WE ARE THE CHAMPIONS

Figure 1. Total antimicrobial drug consumption in ambulatory care in defined daily doses per 1,000 inhabitants per day (DID) by antimicrobial class in 21 European countries in 2004.

NUTRITIONAL SUPPLEMENTS DO NOT PREVENT CANCER

Common Nutritional Supplements Do Not Prevent Cancer in Women

November 4, 2008 — Folic acid, vitamin B₆, and vitamin B₁₂ — all of which are thought to play a role in cancer prevention and are common ingredients in multivitamin supplements — have no significant effect on cancer risk in women.

This conclusion comes from the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a randomized trial of 5442 female health professionals in the United States who had an average age of 62.8 years at baseline and who were observed for an average of 7.3 years.

"Our trial says that this [using the 3 nutritional supplements daily] does not appear to be an effective approach to preventing cancer in women. We know that there are other things that women can do that help prevent cancer, such as stopping smoking and exercising," said lead author Shumin M. Zhang, MD, ScD, associate professor of medicine at Harvard Medical School in Boston, Massachusetts, in an interview with Medscape Oncology.

"There is very good biology behind the hypothesis that they [the 3 nutritional supplements] could play a role in cancer prevention," she added. Approximately one third of adults in the United States take multivitamin supplements containing folic acid, vitamin B₆, and vitamin B₁₂, according the authors of the study, which appears in the in the November 5 issue of the Journal of the American Medical Association.

Despite its main conclusion, the study reveals that 1 treatment subgroup received some benefit: women aged 65 years or older at study entrance had a significantly reduced risk for overall cancer and breast cancer. "This effect in older women may be due to chance," said Dr. Zhang, who said the finding needs to be further substantiated.

The study also serves as further evidence that folic acid (the synthetic form of folate) does not appear to increase cancer occurrences when taken as a daily supplement.

Study Results and a Note of Doubt

WAFACS is a study that is the outgrowth of a parent trial, the Women's Antioxidant Cardiovascular Study. As a result, the women in WAFACS are all older than 42 years and have preexisting cardiovascular disease (CVD) or 3 or more coronary risk factors.

In the randomized WAFACS, participants took either a daily combination of 2.5 mg of folic acid, 50 mg of vitamin B₆, 1 mg of vitamin B₁₂, or a matching placebo starting in 1998. The doses are higher than the adult recommended daily allowances for folate (400 μg/day), vitamin B₆ (1.5 mg/day), and vitamin B₁₂ (2.4 μg/day) in women. The mean age for the women participants was 62.8 years, and the mean body mass index was 30.6 kg/m².

Cancer developed in a total of 379 women (n = 187, treatment group; n = 192, placebo group) during the study, which ended in 2005. Treatment with supplements had no significant effect on the risk for total cancer (101.1/10,000 person-years for the active treatment group vs 104.3/10,000 person-years for the placebo group; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.79 - 1.18; P = .75) or individual cancer endpoints, including breast, colorectal, lung, and uterine cancer. There was also no difference in cancer death or death from any cause.

The lack of effect, beneficial or harmful, of the supplements on cancer risk in these women may be related to the length of the study and latency period of cancer, admitted the study authors.

"Because cancer has a long latency period, we cannot exclude the possibility that there might be beneficial or harmful effects of combined B vitamins on cancer that were not detectable within 7.3 years of treatment," write the authors.

The current study also notes that there were no differences according to current use of multivitamin supplements at the start of the study; intakes of total folate, vitamin B₆, and vitamin B₁₂; or a history of cancer or other risk factors at baseline. Lack of effect for total cancer did not vary with time.

However, among the women in the trial in whom breast cancer developed and who received the supplements, the study shows a "borderline" significant reduction for estrogen receptor–positive and progesterone receptor–negative tumors.

What Other Large Trials Have Shown

Two other large, randomized trials assessing folic acid, vitamin B₆, and vitamin B₁₂ in relationship to CVD risk have reported similar cancer outcomes but during fewer years, according to the study authors.

In the Heart Outcomes Protection Evaluation-2 trial, an average of 5 years of treatment with the same daily combination of 2.5 mg of folic acid, 50 mg of vitamin B₆, and 1 mg of vitamin B₁₂ had no significant effect on the risk for total cancer; cancers of the breast, colon, lung, or prostate; or cancer death. Also, 71.1% of participants were from countries with folic acid fortification, which has been proven to reduce the risk for neural tube defects.

