Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. METHODS: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. RESULTS: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. CONCLUSIONS: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. TRIAL REGISTRATION: NCT00977431 (first posted September 15, 2009).

Factors Predicting Long-term Outcome and the Need for Surgery in Graves Orbitopathy: Extended Follow-up From the CIRTED Trial.

Graves orbitopathy is both disabling and disfiguring. Medical therapies to reduce inflammation are widely used, but there is limited trial data beyond 18 months of follow-up. METHODS: Three-year follow-up of a subset of the CIRTED trial (N = 68), which randomized patients to receive high-dose oral steroid with azathioprine/placebo and radiotherapy/sham radiotherapy. RESULTS: Data were available at 3 years from 68 of 126 randomized subjects (54%). No additional benefit was seen at 3 years for patients randomized to azathioprine or radiotherapy with regard to a binary clinical composite outcome measure (BCCOM), modified European Group on Graves' Orbitopathy score, or Ophthalmopathy Index.Clinical Activity Score (CAS), Ophthalmopathy Index, and Total Eye Score improved over 3 years (P < .001). However, quality of life at 3 years remained poor. Of 64 individuals with available surgical outcome data, 24 of 64 (37.5%) required surgical intervention. Disease duration of greater than 6 months before treatment was associated with increased need for surgery [odds ratio (OR) 16.8; 95% CI 2.95, 95.0; P = .001]. Higher baseline levels of CAS, Ophthalmopathy Index, and Total Eye Score but not early improvement in CAS were associated with increased requirement for surgery. CONCLUSION: In this long-term follow-up from a clinical trial, 3-year outcomes remained suboptimal with ongoing poor quality of life and high numbers requiring surgery. Importantly, reduction in CAS in the first year, a commonly used surrogate outcome measure, was not associated with improved long-term outcomes.

Primary glomus tumour of the pituitary gland: diagnostic challenges of a rare and potentially aggressive neoplasm.

Primary non-neuroendocrine tumours of the pituitary gland and sella are rare lesions often challenging to diagnose. We describe two cases of clinically aggressive primary glomus tumour of the pituitary gland. The lesions occurred in a 63-year-old male and a 30-year-old female who presented with headache, blurred vision and hypopituitarism. Neuroimaging demonstrated large sellar and suprasellar tumours invading the surrounding structures. Histologically, the lesions were characterised by angiocentric sheets and nests of atypical cells that expressed vimentin, smooth muscle actin and CD34. Perivascular deposition of collagen IV was also a feature. Case 2 expressed synaptophysin. INI-1 (SMARCB1) expression was preserved. Both lesions were mitotically active and demonstrated a Ki-67 labelling index of 30%. Next-generation sequencing performed in case 1 showed no mutations in the reading frame of 37 commonly mutated oncogenes, including BRAF and KRAS. Four pituitary glomus tumours have previously been reported, none of which showed features of malignant glomus tumour. Similar to our two patients, three previous examples displayed aggressive behaviour.

Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 × 2 factorial, double-blind, randomised controlled trial.

