Clinical Health Updates

HPV DNA screening detects CIN3 and cancer earlier

Clinical Question:
Is screening for cervical cancer with human papillomavirus DNA testing in addition to cytology more effective than cytology alone?

Bottom Line:
Adding human papillomavirus DNA (HPV DNA) testing to cervical cancer screening programs has the potential to lead to earlier diagnoses of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). Future research should determine whether this will allow longer screening intervals.

Reference:
Bulkmans NW, Berkhof J, Rozendaal L, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: a 5-year follow-up of a randomized controlled implementation trial. Lancet 2007;370(9601):1764-1772.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented. Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131. 8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (> or =6.5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0.007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0.001). The number of CIN3+ lesions over the two rounds did not differ between groups.

Breast feeding interventions are effective

Clinical Question:
Does antenatal breast feeding education or postnatal lactation support improve the rates of exclusive breast feeding?

Bottom Line:
A short video explaining breast feeding and a 2-session postnatal counseling are both effective in increasing the number of women who use breast feeding exclusively. For every 10 to 11 women who receive either intervention, 1 additional woman will choose — and stick to — breast feeding.

Reference:
Su LL, Chong YS, Chan YH, et al. Antenatal education and postnatal support strategies for improving rates of exclusive breast feeding: randomised controlled trial. BMJ 2007;335(7620):596.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
The authors investigated whether antenatal breast feeding education alone or postnatal lactation support alone improves rates of exclusive breast feeding compared with routine hospital care. They did a randomized controlled trial in a tertiary hospital in Singapore. 450 women with uncomplicated pregnancies. Primary outcomes were rates of exclusive breast feeding at discharge from hospital and two weeks, six weeks, three months, and six months after delivery. Secondary outcomes were rates of any breast feeding. Compared with women who received routine care, women in the postnatal support group were more likely to breastfeed exclusively at two weeks (relative risk 1.82, 95% confidence interval 1.14 to 2.90), six weeks (1.85, 1.11 to 3.09), three months (1.87, 1.03 to 3.41), and six months (2.12, 1.03 to 4.37) postnatally. Women receiving antenatal education were more likely to breast feed exclusively at six weeks (1.73, 1.04 to 2.90), three months (1.92, 1.07 to 3.48), and six months (2.16, 1.05 to 4.43) postnatally. The numbers needed to treat to achieve one woman exclusively breast feeding at six months were 11 (6 to 80) for postnatal support and 10 (6 to 60) for antenatal education. Women who received postnatal support were more likely to exclusively or predominantly breast feed two weeks after delivery compared with women who received antenatal education (1.53, 1.01 to 2.31). The rate of any breastfeeding six weeks after delivery was also higher in the postnatal support group compared with women who received routine care (1.16, 1.02 to 1.31).

Clinical rule to diagnose PCOS more accurately

Clinical Question:
What are the key signs and symptoms for the diagnosis of polycystic ovarian syndrome?

Bottom Line:
A simple questionnaire completed by patients before they see the physician can assist in the diagnosis of polycystic ovarian syndrome (PCOS). It is limited by the fact that it has only been validated in a referral setting.

Reference:
Pedersen SD, Brar S, Faris P, Corenblum B. Polycystic ovary syndrome: validated questionnaire for use in diagnosis. Can Fam Physician 2007;53:1041-1047.

Study Design:
Decision rule (validation)

Synopsis:
These authors recruited patients referred to an endocrinology clinic for evaluation. This is a limitation of the study, since these patients have already been filtered by their primary care physicians who made the referral. Patients completed a detailed questionnaire, and then were evaluated by an endocrinologist who was masked to the questionnaire results and who made the final diagnosis of PCOS using standard NIH criteria. Fifty patients had PCOS, 50 did not. The best predictors of PCOS were identified, and the survey was then applied prospectively to a second group of 117 patients, 41 of whom had PCOS using the NIH criteria. The 4 best predictors were: (1) average duration of menstrual cycle greater than 34 days or totally variable; (2) 3 or more sites of dark, coarse hair; (3) obesity between the ages of 16 years and 40 years; and (4) no history of galactorrhea outside of pregnancy or recent childbirth. In the validation cohort, patients with 2 or more factors were likely to have PCOS (positive likelihood ratio = 13), while those with fewer than 2 of these factors were unlikely to have the syndrome (negative likelihood ratio = 0.16).

Cancer risk reduced with vitamin D/calcium supplementation

Clinical Question:
Does supplementation with calcium and vitamin D reduce cancer incidence in postmenopausal women?

