Michael Fay

Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma.

Background Glioblastoma is associated with a poor prognosis in the elderly. Survival has been shown to increase among patients 70 years of age or younger when temozolomide chemotherapy is added to standard radiotherapy (60 Gy over a period of 6 weeks). In elderly patients, more convenient shorter courses of radiotherapy are commonly used, but the benefit of adding temozolomide to a shorter course of radiotherapy is unknown. Methods We conducted a trial involving patients 65 years of age or older with newly diagnosed glioblastoma. Patients were randomly assigned to receive either radiotherapy alone (40 Gy in 15 fractions) or radiotherapy with concomitant and adjuvant temozolomide. Results A total of 562 patients underwent randomization, 281 to each group. The median age was 73 years (range, 65 to 90). The median overall survival was longer with radiotherapy plus temozolomide than with radiotherapy alone (9.3 months vs. 7.6 months; hazard ratio for death, 0.67; 95% confidence interval [CI], 0.56 to 0.80; P<0.001), as was the median progression‐free survival (5.3 months vs. 3.9 months; hazard ratio for disease progression or death, 0.50; 95% CI, 0.41 to 0.60; P<0.001). Among 165 patients with methylated O6‐methylguanine–DNA methyltransferase (MGMT) status, the median overall survival was 13.5 months with radiotherapy plus temozolomide and 7.7 months with radiotherapy alone (hazard ratio for death, 0.53; 95% CI, 0.38 to 0.73; P<0.001). Among 189 patients with unmethylated MGMT status, the median overall survival was 10.0 months with radiotherapy plus temozolomide and 7.9 months with radiotherapy alone (hazard ratio for death, 0.75; 95% CI, 0.56 to 1.01; P=0.055; P=0.08 for interaction). Quality of life was similar in the two trial groups. Conclusions In elderly patients with glioblastoma, the addition of temozolomide to short‐course radiotherapy resulted in longer survival than short‐course radiotherapy alone. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00482677.)

The impact of 18-fluorodeoxyglucose positron emission tomography on the staging, management and outcome of anal cancer.

Accurate inguinal and pelvic nodal staging in anal cancer is important for the prognosis and planning of radiation fields. There is evidence for the role of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging and management of cancer, with early reports of an increasing role in outcome prognostication in a number of tumours. We aimed to determine the effect of FDG-PET on the nodal staging, radiotherapy planning and prognostication of patients with primary anal cancer. Sixty-one consecutive patients with anal cancer who were referred to a tertiary centre between August 1997 and November 2005 were staged with conventional imaging (CIm) (including computed tomography (CT), magnetic resonance imaging, endoscopic ultrasound and chest X-ray) and by FDG-PET. The stage determined by CIm and the proposed management plan were prospectively recorded and changes in stage and management as a result of FDG-PET assessed. Patients were treated with a uniform radiotherapy technique and dose. The accuracy of changes and prognostication of FDG-PET were validated by subsequent clinical follow-up. Kaplan–Meier survival analysis was used to estimate survival for the whole cohort and by FDG-PET and CIm stage. The tumour-stage group was changed in 23% (14 out of 61) as a result of FDG-PET (15% up-staged, 8% down-staged). Fourteen percent of T1 patients (3 out of 22), 42% of T2 patients (10 out of 24) and 40% of T3–4 patients (6 out of 15) assessed using CIm, had a change in their nodal or metastatic stage following FDG-PET. Sensitivity for nodal regional disease by FDG-PET and CIm was 89% and 62%, respectively. The staging FDG-PET scan altered management intent in 3% (2 out of 61) and radiotherapy fields in 13% (8 out of 61). The estimated 5-year overall survival (OS) and progression-free survival (PFS) for the cohort were 77.3% (95% confidence interval (CI): 55.3–90.4%) and 72.2% (95% CI: 51.5–86.4%), respectively. The estimated 5-year PFS for FDG-PET and CIm staged N2-3 disease was 70% (95% CI: 42.8–87.9%) and 55.3% (95% CI: 23.3–83.4%), respectively. FDG-PET shows increased sensitivity over CIm for staging nodal disease in anal cancer and changes treatment intent or radiotherapy prescription in a significant proportion of patients.

Pitfalls of using estimations of glomerular filtration rate in an intensive care population

Background:  Accurate knowledge of the glomerular filtration rate (GFR) is imperative in the intensive care unit (ICU) as renal status is important for medical decisions, including drug dosing.

Correlation of MRI-derived apparent diffusion coefficients in newly diagnosed gliomas with [18F]-fluoro-L-dopa PET: what are we really measuring with minimum ADC?

