Comparative effectiveness of radiotherapy with vs. without temozolomide in older patients with glioblastoma

It is unknown whether the addition of temozolomide (TMZ) to radiotherapy (RT) is associated with improved overall survival (OS) among older glioblastoma patients. We performed a retrospective cohort SEER-Medicare analysis of 1652 patients aged ≥65 years with glioblastoma who received ≥10 fractions of RT from 2005 to 2009, or from 1995 to 1999 before TMZ was available. Three cohorts were assembled based on diagnosis year and treatment initiated within 60 days of diagnosis: (1) 2005–2009 and TMZ/RT, (2) 2005–2009 and RT only, or (3) 1995–1999 and RT only. Associations with OS were estimated using Cox proportional hazards models and propensity score analyses; OS was calculated starting 60 days after diagnosis. Pre-specified sensitivity analyses were performed among patients who received long-course RT (≥27 fractions). Median survival estimates were 7.4 (IQR, 3.3–14.7) months for TMZ/RT, 5.9 (IQR, 2.6–12.1) months for RT alone in 2005–2009, and 5.6 (IQR, 2.7–9.6) months for RT alone in 1995–1999. OS at 2 years was 10.1?% for TMZ/RT, 7.1?% for RT in 2005–2009, and 4.7?% for RT in 1995–1999. Adjusted models suggested decreased mortality risk for TMZ/RT compared to RT in 2005–2009 (AHR, 0.86; 95?% CI, 0.76–0.98) and RT in 1995–1999 (AHR, 0.71; 95?% CI, 0.57–0.90). Among patients from 2005 to 2009 who received long-course RT, however, the addition of TMZ did not significantly improve survival (AHR, 0.91; 95?% CI, 0.80–1.04). In summary, among a large cohort of older glioblastoma patients treated in a real-world setting, the addition of TMZ to RT was associated with a small survival gain.     

Impact of pemetrexed on intracranial disease control and radiation necrosis in patients with brain metastases from non-small cell lung cancer receiving stereotactic radiation

Background

Pemetrexed is a folate antimetabolite used in the management of advanced adenocarcinoma of the lung. We sought to assess the impact of pemetrexed on intracranial disease control and radiation-related toxicity among patients with adenocarcinoma of the lung who received stereotactic radiation for brain metastases.

PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human malignant gliomas

The phosphoinositide 3-kinase (PI3-kinase) signaling pathway is frequently aberrantly activated in glioblastoma multiforme (GM) by mutation or loss of the 3 phospholipid phosphatase PTEN. PTEN abnormalities result in inappropriate signaling to downstream molecules including protein kinase B (PKB/Akt), and mammalian target of rapamycin (mTOR). PI3-kinase activation increases resistance to radiation-induced cell death; conversely, PI3-kinase inhibition enhances the sensitivity of tumors to radiation. The effects of LY294002, a biochemical inhibitor of PI3-kinase, on the response to radiation were examined in the PTEN mutant glioma cell line U251 MG. Low doses of LY294002 sensitized U251 MG to clinically relevant doses of radiation. In contrast to LY294002, rapamycin, an inhibitor of mTOR, did not result in radiosensitization. We demonstrate that among multiple known targets of LY294002, PI3-kinase is the most likely molecule responsible for LY294002-induced radiosensitization. Furthermore, using a myristoylated PKB/Akt construct, we identified PKB/Akt as the downstream molecule that mediates the synergistic cytotoxicity between LY294002 and radiation. Thus PI3-kinase dysregulation may contribute to the notable radioresistance of GM tumors and inhibition of PKB/Akt offers an excellent target to enhance radiosensitivity.     