BACKGROUND: Standard treatment for thyroid eye disease is with systemic corticosteroids. We aimed to establish whether orbital radiotherapy or antiproliferative immunosuppression would confer any additional benefit. METHODS: CIRTED was a multicentre, double-blind, randomised controlled trial with a 2 × 2 factorial design done at six centres in the UK. Adults with active moderate-to-severe thyroid eye disease associated with proptosis or ocular motility restriction were recruited to the trial. Patients all received a 24 week course of oral prednisolone (80 mg per day, reduced to 20 mg per day by 6 weeks, 10 mg per day by 15 weeks, and 5 mg per day by 21 weeks) and were randomly assigned via remote computerised randomisation to receive either radiotherapy or sham radiotherapy and azathioprine or placebo in a 2 × 2 factorial design. Randomisation included minimisation to reduce baseline disparities in potential confounding variables between trial interventions. Patients and data analysts were masked to assignment, whereas trial coordinators (who monitored blood results), pharmacists, and radiographers were not. The radiotherapy dose was 20 Gy administered to the retrobulbar orbit in ten to 12 fractions over 2 to 3 weeks. Azathioprine treatment was provided for 48 weeks at 100-200 mg per day (dispensed as 50 mg tablets), depending on bodyweight (100 mg for <50 kg, 150 mg 50-79 kg, 200 mg for ≥80 kg). The primary outcomes were a binary composite clinical outcome score and an ophthalmopathy index at 48 weeks, and a clinical activity score at 12 weeks. The primary analysis was based on the intention-to-treat allocation and safety was assessed in all participants. This study is registered with ISRCTN, number 22471573. FINDINGS: Between Feb 15, 2006, and Oct 3, 2013, 126 patients were recruited and randomly assigned to groups: 31 patients to radiotherapy plus azathioprine, 31 to sham radiotherapy and azathioprine, 32 to radiotherapy and placebo, and 32 to sham radiotherapy and placebo. Outcome data were available for 103 patients (54 for sham radiotherapy vs 49 for radiotherapy and 53 for placebo vs 50 for azathioprine), of whom 84 completed their allocated treatment of radiotherapy or sham radiotherapy and 57 continued to take azathioprine or placebo up to 48 weeks. There was no interaction betweeen azathioprine and radiotherapy (pinteraction=0·86). The adjusted odds ratio (ORadj) for improvement in the binary clinical composite outcome measure was 2·56 (95% CI 0·98-6·66, p=0·054) for azathioprine and 0·89 (0·36-2·23, p=0·80) for radiotherapy. In a post-hoc analysis of patients who completed their allocated therapy the ORadj for improvement was 6·83 (1·66-28·1, p=0·008) for azathioprine and 1·32 (0·30-4·84, p=0·67) for radiotherapy. The ophthalmopathy index, clinical activity score, and numbers of adverse events (161 with azathioprine and 156 with radiotherapy) did not differ between treatment groups. In both groups, the most common adverse events were mild infections. No patients died during the study. INTERPRETATION: In patients receiving oral prednisolone for 24 weeks, radiotherapy did not have added benefit. We also did not find added benefit for addition of azathioprine in the primary analysis; however, our conclusions are limited by the high number of patients who withdrew from treatment. Results of post-hoc analysis of those who completed the assigned treatment suggest improved clinical outcome at 48 weeks with azathioprine treatment. FUNDING: National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity.

Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma.

PURPOSE: A randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recent in in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. PATIENTS AND METHODS: Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus lomustine (110 mg/m(2)); (3) lomustine (110 mg/m(2)) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans. RESULTS: The primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone (hazard ratio [HR] = 1.05; 95% CI, 0.74 to 1.50; two-sided P = .90) or cediranib in combination with lomustine (HR = 0.76; 95% CI, 0.53 to 1.08; two-sided P = .16) versus lomustine based on independent or local review of postcontrast T1-weighted MRI. CONCLUSION: This study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects.

Symptom experience in patients with primary brain tumours: a longitudinal exploratory study.

PURPOSE: This study was undertaken to further understand the symptom experience and the impact of symptoms in daily life in people treated for brain tumours. METHODS: A qualitative prospective longitudinal design was used with 9 people who were interviewed over 4 time points (soon after diagnosis, 3 months, 6 months and 12-months post-diagnosis), providing 21 interviews in total. RESULTS: Key issues for these participants were ongoing fatigue, memory loss and inability to drive. Fatalistic views about the outcomes of their disease were the norm. Participants made adjustments to their lives to accommodate their functional limitations. These included making home alterations, introducing regular exercise to their lives and using complementary therapies. Their expectations did not always match with the reality of the situation, which made several participants angry and dissatisfied with health care professionals. CONCLUSIONS: Issues of quality of life are paramount in this group of poor prognosis patients, therefore, health professionals should provide preparatory information to patients on what to expect from the illness and its treatments. Health professionals should also assist patients to manage debilitating symptoms such as fatigue and cognitive impairment.

Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma.

PURPOSE: Temozolomide (TMZ) is an alkylating agent licensed for treatment of high-grade glioma (HGG). No prospective comparison with nitrosourea-based chemotherapy exists. We report, to our knowledge, the first randomized trial of procarbazine, lomustine, and vincristine (PCV) versus TMZ in chemotherapy-naive patients with recurrent HGG. PATIENTS AND METHODS: Four hundred forty-seven patients were randomly assigned to PCV (224 patients) or TMZ (sub-random assignment: TMZ-5 [200 mg/m(2) for 5 days, 112 patients] or TMZ-21 [100 mg/m(2) for 21 days, 111 patients]) for up to 9 months or until progression. The primary outcomes were survival (PCV v TMZ) and 12-week progression-free survival (PFS; TMZ-5 v TMZ-21). This study is registered as ISRCTN83176944. RESULTS: Percentages of patients completing 9 months of treatment in the PCV, TMZ-5, and TMZ-21 arms were 17%, 26%, and 13%, respectively. Major toxicity was similar across all three groups. With a median follow-up time of 12 months and 382 deaths, there was no clear survival benefit when comparing PCV with TMZ (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; P = .350). For TMZ-5 versus TMZ-21, 12-week PFS rates were similar (63.6% and 65.7%, respectively; P = .745), but TMZ-5 improved overall PFS (HR, 1.38; 95% CI, 1.05 to 1.82; P = .023), survival (HR, 1.32; 95% CI, 0.99 to 1.75; P = .056), and global quality of life (49% v 19% improved > 10 points at 6 months, respectively; P = .005). CONCLUSION: Although TMZ (both arms combined) did not show a clear benefit compared with PCV, comparison of the TMZ schedules demonstrated that the 21-day schedule was inferior to the 5-day schedule in this setting. This challenges the current understanding of increasing TMZ dose-intensity by prolonged scheduling.

