Occurrence of pituitary hormone deficits in relation to both pituitary and hypothalamic doses after radiotherapy for skull base meningioma.

CONTEXT: Little accurate information is available regarding the risk of hypopituitarism after irradiation of skull base meningiomas. DESIGN: Retrospective study in a single centre. PATIENTS: 48 patients with a skull base meningioma and normal pituitary function at diagnosis, treated with radiotherapy (RXT) between 1998 and 2017 (median follow-up of 90 months). MEASUREMENTS: The GH, TSH, LH/FSH and ACTH hormonal axes were evaluated yearly for the entire follow-up period. Mean doses delivered to the pituitary gland (PitD) and the hypothalamus (HypoD) were calculated, as well as the doses responsible for the development of deficits in 50% of patients after 5 years (TD50). RESULTS: At least one hormone deficit was observed in 38% of irradiated patients and complete hypopituitarism in 13%. The GH (35%), TSH (32%) and LH/FSH axes (28%) were the most frequently affected, while ACTH secretion axis was less altered (13%). The risk of hypopituitarism was independently related to planning target volume (PTV) and to the PitD (threshold dose 45 Gy; TD50 between 50 and 54 Gy). In this series, the risk was less influenced by the HypoD, increasing steadily between doses of 15 and 70 Gy with no clear-cut dose threshold. CONCLUSIONS: Over a median follow-up period of 7.5 years, hypopituitarism occurred in more than one third of patients irradiated for a skull base meningioma, and this prevalence was time- and dose-dependent. In this setting, the risk of developing hypopituitarism was mainly determined by the irradiated target volume and by the dose delivered to the pituitary gland.

Prospective cardiac MRI for the analysis of biventricular function in children undergoing cancer treatments.

BACKGROUND: Cardiotoxicity is one of the most serious long-term complications in childhood cancer survivors. Measurement of the left ventricular ejection and shortening fraction remains the most common screening tool for cardiac systolic dysfunction. However, M-mode echocardiography can be viewed as a crude approach as refined strategies are now available. The aim of this prospective study was to determine the role of cardiac MRI in the detection of subclinical left or right ventricular dysfunction as well as the prevalence of myocardial scaring in patients undergoing cancer treatments. PROCEDURE: Eighty-one children were enrolled in a pre-chemotherapy and then in a yearly protocol including a: (i) clinical evaluation; (ii) laboratory evaluation; (iii) electrocardiogram; (iv) echocardiogram; and (v) a cardiac magnetic resonance imaging (cMRI). RESULTS: Early left ventricular systolic dysfunction was only detected in two patients. The entire cohort presented a significant increase of the left atrial volume as measured by cMRI. This finding correlated with the total cumulative dose of anthracyclines (r = 0.34; P < 0.05) and the mean left ventricular radiation dose (r = 0.86; P < 0.05). We also observed a mild increase of myocardial scaring, similarly correlated to the radiation dose (r = 0.85; P < 0.05). CONCLUSIONS: Screening tools for late-onset cardiomyopathy secondary to cancer treatment are lacking. Our findings support the use of cMRI for the evaluation of the left atrial volume, as an early marker of diastolic dysfunction, and myocardial delayed enhancement, as a marker of myocardial fibrosis and scaring. Longer follow-up and larger studies are still needed to better define the role of cMRI in the evaluation of childhood cancer survivors.

Effects of high-intensity interval training compared with resistance training in prostate cancer patients undergoing radiotherapy: a randomized controlled trial.

BACKGROUND: Exercise training has shown beneficial effects in the management of radiotherapy-related side effects in prostate cancer (PCa) patients undergoing radiation therapy (RT). However, the optimal modality of the exercise programs have not been yet determined. The aim of this randomized controlled trial was to investigate the effects of high-intensity interval training (HIIT) and resistance training (RES) compared to usual care (UC) on cancer-treatment-related fatigue (CTRF) (primary outcome), quality of life, depression, daytime sleepiness, insomnia, sleep quality, functional exercise capacity and executive function in PCa patients during RT. METHODS: PCa patients undergoing RT with or without ADT were randomized in HIIT, RES or UC. Both exercise programs included three sessions per week during 5-8 weeks. HIIT consisted of 8-15 × 60 s intervals (≥85% maximal heart rate). RES was performed with 1-3 sets of 8-12 repetitions for each large muscle groups. The primary outcome was changed in CTRF measured with the Functional Assessment of Chronic Illness Therapy-Fatigue. RESULTS: Seventy-two subjects (69.1 ± 8.2 years) completed the study. No exercise-related adverse events occurred. HIIT (p = 0.012) and RES (p = 0.039) training attenuated increases in CTRF compared to UC. Functional exercise capacity, evaluated by the 6-min walk test, increased after HIIT (p = 0 = 0.43) and RES (p = 0.041) compared to UC (+0.1%). No other secondary variables were different between groups. CONCLUSIONS: Both intervention groups displayed beneficial effects on CTRF and functional exercise capacity in PCa patients undergoing RT. In addition, HIIT and RES are both safe with an excellent attendance rate to the exercise sessions.