BACKGROUND AND PURPOSE: There is significant interest in whether diffusion-weighted MR imaging indices, such as the minimum apparent diffusion coefficient, may be useful clinically for preoperative tumor grading and treatment planning. To help establish the pathologic correlate of minimum ADC, we undertook a study investigating the relationship between minimum ADC and maximum FDOPA PET uptake in patients with newly diagnosed glioblastoma multiforme. MATERIALS AND METHODS: MR imaging and FDOPA PET data were acquired preoperatively from 15 patients who were subsequently diagnosed with high-grade brain tumor (WHO grade III or IV) by histopathologic analysis. ADC and SUVR normalized FDOPA PET maps were registered to the corresponding CE MR imaging. Regions of minimum ADC within the FDOPA-defined tumor volume were anatomically correlated with areas of maximum FDOPA SUVR uptake. RESULTS: Minimal anatomic overlap was found between regions exhibiting minimum ADC (a putative marker of tumor cellularity) and maximum FDOPA SUVR uptake (a marker of tumor infiltration and proliferation). FDOPA SUVR measures for tumoral regions exhibiting minimum ADC (1.36 ± 0.22) were significantly reduced compared with those with maximum FDOPA uptake (2.45 ± 0.88, P = .0001). CONCLUSIONS: There was a poor correlation between minimum ADC and the most viable/aggressive component of high-grade gliomas. This study suggests that other factors, such as tissue compression and ischemia, may be contributing to restricted diffusion in GBM. Caution should be exercised in the clinical use of minimum ADC as a marker of tumor grade and the use of this index for guiding tumor biopsies preoperatively.

Hypoxia Imaging in Gliomas With 18F-Fluoromisonidazole PET: Toward Clinical Translation

There is significant interest in the development of improved image-guided therapy for neuro-oncology applications. Glioblastomas (GBM) in particular present a considerable challenge because of their pervasive nature, propensity for recurrence, and resistance to conventional therapies. MRI is routinely used as a guide for planning treatment strategies. However, this imaging modality is not able to provide images that clearly delineate tumor boundaries and affords only indirect information about key tumor pathophysiology. With the emergence of PET imaging with new oncology radiotracers, mapping of tumor infiltration and other important molecular events such as hypoxia is now feasible within the clinical setting. In particular, the importance of imaging hypoxia levels within the tumoral microenvironment is gathering interest, as hypoxia is known to play a central role in glioma pathogenesis and resistance to treatment. One of the hypoxia radiotracers known for its clinical utility is (18)F-fluoromisodazole ((18)F-FMISO). In this review, we highlight the typical causes of treatment failure in gliomas that may be linked to hypoxia and outline current methods for the detection of hypoxia. We also provide an overview of the growing body of studies focusing on the clinical translation of (18)F-FMISO PET imaging, strengthening the argument for the use of (18)F-FMISO hypoxia imaging to help optimize and guide treatment strategies for patients with glioblastoma.

PET, MRI, and simultaneous PET/MRI in the development of diagnostic and therapeutic strategies for glioma.

Glioma is the most aggressive brain tumour, resulting in death often within 1-2 years. Current treatment strategies involve surgical resection followed by chemoradiation therapy. Despite continuing improvements in the delivery of adjuvant therapies, there has not been a dramatic increase in survival for glioma. Molecular imaging techniques have become central in the development of new therapeutic strategies in recent years. The multimodal imaging technology of positron emission tomography/magnetic resonance imaging (PET/MRI) has recently been realised on a preclinical scale and the effect of this technology is starting to be observed in preclinical drug development for glioma. Here, we propose that PET/MRI will play an integral part in the development of new diagnostic and therapeutic strategies for glioma.

Gender-specific activity of chemotherapy correlates with outcomes in chemosensitive cancers of young adulthood

Good evidence indicates that adolescents and young adults (AYAs) with cancer do badly compared with children with similar cancers. The reasons are poorly understood. Australian registry data on 14,824 cancers of adolescence and young adulthood seen between 1982 and 2002 were reviewed. A detailed substudy of clinical characteristics was analyzed from 179 AYAs with Hodgkin lymphoma (HL), Ewing sarcoma (ES) or osteosarcomas (OS) treated at a single institution. Despite significant improvements in survival for both groups over the period in question, for acute lymphoblastic leukaemia, rhabdomyosarcoma, ES, OS and HL, survival for AYAs was worse than for children. For ES, OS and HL, the survival gap occurred almost entirely in males (Hazard ratios compared with female AYAs of 1.8 [p < 0.01], 1.4 [p = 0.03] and 1.5 [p < 0.01] respectively). Survival outcomes from ES, OS and HL for female AYAs were not significantly different from children of either sex. For brain tumors and thyroid cancers, which are primarily treated surgically, there were no gender‐related differences in outcomes. Although no differences in tumor stage or compliance were identified, male AYAs experienced less toxicity and lower response rates to chemotherapy (p = 0.008). Young males account almost entirely for excess mortality from chemosensitive cancers of adolescence and young adulthood compared to children, which may be due to relative underdosing with current chemotherapy dosing algorithms.

