EORTC CNS toxicity criteria, P < or = 0.01). Improved scores for role functioning and quality of life were seen 6 weeks after radiosurgery (P < 0.05); this difference was lost 6 months after treatment. CONCLUSIONS: In patients harboring a single, small-sized metastasis, Gamma Knife surgery alone is less invasive; local tumor control seems to be as high as after surgery plus WBRT. Distant tumor control, however, is significantly less frequently achieved (after radiosurgery alone). The role of radiosurgical salvage therapy (alternatively to WBRT) for distant tumor control deserves further prospective evaluation.

Photofrin as a radiosensitizer in an in vitro cell survival assay.

Chemical modifiers (radiosensitizers) are used in order to increase the efficacy of radiotherapy. The use of Photodynamic Therapy for tumor treatment, especially with Photofrin II, is also known. At present, no chemical modifier has been found to act as a selective radiosensitizer. Experiments using several series of cell lines were performed; human bladder cancer cell line (RT4), colon adenocarcinoma cells (HT-29), and the glioblastoma cells (U-373 MG) were investigated, with and without incubation with Photofrin II, before irradiation. The irradiation was performed using doses ranging from 0 to 8Gy. Colony forming tests were applied to determine the efficiency of Photofrin II as a radiation sensitizer in comparison to irradiation alone. Two of the cell lines tested, cultures of the RT4 and U-373 MG, treated with Photofrin II prior to radiation, showed cell survival lower than cultures untreated with Photofrin II but irradiated under identical conditions. For the HT-29 cells, the results did not differ between the two groups (with and without Photofrin). The results of this study showed that Photofrin II can act, under certain conditions as a tumor radiosensitizer.