Bottom Line:
Women receiving calcium and vitamin D, but not calcium alone, were less likely to develop a non-skin cancer over 4 years of supplementation. This is good news, though the study is too small to be definitive — despite enrolling more than 1000 women — since no single cancer incidence was reduced. The dose of vitamin D (1000 IU) was higher than what is typically used in research but can be found in several calcium/vitamin D products.

Reference:
Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85:1586-1591.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Numerous observational studies have found supplemental calcium and vitamin D to be associated with reduced risk of common cancers. However, interventional studies to test this effect are lacking. The authors determined the efficacy of calcium alone and calcium plus vitamin D in reducing incident cancer risk of all types. This was a 4-y, population-based, double-blind, randomized placebo-controlled trial. The primary outcome was fracture incidence, and the principal secondary outcome was cancer incidence. The subjects were 1179 community-dwelling women randomly selected from the population of healthy postmenopausal women aged >55 y in a 9-county rural area of Nebraska centered at latitude 41.4 degrees N. Subjects were randomly assigned to receive 1400-1500 mg supplemental calcium/d alone (Ca-only), supplemental calcium plus 1100 IU vitamin D3/d (Ca + D), or placebo. When analyzed by intention to treat, cancer incidence was lower in the Ca + D women than in the placebo control subjects (P < 0.03). With the use of logistic regression, the unadjusted relative risks (RR) of incident cancer in the Ca + D and Ca-only groups were 0.402 (P = 0.01) and 0.532 (P = 0.06), respectively. When analysis was confined to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to 0.232 (CI: 0.09, 0.60; P < 0.005) but did not change significantly for the Ca-only group. In multiple logistic regression models, both treatment and serum 25-hydroxyvitamin D concentrations were significant, independent predictors of cancer risk.

Diet high in vegetables, fruit and fiber/low in fat does not reduce risk of recurrent breast CA

Clinical Question:
Can a diet high in vegetables, fruit, and fiber and low in fat reduce the risk of recurrent breast cancer?

Bottom Line:
Among survivors of early stage breast cancer, adoption of a diet that was very high in vegetables, fruit, and fiber and low in fat did not reduce additional breast cancer events or mortality during a 7.3-year follow-up period.

Reference:
Pierce JP, Natarajan L, Caan BJ, et al. Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer. The Women’s Healthy Eating and Living (WHEL) randomized trial. JAMA 2007;298:289-298.

Study Design:
Cross-over trial (randomized)

Synopsis:
Evidence is lacking that a dietary pattern high in vegetables, fruit, and fiber and low in total fat can influence breast cancer recurrence or survival. The authors assessed whether a major increase in vegetable, fruit, and fiber intake and a decrease in dietary fat intake reduces the risk of recurrent and new primary breast cancer and all-cause mortality among women with previously treated early stage breast cancer. Multi-institutional randomized controlled trial of dietary change in 3088 women previously treated for early stage breast cancer who were 18 to 70 years old at diagnosis. Women were enrolled between 1995 and 2000 and followed up through June 1, 2006. The intervention group (n = 1537) was randomly assigned to receive a telephone counseling program supplemented with cooking classes and newsletters that promoted daily targets of 5 vegetable servings plus 16 oz of vegetable juice; 3 fruit servings; 30 g of fiber; and 15% to 20% of energy intake from fat. The comparison group (n = 1551) was provided with print materials describing the “5-A-Day” dietary guidelines. Invasive breast cancer event (recurrence or new primary) or death from any cause. From comparable dietary patterns at baseline, a conservative imputation analysis showed that the intervention group achieved and maintained the following statistically significant differences vs the comparison group through 4 years: servings of vegetables, +65%; fruit, +25%; fiber, +30%, and energy intake from fat, -13%. Plasma carotenoid concentrations validated changes in fruit and vegetable intake. Throughout the study, women in both groups received similar clinical care. Over the mean 7.3-year follow-up, 256 women in the intervention group (16.7%) vs 262 in the comparison group (16.9%) experienced an invasive breast cancer event (adjusted hazard ratio, 0.96; 95% confidence interval, 0.80-1.14; P = .63), and 155 intervention group women (10.1%) vs 160 comparison group women (10.3%) died (adjusted hazard ratio, 0.91; 95% confidence interval, 0.72-1.15; P = .43). No significant interactions were observed between diet group and baseline demographics, characteristics of the original tumor, baseline dietary pattern, or breast cancer treatment.

Azithromycin at least as effective as doxycycline for PID

Clinical Question:
Is ceftriaxone plus azithromycin (Zithromax) as effective as ceftriazone (Rocephin) plus doxycycline (Vibramycin) for the treatment of mild pelvic inflammatory disease?

