Day: 11/13/2010

High-Dose Methotrexate With or Without Whole Brain Radiotherapy for Primary CNS Lymphoma

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Although whole brain radiotherapy has a role in disease control, the absence of a survival benefit in this study could justify its omission from first-line treatment in primary CNS lymphoma.

Background: High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival.

Methods: Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (<60 vs ≥60 years) and institution (Berlin vs Tübingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m2) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1•5 g/m2) on days 3–5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1•5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0•9. This trial is registered with ClinicalTrials.gov, number NCT00153530.

Findings: 551 patients (median age 63 years, IQR 55–69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32•4 months (95% CI 25•8–39•0) in patients receiving whole brain radiotherapy (n=154), and 37•1 months (27•5–46•7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1•06 (95% CI 0•80–1•40; p=0•71). Thus our primary hypothesis was not proven. Median progression-free survival was 18•3 months (95% CI 11•6–25•0) in patients receiving whole brain radiotherapy, and 11•9 months (7•3–16•5; p=0•14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%).

Interpretation: No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors.

Vascular Events After Invasive Dental Procedures

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A case-series analysis raises questions about inflammation and risk, bolstering recommendations to continue aspirin therapy during minor surgery.

Periodontal disease is a known risk factor for cardiovascular events, but might an association exist between therapeutic dental procedures and acute vascular events? To find out, investigators conducted a self-controlled case-series analysis of Medicaid claims data from 2002 through 2006.

Of 20,369 adults (median age, 67.3) with at least one primary hospital discharge diagnosis of myocardial infarction (MI) or ischemic stroke, 1152 had undergone at least one invasive dental procedure. In this cohort (ischemic stroke, 629; MI, 504; both, 19), the mean duration of observation was 4.2 years. The rate of vascular events was significantly increased in the first 4 weeks — and gradually declined within 6 months — after invasive dental procedures, compared with other periods. None of the vascular events occurred on the day of the dental procedure. Excluding patients with diabetes, hypertension, or coronary artery disease did not affect the results.

Comment: These findings challenge the assumption that patients undergoing invasive dental procedures are at low risk for cardiovascular events. As editorialists note, most of the events occurred in women, and 30% occurred in patients younger than 50. The short-term risk of dental procedures must be weighed against the long-term cardiovascular benefits of alleviating periodontal disease. No direct evidence from this study suggests that inflammation is a causative mechanism in vascular events that occur after dental procedures. However, clinicians would be prudent to heed guideline recommendations to continue aspirin therapy during and immediately after minor surgical procedures.

— Joel M. Gore, MD

Published in Journal Watch Cardiology November 10, 2010

Vitamin B Supplementation and Cognition

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In older men, supplementation did not affect cognition.

Because high plasma homocysteine levels are associated with cognitive impairment in epidemiologic studies, in multiple clinical trials researchers have examined whether vitamin B supplementation — which lowers homocysteine levels — improves cognition or delays onset of cognitive impairment in older adults; results have been mostly negative. In a new study, Australian researchers randomized 299 community-dwelling hypertensive men (age, ≥75) without dementia to receive either placebo or a combination of vitamin B6, vitamin B12, and folic acid.

During 2 years of treatment, no differences between groups were noted on several measures of cognition. Even in subgroups in which benefit seemed likely — men with high baseline homocysteine levels (≥15 µmol/L) and men with mild cognitive impairment at baseline — the investigators found no benefit from vitamin B supplementation.

Comment: This study adds to a growing body of evidence that vitamin B supplementation does not favorably affect cognition in older adults. One possible inference is that homocysteine is a marker — not a cause — of cognitive impairment in older adults.

— Allan S. Brett, MD

Published in Journal Watch General Medicine November 10, 2010

Isotretinoin Use Associated with Increased Risk for Suicide Attempts in Patients with Severe Acne

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The risk for attempted suicide increases during and after treatment with isotretinoin (Accutane) in patients with severe acne, according to a retrospective study in BMJ.

Swedish researchers assessed suicide attempts requiring hospitalization in nearly 5800 patients with severe acne who were prescribed isotretinoin. Within 6 months after treatment started, patients had an increased risk for first suicide attempt and for all attempts, compared with the general population. Within 3 years after treatment, suicide attempts returned to the background rate.

The authors point to a gradually increasing suicide risk in the 3 years before treatment. They write: “We cannot exclude the possibility that the raised risk of suicide attempts during treatment and six months after treatment is due to the exposure to isotretinoin. However, a more probable interpretation is that the underlying severe acne may best explain the raised risk.”

Editorialists recommend that primary care physicians monitor all patients with severe acne for suicidal intent before, during, and after treatment.

The risk for attempted suicide increases during and after treatment with isotretinoin (Accutane) in patients with severe acne, according to a retrospective study in BMJ.

Swedish researchers assessed suicide attempts requiring hospitalization in nearly 5800 patients with severe acne who were prescribed isotretinoin. Within 6 months after treatment started, patients had an increased risk for first suicide attempt and for all attempts, compared with the general population. Within 3 years after treatment, suicide attempts returned to the background rate.

The authors point to a gradually increasing suicide risk in the 3 years before treatment. They write: “We cannot exclude the possibility that the raised risk of suicide attempts during treatment and six months after treatment is due to the exposure to isotretinoin. However, a more probable interpretation is that the underlying severe acne may best explain the raised risk.”

Editorialists recommend that primary care physicians monitor all patients with severe acne for suicidal intent before, during, and after treatment.

Tesamorelin Approved to Treat Lipodystrophy in HIV-Infected Patients

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The FDA has approved tesamorelin (Egrifta) to treat HIV-infected patients with lipodystrophy, a side effect of many antiretroviral agents.

The drug, a growth hormone-releasing factor, is given once daily as an injection.

Approval was based on two clinical trials, comprising some 800 patients, in which those treated with tesamorelin had greater reductions in abdominal fat than those treated with placebo. The most common adverse effects were arthralgia, stomach pain, swelling, myalgia, and erythema and pruritus at the injection site.

 

Hydrochlorothiazide Versus Chlorthalidone in the Management of Hypertension

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Neff KM et al. – Although there are favorable trends both in terms of antihypertensive efficacy as well as clinical outcomes data with chlorthalidone compared with hydrochlorothiazide (HCTZ), the results are not conclusive, and as such may not be enough to shift the treatment paradigm in favor of chlorthalidone, given the comfort level that most prescribers have with HCTZ. A head–to–head study looking at hard clinical outcomes, which may or may not ever be performed, may be the only way to resolve the ongoing debate as to which is the preferred thiazide for treating hypertension.