Protocol for the combined immunosuppression & radiotherapy in thyroid eye disease (CIRTED) trial: a multi-centre, double-masked, factorial randomised controlled trial.

BACKGROUND: Medical management of thyroid eye disease remains controversial due to a paucity of high quality evidence on long-term treatment outcomes. Glucocorticoids are known to be effective initially but have significant side-effects with long-term use and recrudescence can occur on cessation. Current evidence is conflicting on the efficacy of radiotherapy and non-steroid systemic immunosuppression, and the majority of previous studies have been retrospective, uncontrolled, small or poorly designed.The Combined Immunosuppression and Radiotherapy in Thyroid Eye Disease (CIRTED) trial was designed to investigate the efficacy of radiotherapy and azathioprine in combination with a standard course of oral prednisolone in patients with active thyroid eye disease. METHODS/DESIGN: Patients with active thyroid eye disease will be randomised to receive (i) azathioprine or oral placebo and (ii) radiotherapy or sham-radiotherapy in this multi-centre, factorial randomised control trial. The primary outcome is improvement in disease severity (assessed using a composite binary measure) at 12 months and secondary end-points include quality of life scores and health economic measures. DISCUSSION: The CIRTED trial is the first study to evaluate the role of radiotherapy and azathioprine as part of a long-term, combination immunosuppressive treatment regime for Thyroid Eye Disease. It will provide evidence for the role of radiotherapy and prolonged immunosuppression in the management of this condition, as well as pilot data on their use in combination. We have paid particular attention in the trial design to establishing (a) robust placebo controls and masking protocols which are effective and safe for both radiotherapy and the systemic administration of an antiproliferative drug; (b) constructing effective inclusion and exclusion criteria to select for active disease; and (c) selecting pragmatic outcome measures. TRIAL REGISTRATION: Current controlled trials ISRCTN22471573.

Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study.

BACKGROUND: Over half of childhood intracranial ependymomas occur in children younger than 5 years. As an adjuvant treatment, radiotherapy can be effective, but has the potential to damage the child's developing nervous system at a crucial time-with a resultant reduction in IQ and cognitive impairment, endocrinopathy, and risk of second malignancy. We aimed to assess the role of a primary chemotherapy strategy in avoiding or delaying radiotherapy in children younger than 3 years with intracranial ependymoma. METHODS: Between December, 1992, and April, 2003, we enrolled 89 children with ependymoma who were aged 3 years or younger at diagnosis, of whom nine had metastatic disease on pre-operative imaging. After maximal surgical resection, children received alternating blocks of myelosuppressive and non-myelosuppressive chemotherapy every 14 days for an intended duration of 1 year. Radiotherapy was withheld unless local imaging (ie, from the child's treatment centre) showed progressive disease. FINDINGS: 50 of the 80 patients with non-metastatic disease progressed, 34 of whom were irradiated for progression. The 5-year cumulative incidence of freedom from radiotherapy for the 80 non-metastatic patients was 42% (95% CI 32-53). With a median follow-up of 6 years (range 1.5-11.3), overall survival for the non-metastatic patients at 3 years was 79.3% (95% CI 68.5-86.8) and at 5 years 63.4% (51.2-73.4). The corresponding values for event-free survival were 47.6% (36.2-58.1) and 41.8% (30.7-52.6). There was no significant difference in event-free or overall survival between complete and incomplete surgical resection, nor did survival differ according to histological grade, age at diagnosis, or site of disease. In 47 of 59 (80%) patients who progressed, relapse resulted from local control only. The median time to progression for the 59 patients who progressed was 1.6 years (range 0.1-10.2 years). The median age at irradiation of the whole group was 3.6 years (range 1.5-11.9). For the 80 non-metastatic patients, the 23 who achieved the highest relative dose intensity of chemotherapy had the highest post-chemotherapy 5-year overall survival of 76% (95% CI 46.6-91.2), compared with 52% (33.3-68.1) for the 32 patients who achieved the lowest relative dose intensity of chemotherapy. INTERPRETATION: This protocol avoided or delayed radiotherapy in a substantial proportion of children younger than 3 years without compromising survival. These results suggest, therefore, that primary chemotherapy strategies have an important role in the treatment of very young children with intracranial ependymoma.