Corrigendum to: Impact of lymphopenia on survival for elderly patients with glioblastoma: A secondary analysis of the CCTG CE.6 (EORTC 26062-22061, TROG 08.02) randomized clinical trial.

[This corrects the article DOI: 10.1093/noajnl/vdab153.].

Impact of lymphopenia on survival for elderly patients with glioblastoma: A secondary analysis of the CCTG CE.6 (EORTC 26062-22061, TROG03.01) randomized clinical trial.

BACKGROUND: Lymphopenia may lead to worse outcomes for glioblastoma patients. This study is a secondary analysis of the CCTG CE.6 trial evaluating the impact of chemotherapy and radiation on lymphopenia, and effects of lymphopenia on overall survival (OS). METHODS: CCTG CE.6 randomized elderly glioblastoma patients (≥ 65 years) to short-course radiation alone (RT) or short-course radiation with temozolomide (RT + TMZ). Lymphopenia (mild-moderate: grade 1-2; severe: grade 3-4) was defined per CTCAE v3.0, and measured at baseline, 1 week and 4 weeks post-RT. Preselected key factors for analysis included age, sex, ECOG, resection extent, MGMT methylation, Mini-Mental State Examination, and steroid use. Multinomial logistic regression and multivariable Cox regression models were used to identify lymphopenia-associated factors and association with survival. RESULTS: Five hundred and sixty-two patients were analyzed (281 RT vs 281 RT+TMZ). At baseline, both arms had similar rates of mild-moderate (21.4% vs 21.4%) and severe (3.2% vs 2.9%) lymphopenia. However, at 4 weeks post-RT, RT+TMZ was more likely to develop lymphopenia (mild-moderate: 27.9% vs 18.2%; severe: 9.3% vs 1.8%; p<0.001). Developing any lymphopenia post-RT was associated with baseline lymphopenia (P < .001). Baseline lymphopenia (hazard ratio [HR] 1.3) was associated with worse OS (HR: 1.30, 95% confidence interval [CI] 1.05-1.62; P = .02), regardless of MGMT status. CONCLUSIONS: Development of post-RT lymphopenia is associated with addition of TMZ and baseline lymphopenia and not with RT alone in patients treated with short-course radiation. However, regardless of MGMT status, only baseline lymphopenia is associated with worse OS, which may be considered as a prognostic biomarker for elderly glioblastoma patients.

Temozolomide and seizure outcomes in a randomized clinical trial of elderly glioblastoma patients.

INTRODUCTION: Tumor-related epilepsy may respond to chemotherapy. In a previously-published multi-centre randomized clinical trial of 562 elderly glioblastoma patients, temozolomide plus short-course radiotherapy conferred a survival benefit over radiotherapy alone. Seizure outcomes were not reported. METHODS: We performed an unplanned secondary analysis of this trial's data. The trial design has been previously reported. Seizures were recorded by clinicians as adverse events and by patients in quality of life questionnaires. A Chi-square test of seizure rates between the two groups (α = 0.05) and a Kaplan-Meier estimator of time-to-first self-reported seizure were planned. RESULTS: Almost all patients were followed until they died. In the radiotherapy alone group, 68 patients (24%) had a documented or self-reported seizure versus 83 patients (30%) in the temozolomide plus radiotherapy group, Chi-square analysis showed no difference (p = 0.15). Patients receiving radiotherapy alone tended to develop seizures earlier than those receiving temozolomide plus radiotherapy (p = 0.054). Patients with seizures had shorter overall survival than those without seizures (hazard ratio 1.24, p = 0.02). CONCLUSIONS: This study was not powered to detect differences in seizure outcomes, but temozolomide seemed to have minimal impact on seizure control in elderly patients with glioblastoma. CLINICAL TRIAL REGISTRATION: NCT00482677 2007-06-05.

A phase I study of romidepsin, gemcitabine, dexamethasone and cisplatin combination therapy in the treatment of peripheral T-cell and diffuse large B-cell lymphoma; the Canadian cancer trials group LY.15 study†.

We investigated GDP (gemcitabine, 1000 mg/m2 IV d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m2 IV d1) combined with romidepsin on days 1 and 8 every 21 days to a maximum of six cycles in a standard 3 + 3, phase I dose escalation trial for patients with relapsed/refractory peripheral T-cell (PTCL) or diffuse large B-cell (DLBCL) lymphoma (NCT01846390). After treating four patients, gemcitabine and romidepsin were given on days 1 and 15 every 28 days. On the 21-day schedule at 6 mg/m2 romidepsin, there were three dose-limiting toxicities (DLTs) among four patients. On the 28-day schedule, there were no DLTs at the 6, 8, or 10 mg/m2 dose. At 12 mg/m2, there were four observed grade 3 DLTs among six evaluable patients. Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m2 if given on a day 1, 15 every 28 days schedule.

The Future Is Now-Prospective Study of Radiosurgery for More Than 4 Brain Metastases to Start in 2018!

Stereotactic radiosurgery (SRS) has replaced whole brain radiotherapy (WBRT) as standard therapy for most patients with four or fewer brain metastases due to improved cognitive outcomes and more favorable health related quality of life (QoL). Whether SRS or WBRT is the optimal radiation modality for patients with five to fifteen brain metastases remains an open question. Efforts are underway to develop prospective evidence to answer this question. One of the planned trials is a Canadian Cancer Trials Group (CCTG)-lead North American intergroup trial. In general cancer treatments must have two basic aims: prolonging and improving QoL. In this vein, the selection of overall survival and QoL metrics as outcomes appear obvious. Potential secondary outcomes are numerous: patient/disease related, treatment related, economic, translational, imaging, and dosimetric. In designing a trial, one must also ponder what is standard WBRT-specifically, whether it should be associated with memantine. With the rapid accrual of an intergroup trial of hippocampal-sparing WBRT, we may find that the standard WBRT regimen changes in the course of planned trials. As up-front radiosurgery is increasingly used for more than 4 brain metastases without high level evidence, we have a window of opportunity to develop high quality evidence which will help guide our future clinical and policy decisions.

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 .).