Increasing feasibility and utility of 18F-FDOPA PET for the management of glioma

INTRODUCTION Despite radical treatment therapies, glioma continues to carry with it a uniformly poor prognosis. Patients diagnosed with WHO Grade IV glioma (glioblastomas; GBM) generally succumb within two years, even those with WHO Grade III anaplastic gliomas and WHO Grade II gliomas carry prognoses of 2-5 and 2 years, respectively. PET imaging with (18)F-FDOPA allows in vivo assessment of the metabolism of glioma relative to surrounding tissues. The high sensitivity of (18)F-DOPA imaging grants utility for a number of clinical applications. METHODS A collection of published work about (18)F-FDOPA PET was made and a critical review was discussed and written. RESULTS A number of research papers have been published demonstrating that in conjunction with MRI, (18)F-FDOPA PET provides greater sensitivity and specificity than these modalities in detection, grading, prognosis and validation of treatment success in both primary and recurrent gliomas. In further comparisons with (11)C-MET, (18)F-FLT, (18)F-FET and MRI, (18)F-FDOPA has shown similar or better efficacy. Recently synthesis cassettes have become available, making (18)F-FDOPA more accessible. CONCLUSIONS According to the available data, (18)F-FDOPA PET is a viable radiotracer for imaging and treatment planning of gliomas. ADVANCES IN KNOWLEDGE AND IMPLICATION FOR PATIENT CARE (18)F-FDOPA PET appears to be a viable radiopharmaceutical for the diagnosis and treatment planning of gliomas cases, improving on that of MRI and (18)F-FDG PET.

Percutaneous CT-guided thermal ablation as salvage therapy for recurrent non-small cell lung cancer after external beam radiotherapy: A retrospective study

Abstract Purpose: The aim of this study was to evaluate radiofrequency ablation (RFA) and microwave ablation (MWA) as a viable salvage option for patients with locally recurrent non-small cell lung cancer (NSCLC) after radiotherapy. Materials and methods: This retrospective study was conducted on patients who had received thermal ablation for recurrent NSCLC post-curative radiotherapy. Medical records and follow-up imaging with computed tomography (CT) and PET-CT were analysed to determine time to local progression (TTLP) and overall survival (OS). TTLP was determined according to the modified RECIST criteria. Results: Twelve patients, mean age 71 ± 7 years, received 17 thermal ablation sessions, with RFA performed for four lesions and MWA for 13. Nine tumours were squamous cell cancers (SCC) and eight were adenocarcinomas. Eleven tumours had recurred post-external beam radiation and one post-stereotactic body radiation therapy. Mean tumour size was 34.2 ± 12.8 mm, tumour stages prior to radiotherapy were Ia (2), Ib (3), IIa (4), IIb (1) and III (2). Follow-up period was 19 ± 11 months. Overall median TTLP was 14 months (95% CI: 8, 19), and median OS was 35 months (95% CI: 12, 58). Mean TTLP for tumours <30 mm was 23 months and for tumours >30 mm 14 months (p = 0.20). Recurrence rates reduced from 50% after initial ablation to 20% with a second ablation. Complication rate for pneumothorax requiring intervention was 17%. Conclusion: Both RFA and MWA ablation prolonged local tumour control with minimal morbidity in this study group of recurrent NSCLC after radiotherapy.

Valproate in Adjuvant Glioblastoma Treatment

TO THE EDITOR: We are a group of clinicians and researchers who have been studying the effect of sodium valproate (VPA) in glioblastoma (GBM) since 2010. The study recently published in Journal of Clinical Oncology by Happold et al pooled a number of trial data sets to study a variety of interventions for glioblastoma in which patients had taken anticonvulsants, including VPA. The study concluded that VPA showed no benefit on survival. The motivation for the publication may be to dissuade clinicians from using VPA in the absence of a randomized prospective phase III trial that shows evidence of progression-free or overall survival benefit. However, the analysis may prematurely discourage other groups from studying the interaction between VPA and chemoradiotherapy as well as clinical outcomes with older drug therapies. This type of analysis typically suffers from bias because the included trials were not equipped to answer the question of whether VPA improves survival in GBM. Without identification and control of confounders, the significance of the findings is compromised. An example of a biased GBM study that led to potentially poor practice is the recommendation to avoid VPA as an anticonvulsant around the time of surgery based on reports of increased incidence of bleeding. However, sicker patients with larger or more aggressive tumors were more likely to have received VPA because of their increased likelihood of having seizures. A large tumor cavity itself,