Brain metastases after breast-conserving therapy and systemic therapy: incidence and characteristics by biologic subtype

The characteristics of brain metastases (BM) that develop after breast-conserving therapy (BCT) for early-stage breast cancer (BC) remain incompletely defined. We examined 1,434 consecutive patients with stage I/II invasive BC who received BCT from 1997 to 2006, 91?% of whom received adjuvant systemic therapy, according to BC subtype. Median follow-up was 85?months. Overall 5-year cumulative incidence of BM was 1.7?%; 0.1?% for luminal A, 3.3?% for luminal B, 3.2?% for luminal-HER2, 3.7?% for HER2, and 7.4?% for triple negative (TN). Women who developed BM were more likely at BC diagnosis to be younger (P?<?.0001) and have node-positive (P?<?.0001), grade 3 (P?<?.0001), hormone receptor-negative (P?=?.006), and HER2-positive (P?=?.01) tumors. Median time from BC diagnosis to BM was 51.4?months (range, 7.6?C108?months), which was longer among luminal versus non-luminal subtypes (P?=?.0002; median, 61.4 vs. 34.5?months). Thirty-four percent of patients who developed distant metastases (DM) eventually developed BM. Median time from DM to BM was 12.8?months but varied by subtype, including 7.4?months for TN, 9.6?months for luminal B, and 27.1?months for HER2. Eighty-one percent of all BM patients presented with neurologic symptoms. Median number of BM at diagnosis was two, and median BM size was 15?mm, with TN (27?mm) and luminal B (16?mm) exhibiting the largest median sizes. In conclusion, the risk of BM after BCT varies significantly by subtype. Given the large size and symptomatic presentation among luminal B and TN subtypes, earlier BM detection might improve quality of life or increase eligibility for non-invasive treatments including stereotactic radiosurgery. Women with DM from these two BC subtypes have a high incidence of BM with a short latency, suggesting an ideal target population for trials evaluating the utility of MRI screening.     

Antihypertensive efficacy of metoprolol XL/Low dose chlorthalidone (6.25 mg) combination: a randomized,comparative study in Indian patients with mild-to-moderate essential hypertension

Objective

High blood pressure is one of the most important risk factors, directly responsible for increasing the cardiovascular morbidity and mortality. The primary objective was to evaluate the efficacy of metoprolol XL/chlorthalidone against metoprolol XL/hydrochlorothiazide with respect to mean fall in systolic and diastolic blood pressure. The secondary objective was to compare the response rates and to evaluate the tolerability of study medications in patients with mild-tomoderate essential hypertension.

Methods

Total 130 eligible patients (65: metoprolol XL 25 mg/chlorthalidone 6.25 mg; 65: metoprolol XL 25 mg/HCTZ 12.5 mg) were enrolled in this randomized, comparative, multicentric, 12-weeks study. Sixty-two patients from each group completed the study. After 4-weeks of treatment, non-responders from chlorthalidone 6.25 mg combination group were shifted to metoprolol XL 50 mg/chlorthalidone 12.5 mg and non-responders from HCTZ 12.5 mg combination group were escalated to metoprolol XL 50 mg/HCTZ 12.5 mg.

Results

The study treatment groups were comparable with respect to demography and baseline disease characteristics. Both the starting therapies were comparable with respect to mean fall in SBP (p = 0.788) and DBP (p = 0.939), and response rates (p = 1.0) after 4-weeks of therapy. Also both the step-up therapies showed similar mean fall in SBP (p = 0.277) and DBP (p = 0.507) at the end of 12-weeks. However, significantly more number of patients from chlorthalidone 12.5 mg/metoprolol XL 50 mg group responded to therapy as compared to that from HCTZ 12.5 mg/metoprolol XL 50 mg group (p = 0.045). All the reported adverse events were of mild-to-moderate intensity. There were no clinically significant trends in electrolytes (Na⁺, K⁺, Cl^-)and fasting blood sugar, evident across the treatment groups.

Conclusion

Chlorthalidone in combination with metoprolol XL is as effective and well tolerated as widely used combination of metoprolol XL/HCTZ, thus providing an alternative therapeutic option.