Long-term survival after glioblastoma resection: hope despite poor prognosis factors.

BACKGROUND: In spite of aggressive multimodal treatment, survival for patients with glioblastoma (GBM) remains short. Nevertheless, some patients survive much longer than expected and become long-term survival patients. The extent of resection (EoR), Karnofsky Performance Scale (KPS), age and methyl-guanine methyltransferase gene (MGMT) methylation are well-defined prognostic factors, but the characteristics of patients with long-term survival (LTS, survival of at least three years after diagnosis) has not been fully determined yet. That is the reason why we analyzed the GBM patients with LTS at our center. METHODS: We retrospectively reviewed all consecutive patients who underwent surgery for GBM between January 2002 and November 2011, including patients treated with surgical resection under neuronavigation with or without intraoperative MRI (ioMRI) and those who had stereotactic biopsy. We identified and further analyzed those patients with LTS. RESULTS: A total of 127 patients underwent surgery for GBM during the study period. 101 (79.6%) of whom had surgical resection and 26 (20.4%) of whom had stereotactic biopsy. Of the 101 patients who were treated with surgical resection, 12 had LTS. After two other pathologists reviewed the patients' cases, they confirmed that 11 (11%) of the 12 patients had a GBM (female/male ratio 4.5; average age 50 years; preoperative Karnofsky Score 82%), and one patient had an anaplastic glioma. The mean survival in the LTS patients with confirmed GBM was 74 (36-150) months. Seven of the LTS patients (63.6%) had a gross total resection (GTR), including two with an additional resection after ioMRI. Three (27.3%) had a near total resection (NTR: residue ≤5%) and one (9.1%) had a partial resection. Ten (90.9%) patients had a methylation of MGMT, only two (18.8%) had an IDH1 mutation, and seven (63.6%) received a full Stupp protocol. CONCLUSIONS: Among patients with a GBM who were treated with one or more resections, 11% had LTS with 90.9% with at least a near total resection (36% with ioMRI) and a methylated MGMT. 50% of the patients with a second surgery survived at least two years postoperatively. Those encouraging observations emphasize the importance of maximizing the resection by using, if possible, an intraoperative guidance method like ioMRI with an analysis of biomarkers such as MGMT and if necessary, multiple surgical procedures.

Adjuvant postoperative high-dose radiotherapy for atypical and malignant meningioma: A phase-II parallel non-randomized and observation study (EORTC 22042-26042).

PURPOSE: The therapeutic strategy for non-benign meningiomas is controversial. The objective of this study was to prospectively investigate the impact of high dose radiation therapy (RT) on the progression-free survival (PFS) rate at 3 years in WHO grade II and III meningioma patients. MATERIALS AND METHODS: In this multi-cohorts non-randomized phase II and observational study, non-benign meningioma patients were treated according to their WHO grade and Simpson's grade. Patients with atypical meningioma (WHO grade II) and Simpson's grade 1-3 [Arm 1] entered the non-randomized phase II study designed to show a 3-year PFS > 70% (primary endpoint). All other patients entered the 3 observational cohorts: WHO grade II Simpson grade 4-5 [Arm 2] and Grade III Simpson grade 1-3 or 4-5 [Arm 3&4] in which few patients were expected. RESULTS: Between 02/2008 and 06/2013, 78 patients were enrolled into the study. This report focuses on the 56 (median age, 54 years) eligible patients with WHO grade II Simpson's grade 1-3 meningioma who received RT (60 Gy). At a median follow up of 5.1 years, the estimated 3-year PFS is 88.7%, hence significantly greater than 70%. Eight (14.3%) treatment failures were observed. The 3-year overall survival was 98.2%. The rate of late signs and symptoms grade 3 or more was 14.3%. CONCLUSIONS: These data show that 3-year PFS for WHO grade II meningioma patients undergoing a complete resection (Simpson I-III) is superior to 70% when treated with high-dose (60 Gy) RT.

The EPTN consensus-based atlas for CT- and MR-based contouring in neuro-oncology.

PURPOSE: To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging. METHODS: CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed by European radiation oncologists until consensus was reached. RESULTS: The online atlas includes one CT-scan at two different window settings and one MR scan (3T) showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for neuro-cognition, the posterior cerebellum (illustrated on 7T MR images). CONCLUSION: In order to decrease inter- and intra-observer variability in delineating OARs relevant for neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon and particle therapy. The atlas is available online at www.cancerdata.org and will be updated whenever required.