The Norwegian Vitamin Trial in Norway, a country that has no mandatory folic acid fortification in foods, also reported no effect on cancer outcomes in a placebo-controlled trial, with an average of 3.3 years of treatment and follow-up. Compared with the placebo group, there was no difference in cancer risk in those patients receiving the combined folic acid (0.8 mg), vitamin B₆ (40 mg), and vitamin B₁₂ (0.4 mg) treatment or combined folic acid (0.8 mg) and vitamin B₁₂ (0.4 mg) treatment at an average of 3.3 years of treatment and follow-up. However, in this trial, there was a suggestion of beneficial effect on cancer risk in those patients treated with vitamin B₆ alone vs those assigned to placebo.

These 3 trials, including WAFACS, are an endorsement of the safety of folic acid daily supplementation with regard to cancer risk, suggest the study authors. The combined data from these randomized trials of combined B vitamins provide "reassurance that folic acid supplementation up to a dose of 2.5 mg/d when combined with vitamin B₆ and vitamin B₁₂ does not appear to increase cancer occurrences and deaths among individuals at high risk for CVD during the folic acid fortification era" write the study authors. Folate has been a concern because of its potential to promote tumor development when administered late in carcinogenesis, note the study authors.

A Note on Participant Adherence

Participant adherence to the pill-taking regimen seemed strong in the new study. Adherence is defined as taking at least two thirds of the study pills during the course of participation; adherence was 83% for both treatment and placebo groups. Also, in a random sample of 300 women, there were no differences in median plasma folate levels between the 2 groups at the start of the study, but it was significantly higher at the end of the trial, which is a sign of participant adherence.

AN OLD DRUG MAY PREVENT DIABETES

Hydroxychloroquine May Prevent Diabetes in Patients With Rheumatoid Arthritis

NEW YORK (Reuters Health) Oct 29 - The risk of developing diabetes is cut in half among rheumatoid arthritis patients who use hydroxychloroquine for treatment, according to research findings reported this week at the American College of Rheumatology Annual Scientific Meeting in San Francisco.

"People with rheumatoid arthritis are at increased risk for diabetes, due to sedentary lifestyle, chronic inflammation, and use of steroid medications that can cause weight gain," Dr. Androniki Bili told Reuters Health prior to her presentation.

"A study published in JAMA in 2007 showed an impressive 77% reduction of new cases of diabetes in rheumatoid arthritis patients who took hydroxychloroquine for more than 4 years," she added.

Because that research was based on patient self-report, she and her associates sought to verify those findings using the electronic health records database maintained at the Geisinger Medical Center in Danville, Pennsylvania.

The patient cohort comprised 1824 RA patients without diabetes at baseline; 525 had used hydroxychloroquine and 1299 had never used the drug.

During a mean follow-up of 3 years, diabetes was diagnosed in 16 hydroxychloroquine users and 154 never-users (incidence rates 17.2 vs 33.8 per 1000 patient-years), the investigators report in their meeting abstract.

The hazard ratio for incident diabetes with hydroxychloroquine use versus without was 0.47 (p = 0.008) after controlling for demographics, BMI, clinical factors, and medications.

"We should revisit hydroxychloroquine in the treatment of rheumatoid arthritis, because in addition to its disease-modifying properties, it might prevent the development of diabetes in this high risk group," Dr. Bili stated. "Given the relative safety and low cost of this generic drug, hydroxychloroquine may be useful in preventing diabetes in other high risk groups as well."

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BETTER SURVIVAL FOR CHILDHOOD HEMATOLOGIC MALIGNANCIES

Background: Advances in the treatment of childhood hematologic malignancies have led to improvements in survival for several of these conditions during the past few decades, but most population-based survival data available to date refer only to patients diagnosed up to the mid-1990s.
Methods: We used period analysis to assess trends in 5- and 10-year survival in US patients younger than 15 years of age at diagnosis with four hematologic malignancies -- acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma -- over three recent 5-year intervals, 1990-1994, 1995-1999, and 2000-2004, using data on a total of 6957 patients from the Surveillance, Epidemiology, and End Results database. Expected survival for 2005-2009 was estimated by modeling from trends in the preceding intervals.
Results: Major improvements in 5- and 10-year relative survival between 1990-1994 and 2000-2004 were seen for acute lymphoblastic leukemia (from 80.2% to 87.5% and from 73.4% to 83.8%, respectively), acute non-lymphoblastic leukemia (from 41.9% to 59.9% and from 38.7% to 59.1%, respectively), and non-Hodgkin lymphoma (from 76.6% to 87.7% and from 73.0% to 86.9%, respectively). For those diagnosed with Hodgkin lymphoma, 5- and 10-year survival rates for the 1990-1994 period were 96.1% and 94.4%, respectively, and these rates did not change substantially in the later time periods. Projected 10-year survival rates for children diagnosed in the 2005-2009 period were 88.0% for acute lymphoblastic leukemia, 63.9% for acute non-lymphoblastic leukemia, 90.6% for non-Hodgkin lymphoma, and 94.3% for Hodgkin lymphoma.
Conclusions: Application of period analysis to a population-based study of childhood hematologic malignancies reveals ongoing increases in survival for three of the four common childhood hematologic malignancies.