Bottom Line:
Ceftriaxone plus azithromycin is as at least as effective as ceftriaxone plus doxycycline for the treatment of pelvic inflammatory disease (PID). A larger trial is needed to determine whether azithromycin is superior.

Reference:
Savaris RF, Teixeira LM, Torres TG, Edelweiss MI, Moncada J, Schachter J. Comparing ceftriaxone plus azithromycin or doxycycline for pelvic inflammatory disease: A randomized controlled trial. Obstet Gynecol 2007;110:53-60.

Study Design:
Randomized controlled trial (single-blinded)

Synopsis:
The authors evaluated the equivalence of ceftriaxone plus doxycycline or azithromycin for cases of mild pelvic inflammatory disease (PID). Patients with PID received an intramuscular injection of 250 mg of ceftriaxone, and were randomly assigned to receive 200 mg/d of doxycycline for 2 weeks, or 1 g of azithromycin per week, for 2 weeks. The degree of pain was assessed on days 2, 7, and 14 and clinical cure was assessed on day 14. From 133 patients eligible for the study, 13 were excluded for having conditions other than PID, 11 were lost on follow-up, and three had oral intolerance to the antibiotics, yielding 106 for protocol analysis. No significant difference was observed regarding the degree of pain between the doxycycline and azithromycin groups. Clinical cure per protocol was 98.2% (56 of 57; 95% confidence interval [CI], 0.9-0.99) with azithromycin, and 85.7% (42 of 49; 95% CI, 0.72-0.93) with doxycycline (P=0.02). In a modified intention to treat analysis, clinical cure was 90.3% (56 of 62; 95% CI, 0.80-0.96) with azithromycin, and 72.4% (42 of 58; 95% CI, 0.58-0.82) with doxycycline (P=.01); a relative risk of 0.35, and a number needed to treat of six for benefit with azithromycin.

Transdermal testosterone does not improve libido in female cancer survivors

Clinical Question:
Does transdermal testosterone improve libido in female cancer survivors?

Bottom Line:
In female cancer survivors, transdermal testosterone does not improve sexual desire even though it increases hormone levels.

Reference:
Barton DL, Wender DB, Sloan JA, et al. Randomized controlled trial to evaluate transdermal testosterone in female cancer survivors with decreased libido; North Central Cancer Treatment Group protocol N02C3. J Natl Cancer Inst 2007;99:672-679.

Study Design:
Cross-over trial (randomized)

Synopsis:
Decreased libido is one of several changes in sexual function that are often experienced by female cancer patients. Transdermal testosterone therapy has been associated with increased libido among estrogen-replete women who report low libido. In a phase III randomized, placebo-controlled crossover clinical trial, we evaluated whether transdermal testosterone would increase sexual desire in female cancer survivors. Postmenopausal women with a history of cancer and no current evidence of disease were eligible if they reported a decrease in sexual desire and had a sexual partner. Eligible women were randomly assigned to receive 2% testosterone in Vanicream for a testosterone dose of 10 mg daily or placebo Vanicream for 4 weeks and were then crossed over to the opposite treatment for an additional 4 weeks. The primary endpoint was sexual desire or libido, as measured using the desire subscales of the Changes in Sexual Functioning Questionnaire, as assessed at baseline and at the end of 4 and 8 weeks of treatment. Serum levels of bioavailable testosterone were measured at the same times. All statistical tests were two-sided. They enrolled 150 women. Women who were on active testosterone cream had higher serum levels of bioavailable testosterone than women on placebo (mean change from baseline, testosterone versus placebo, week 4, 11.57% versus 0%, difference = 11.57%, 95% confidence interval [CI] = 8.49% to 14.65%; week 8, 10.21% versus 0.28%, difference = 9.92%, 95% CI = 5.42% to 14.42%; P<.001 for all). However, the average intrapatient libido change from baseline to weeks 4 and 8 was similar on both arms.

Quadrivalent HPV vaccine prevents CIN 2/3, anogenital warts (FUTURE II)

Clinical Question:
Does a quadrivalent vaccine against human papillomavirus reduce the risk of high-grade cervical intraepithelial neoplasia?

Bottom Line:
The quadrivalent vaccine against human papillomavirus (HPV) types 6, 11, 16 and 18 significantly reduces the risk of grade 2 or 3 cervical intraepithelial neoplasia (CIN2/3). It is also prevents anogenital warts.