Radiation dose constraints for organs at risk in neuro-oncology; the European Particle Therapy Network consensus.

PURPOSE: For unbiased comparison of different radiation modalities and techniques, consensus on delineation of radiation sensitive organs at risk (OARs) and on their dose constraints is warranted. Following the publication of a digital, online atlas for OAR delineation in neuro-oncology by the same group, we assessed the brain OAR-dose constraints in a follow-up study. METHODS: We performed a comprehensive search to identify the current papers on OAR dose constraints for normofractionated photon and particle therapy in PubMed, Ovid Medline, Cochrane Library, Embase and Web of Science. Moreover, the included articles' reference lists were cross-checked for potential studies that met the inclusion criteria. Consensus was reached among 20 radiation oncology experts in the field of neuro-oncology. RESULTS: For the OARs published in the neuro-oncology literature, we summarized the available literature and recommended dose constraints associated with certain levels of normal tissue complication probability (NTCP) according to the recent ICRU recommendations. For those OARs with lacking or insufficient NTCP data, a proposal for effective and efficient data collection is given. CONCLUSION: The use of the European Particle Therapy Network-consensus OAR dose constraints summarized in this article is recommended for the model-based approach comparing photon and proton beam irradiation as well as for prospective clinical trials including novel radiation techniques and/or modalities.

Primary orbital melanoma treated with iodine-125 plaque radiotherapy.

PURPOSE: To report a case of primary orbital melanoma successfully managed by custom-designed iodine-125 plaque. DESIGN: Case report. METHODS: A 59-year-old man with no systemic or secondary melanocytic tumor was diagnosed with primary orbital melanoma after transconjunctival incisional biopsy. He was treated with unshielded iodine-125 plaque (90 Gy) that was sutured to the sclera. The radiation plan was calculated to safely target the initial tumor volume and any residual intrascleral or loose orbital melanoma cells that could have been disseminated to the surrounding orbital tissues during incisional biopsy. RESULTS: After 66 months' follow-up, the patient was still alive with partial remission of his liver metastases. Routine orbital magnetic resonance imaging studies confirmed the lack of orbital recurrence. CONCLUSIONS: Plaque radiotherapy appears to be a reasonable alternative to exenteration or external irradiation for orbital melanoma after biopsy confirmation.

Short Androgen Suppression and Radiation Dose Escalation for Intermediate- and High-Risk Localized Prostate Cancer: Results of EORTC Trial 22991.

PURPOSE: Up to 30% of patients who undergo radiation for intermediate- or high-risk localized prostate cancer relapse biochemically within 5 years. We assessed if biochemical disease-free survival (DFS) is improved by adding 6 months of androgen suppression (AS; two injections of every-3-months depot of luteinizing hormone-releasing hormone agonist) to primary radiotherapy (RT) for intermediate- or high-risk localized prostate cancer. PATIENTS AND METHODS: A total of 819 patients staged: (1) cT1b-c, with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≥ 7, or (2) cT2a (International Union Against Cancer TNM 1997), with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread, with PSA ≤ 50 ng/mL, were centrally randomized 1:1 to either RT or RT plus AS started on day 1 of RT. Centers opted for one dose (70, 74, or 78 Gy). Biochemical DFS, the primary end point, was defined from entry until PSA relapse (Phoenix criteria) and clinical relapse by imaging or death of any cause. The trial had 80% power to detect hazard ratio (HR), 0.714 by intent-to-treat analysis stratified by dose of RT at the two-sided α = 5%. RESULTS: The median patient age was 70 years. Among patients, 74.8% were intermediate risk and 24.8% were high risk. In the RT arm, 407 of 409 patients received RT; in the RT plus AS arm, 403 patients received RT plus AS and three patients received RT only. At 7.2 years median follow-up, RT plus AS significantly improved biochemical DFS (HR, 0.52; 95% CI, 0.41 to 0.66; P < .001, with 319 events), as well as clinical progression-free survival (205 events, HR, 0.63; 95% CI, 0.48 to 0.84; P = .001). In exploratory analysis, no statistically significant interaction between treatment effect and dose of RT could be evidenced (heterogeneity P = .79 and P = .66, for biochemical DFS and progression-free survival, respectively). Overall survival data are not mature yet. CONCLUSION: Six months of concomitant and adjuvant AS improves biochemical and clinical DFS of intermediate- and high-risk cT1b-c to cT2a (with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread) prostatic carcinoma, treated by radiation.

A multi-institutional analysis comparing adjuvant and salvage radiation therapy for high-risk prostate cancer patients with undetectable PSA after prostatectomy.