A RARE EVENT AFTER BREAST IMPLANT

Breast Implants May Increase Risk of Rare Cancer

NEW YORK (Reuters Health) Nov 04 - The results of a case-control study suggest that silicone breast prostheses may increase the risk of developing anaplastic large T-cell lymphoma (ALCL) of the breast. However, the authors emphasize that because the malignancy is so rare in general, the absolute risk is still very low.

Dr. Daphne de Jong, from The Netherlands Cancer Institute, Amsterdam, and colleagues evaluated the association after identifying two patients who had ALCL in the fibrous capsule surrounding their silicone breast implants. Although similar cases had been reported in the literature, no formal studies had examined the topic.

A search of a Netherlands pathology database identified 11 women (median age 40 years) who were diagnosed with ALCL of the breast from 1990 to 2006. Each case patient was matched by age and year of diagnosis to one or more controls (n = 35) with other types of lymphomas in the breast.

Five of the case patients had received bilateral silicone breast prostheses 1 to 23 years prior to diagnosis, the authors report in the Journal of the American Medical Association for November 5. In all five, the prostheses were placed for cosmetic reasons.

The most common lymphoma in the control group was diffuse large B-cell lymphoma, followed by mucosa-associated lymphoid tissue-type lymphoma. Just 1 of the 35 control patients had a breast implant prior to their lymphoma diagnosis.

"The odds ratio for ALCL in the breast associated with silicone breast prosthesis placed for cosmetic reasons was 18.2," the investigators calculate.

As noted, though, the absolute risk of ALCL with silicone breast implants is exceedingly small. The authors calculate that just 0.1 to 0.3 cases per 100,000 women with implants would arise per year.

"These findings must be considered preliminary and hypothesis-generating and are not strong enough to definitively conclude that breast implants predispose women to non-Hodgkin lymphoma," Dr. Andrew M. Evens and Dr. Brian C.-H. Chiu, from Northwestern University, Chicago, write in an accompanying editorial.

"However," they add, "given that silicone is immunogenic, further evaluation of breast implant-related lymphoma is warranted, particularly by studies with statistical power, sufficient follow-up, and information on other factors."

PET-CT NOT SO ACCURATE AFTER RITUXIMAB

Ann Oncol. 2008 Oct 7. [Epub ahead of print]

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High incidence of false-positive PET scans in patients with aggressive non-Hodgkin's lymphoma treated with rituximab-containing regimens.

Han HS, Escalón MP, Hsiao B, Serafini A, Lossos IS.

Division of Hematology and Oncology, The Sylvester Comprehensive Cancer Center.

BACKGROUND: Positron emission tomography (PET) is a powerful predictor of relapse and survival in non-Hodgkin's lymphomas (NHLs) based on studies carried out in the prerituximab era. Little is known about the predictive power of PET in rituximab-treated patients. PATIENTS AND METHODS: Patients with aggressive B-cell NHL with baseline and follow-up PET studies were included. Clinical characteristics, PET and computed tomography scans, biopsy results, and outcomes were reviewed. PET was defined as positive if higher than mediastinal or background activity was observed. RESULTS: In all, 51 patients (diffuse large B cell-38; mantle cell lymphoma-13) treated with rituximab-containing regimens were included. For 13 of 40 patients (32.5%), mid-therapy PET studies were positive and 9 of 48 patients (18.7%) had positive posttherapy PET. The positive predictive value (PPV), negative predictive value (NPV), sensitivity (Se), and specificity (Sp) of the mid-therapy PET for predicting relapse were 33% [95% confidence interval (CI) 19% to 49%], 68% (95% CI 51% to 81%), 33% (95% CI 6% to 76%), and 68% (95% CI 49% to 82%), respectively. For posttherapy PET, the relapse PPV, NPV, Se and Sp were 19% (95% CI 9% to 33%), 81% (95% CI 67% to 91%), 13% (95% CI 0.6% to 53%), and 80%(95% CI 64% to 90%), respectively. CONCLUSIONS: Compared with previous reports in prerituximab era, addition of rituximab resulted in reduced PPV and sensitivity of mid- and posttherapy PET in patients with aggressive B-cell N