Reference:
FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915-1927.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Human papillomavirus types 16 (HPV-16) and 18 (HPV-18) cause approximately 70% of cervical cancers worldwide. A phase 3 trial was conducted to evaluate a quadrivalent vaccine against HPV types 6, 11, 16, and 18 (HPV-6/11/16/18) for the prevention of high-grade cervical lesions associated with HPV-16 and HPV-18. In this randomized, double-blind trial, they assigned 12,167 women between the ages of 15 and 26 years to receive three doses of either HPV-6/11/16/18 vaccine or placebo, administered at day 1, month 2, and month 6. The primary analysis was performed for a per-protocol susceptible population that included 5305 women in the vaccine group and 5260 in the placebo group who had no virologic evidence of infection with HPV-16 or HPV-18 through 1 month after the third dose (month 7). The primary composite end point was cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18. Subjects were followed for an average of 3 years after receiving the first dose of vaccine or placebo. Vaccine efficacy for the prevention of the primary composite end point was 98% (95.89% confidence interval [CI], 86 to 100) in the per-protocol susceptible population and 44% (95% CI, 26 to 58) in an intention-to-treat population of all women who had undergone randomization (those with or without previous infection). The estimated vaccine efficacy against all high-grade cervical lesions, regardless of causal HPV type, in this intention-to-treat population was 17% (95% CI, 1 to 31).

Sertraline (Zoloft) ineffective for hot flushes

Clinical Question:
Is sertraline an effective treatment for menopausal hot flushes?

Bottom Line:
Treatment with sertraline did not improve hot flush frequency or severity in generally healthy perimenopausal and postmenopausal women, but was associated with bothersome side effects.

Reference:
Grady D, Cohen B, Tice J, Kristof M, Olyaie A, Sawaya GF. Ineffectiveness of sertraline for treatment of menopausal hot flushes. Obstet Gynecol 2007;109:823-830.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
To estimate the effect of the selective serotonin reuptake inhibitor sertraline on hot flush frequency and severity in perimenopausal and postmenopausal women. The authors performed a randomized, blinded, placebo-controlled trial in women aged 40 to 60 years with 14 or more hot flushes per week (N=99). Women were randomly assigned initially to daily oral sertraline (50 mg) or identical placebo for 2 weeks. If no substantial side effects were noted, the dose was increased to two tablets daily (100 mg sertraline or placebo) and continued for an additional 4 weeks. Hot flush frequency and severity were recorded on a daily diary. Hot flush score was calculated as frequency multiplied by severity. Participants also completed questionnaires addressing quality of life, menopausal symptoms, sleep quality, sexual function, mood, and side effects. After 6 weeks of treatment, hot flush frequency decreased similarly in both the placebo (38%) and sertraline (39%) groups (P=.94). Mean hot flush scores also decreased similarly in both groups (41% and 42%, respectively, P=.86). Compared with placebo, women in the sertraline group were more likely to report gastrointestinal complaints, dry mouth, and dizziness. Treatment with sertraline also resulted in greater worsening of scores on the Medical Outcomes Study (MOS) Short Form 36 standardized physical component and the global Female Sexual Function Index. Results were similar in women at least 80% adherent to study medication.

Guideline: Mammography optional in women 40-49

Clinical Question:
Should screening mammography be used in women between the ages of 40 years and 49 years?

Bottom Line:
Although few women 50 years of age or older have risks from mammography that outweigh the benefits, the evidence suggests that more women 40 to 49 years of age have such risks.

Reference:
Armstrong K, Moye E, Williams S, Berlin JA, Reynolds EE. Screening mammography in women 40 to 49 years of age: a systematic review for the American College of Physicians. Ann Intern Med 2007;146:516-526.

Study Design:
Practice guideline

Synopsis:
The risks and benefits of mammography screening among women 40 to 49 years of age remain an important issue for clinical practice. The authors evaluated the evidence about the risks and benefits of mammography screening for women 40 to 49 years of age. They looked at only english-language publications in MEDLINE (1966-2005), Pre-MEDLINE, and the Cochrane Central Register of Controlled Trials and references of selected studies through May 2005. Selected only previous systematic reviews; randomized, controlled trials; and observational studies. In addition to publications from the original mammography trials, 117 studies were included in the review. Meta-analyses of randomized, controlled trials demonstrate a 7% to 23% reduction in breast cancer mortality rates with screening mammography in women 40 to 49 years of age. Screening mammography is associated with an increased risk for mastectomy but a decreased risk for adjuvant chemotherapy and hormone therapy. The risk for death due to breast cancer from the radiation exposure involved in mammography screening is small and is outweighed by a reduction in breast cancer mortality rates from early detection. Rates of false-positive results are high (20% to 56% after 10 mammograms), but false-positive results have little effect on psychological health or subsequent mammography adherence. Although many women report pain at the time of the mammography, few see pain as a deterrent to future screening. Evidence about the effect of negative screening mammography on psychological well-being or the subsequent clinical presentation of breast cancer is insufficient.