BACKGROUND AND PURPOSE: In men with adverse pathology at the time of radical prostatectomy (RP), the most appropriate timing to administer radiotherapy (RT) remains a subject for debate. To determine whether salvage radiotherapy (SRT) upon early prostate-specific antigen (PSA) relapse is equivalent to immediate adjuvant radiotherapy (ART) post RP. MATERIAL AND METHODS: 130 patients receiving ART and 89 receiving SRT were identified. All had an undetectable PSA after RP. Homogeneous subgroups were built based on the status (±) of lymphatic invasion (LVI) and surgical margins (SM), to allow a comparison of ART and SRT. Biochemical disease-free survival (bDFS) was calculated from the date of surgery and from the end of RT. The multivariate analysis was performed using the Cox Proportional hazard model. RESULTS: In the SM-/LVI- and SM+/LVI- groups, SRT was a significant predictor of a decreased bDFS from the date of surgery, while in the SM+/LVI+ group, there was a trend towards significance. From the end of RT, SRT was also a significant predictor of a decreased bDFS in three patient groups: SM-/LVI-, SM+/LVI- and SM+/LVI+. Gleason score >7 showed to be another factor on multivariate analysis associated with decreased bDFS in the SM-/LVI- group, from the date of surgery and end of RT. Preoperative PSA was a significant predictor in the SM-/LVI- group from the date of RP only. CONCLUSIONS: Immediate ART post RP for patients with high risk features in the prostatectomy specimen significantly reduces bDFS after RP compared with early SRT upon PSA relapse.

Evaluation of MVCT protocols for brain and head and neck tumor patients treated with helical tomotherapy.

PURPOSE: Helical tomotherapy is a modality of radiation treatment delivery which is equipped with an on-board imaging device (MVCT) allowing for daily patient set-up verification and correction in the medial-lateral (m-l), cranial-caudal (c-c), anterior-posterior (a-p) and transversal angular (roll) directions. In this study, we measured set-up deviations and evaluated different MVCT protocols for brain and head and neck (H&N) cancer patients. MATERIALS AND METHODS: The daily set-up errors of 75 H&N cancer patients immobilized with 5-point fixation thermoplastic masks and 30 brain cancer patients immobilized with 3-point fixation thermoplastic masks were detected by matching the MVCT with the treatment planning CT images. This co-registration procedure was accomplished automatically by the system's software (automatic deviations), then corrected manually by the radiation therapists (total deviations). Systematic and random errors were analyzed on a patient and a population basis. Moreover, 2 MVCT protocols were retrospectively evaluated; MVCTs were either acquired during the first five fractions (FFFs) or on alternate week (ALT). Systematic deviations were calculated based upon prior "MVCT" fractions and applied during the "non-MVCT" fractions. The resulting residual deviations were then analyzed. RESULTS: The total systematic (and random) deviations reached 1.7mm (1.4mm), 1.6mm (1.5mm), 1.5mm (1.5mm) and 0.6 degrees (0.6 degrees ) for H&N cancer patients and reached 1.6mm (0.9mm), 1.7mm (1.1mm), 1.1mm (0.8mm) and 0.9 degrees (0.6 degrees ) for brain cancer patients in the m-l, c-c, a-p and roll directions, respectively. A t-test detected small but statistically significant differences between the automatic and total deviations. Both MVCT protocols gave rise to similar residual deviations. However, for H&N cancer patients the ALT protocol resulted in smaller residual deviations and CTV-PTV margins, particularly in the a-p direction. CONCLUSION: The total systematic and random deviations were comparable to the previously published data. No clinical difference exists between the automatic and total deviations. Both MVCT protocols were similar. But, for H&N cancer patients, the ALT protocol gave rise to smaller residual deviations and therefore is the correct formula to adopt in order to reduce the frequency of pre-treatment MVCTs.

A novel mutation in the SDHD gene in a family with inherited paragangliomas--implications of genetic diagnosis for follow up and treatment.

BACKGROUND: Early detection of paragangliomas (PGs) has been linked to low morbidity after surgical resection. Recent identification of causative genes (SDHB, SDHC, and SDHD) has made it possible to detect individuals at high risk for tumors. METHODS: We identified a three-generation family, with four individuals affected with PGs. Because pedigree analysis suggested maternal imprinting (the phenotype is present only if inherited through the paternal line), the SDHD gene (PGL1) was screened. RESULTS: A novel mutation that causes skipping of exon 3 was identified. Ten of the seventeen tested individuals carried the mutation. All six clinically unaffected individuals inherited the mutation from their mother. Five of them are men, with a 50% risk for affected progeny. CONCLUSIONS: To allow early treatment with low morbidity, genetic counseling is needed when familial paraganglioma is suspected. Asymptomatic carriers should be followed by cervical MRI. In addition, because pheochromocytomas may occur, catecholamine excretion can be performed. This screening should probably be proposed at 5 to 10 years of age.