ANTIDEPRESSANTS INCREASE CARDIOVASCULAR MORTALITY

December 22, 2009 — Postmenopausal women taking either a tricyclic antidepressant (TCA) or a selective serotonin-reuptake inhibitor (SSRI) appear to be at increased risk for all-cause mortality, and SSRIs users seem to be at increased risk for hemorrhagic and fatal stroke, although the absolute event risks are low, according to an analysis from the Women's Health Initiative (WHI) study.

In an article published in the December issue of the Archives of Internal Medicine, Jordan Smoller, MD, from Massachusetts General Hospital, Boston, and colleagues report that new use of either a TCA or an SSRI during a mean follow-up of 5.9 years was not significantly associated with an increased risk for coronary heart disease (CHD) in this large prospective cohort of postmenopausal women.

In contrast, compared with women who did not use antidepressants, "those using SSRIs had a 45% increased relative risk of incidence stroke and a 32% increased risk of death in models stratified on propensity and adjusted for multiple covariates," the investigators report. TCA use in turn was associated with a 67% higher relative risk for all-cause death (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.33 - 2.09). The TCAs also increase stroke risk, but not significantly so.

"Depression is still a much more established risk factor for cardiovascular disease (CVD) than antidepressants, so it's not as though not taking an antidepressant removes the risk because then you have untreated depression, which itself is risky," Dr. Smoller told Medscape Psychiatry. "But if a woman is concerned about taking medication, there are alternative treatments for depression, such as cognitive behavioral therapy, which can be effective."

Association Explored

For the analysis, investigators examined the association between new antidepressant use and first occurrence of CHD, fatal or nonfatal stroke, and all-cause mortality occurring after the first follow-up visit.

The first follow-up visit for women enrolled in the longitudinal cohort observational study was at 3 years; for women enrolled in 1 of the 3 overlapping clinical trials it took place at 1 year after baseline.

A total of 136,293 postmenopausal women were involved in the WHI, and women taking no antidepressants at study entry and who had at least 1 follow-up visit were included in the analysis.

During the follow-up interval, 5496 women initiated antidepressant treatment. Antidepressant users had higher levels of several CVD risk factors than nonusers. To address potential confounders, investigators obtained a propensity score from a logistic regression model.

Annualized rates per 1000 person-years of stroke with no antidepressant use were 2.99 vs 4.16 for SSRI users. Death rates for non–antidepressant users were 7.79 per 1000 person-years and 12.77 for SSRI users. Annualized mortality rates for TCA users were 14.14 deaths per 1000 person-years.

As investigators point out, the excess risk for stroke seen in association with SSRIs was largely hemorrhagic (HR, 2.12; 95% CI, 1.10 - 4.07), whereas the risk for ischemic stroke with SSRI use did not reach statistical significance (HR, 1.21; 95% CI, 0.80 - 1.83).

In contrast, both the SSRIs and the TCAs were associated with an increased risk for all fatal strokes (HR, 2.10; 95% CI, 1.15 - 3.81; and HR, 2.56; 95% CI, 1.26 - 5.26, respectively).

Table. CV Events and Annualized Rates in All Cohorts (Observational Study and Clinical Trials)

AD Status	Participants (n)	CHD Events (n)	CHD Annualized Rate/1000 Person-Years	Stroke Events (n)			Annualized Rate/1000 Person-Years
No AD at Follow-up	130,797	2843	3.81	2232	2.99	5881	7.79
Incident SSRI	3040	73	4.73	64	4.16	201	12.77
Incident TCA	1490	41	5.18	39	4.92	114	14.14
Incident other or multiple ADs	966	26	5.38	22	4.55	66	13.42

Key Question

A key question is whether the association between antidepressant use and CV morbidity and mortality is truly related to drug exposure or to underlying differences in other CV risk factors, including depression.

As Dr. Smoller explained to Medscape Psychiatry, the propensity score used in this study did help control for risk factors that could have explained differences in CV outcomes between antidepressant users and nonusers, "but you can't fully tease out the effect that depression itself and some of these risk factors may have had vs the contribution of the medication."

He continued, "If you look at the annualized death rates in all cohorts, the absolute differences [between AD users and nonusers] is very small, so our findings have to be weighed against the risk of CV disease and mortality associated with untreated depression vs antidepressant use because we know it can have a dramatic effect on the ability of patients to enjoy life."

In an invited commentary, Christopher O'Connor, MD, and Mona Fiuzat, PharmD, from Duke University Medical Center, Durham, North Carolina, agreed that the most difficult aspect of these trials is that patients who are likely to be treated with antidepressants have additional risk factors for mortality and CV risk that are difficult to control for.

They also point out that the study cannot fully address situations in which patients begin treatment with antidepressants but do not respond to treatment, and that these patients may represent the highest-risk mortality group.

Nevertheless they indicate that the findings — in the largest cohort of women yet studied — provide "additional warning" that antidepressant use does have certain negative consequences in this particular demographic and that its risks should be considered against the potential benefits of treating depression.

HERCEPTIN FOR MUCINOUS OVARIAN CANCER?

HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy.

McAlpine JN, Wiegand KC, Vang R, Ronnett BM, Adamiak A, Kobel M, Kalloger SE, Swenerton KD, Huntsman DG, Gilks CB, Miller DM.

ABSTRACT: BACKGROUND: The response rate of ovarian mucinous carcinomas to paclitaxel/carboplatin is low, prompting interest in targeted molecular therapies. We investigated HER2 expression and amplification, and the potential for trastuzumab therapy in this histologic subtype of ovarian cancer. METHODS: HER2 status was tested in 33 mucinous carcinomas and 16 mucinous borderline ovarian tumors (BOT)). Five cases with documented recurrence and with tissue from the recurrence available for testing were analyzed to determine whether HER2 amplification status changed over time. Three prospectively identified recurrent mucinous ovarian carcinomas were assessed for HER2 amplification and patients received trastuzumab therapy with conventional chemotherapy. RESULTS: Amplification of HER2 was observed in 6/33 (18.2%) mucinous carcinomas and 3/16 (18.8%) BOT. HER2 amplification in primary mucinous carcinomas was not associated with an increased likelihood of recurrence. The prospectively identified recurrent mucinous carcinomas showed overexpression and amplification of HER2; one patient's tumor responded dramatically to trastuzumab in combination with conventional chemotherapy, while another patient experienced an isolated central nervous system recurrence after trastuzumab therapy. CONCLUSIONS: HER2 amplification is relatively common in ovarian mucinous carcinomas (6/33, 18.2%), although not of prognostic significance. Trastuzumab therapy is a treatment option for patients with mucinous carcinoma when the tumor has HER2 amplification and overexpression.

MUCINOUS BREAST CANCER IS OFTEN MULTICENTRIC-MULTIFOCAL

December 18, 2009 (San Antonio, Texas) — A rare subtype of breast cancer, described as mucinous because the tumor produces mucous, has long been associated with a favorable prognosis, but new research suggests that the picture may be less rosy than previously thought. Researchers found that about one third of these women have multiple tumors that are undetected by mammography and ultrasound, and they caution against undertreatment of this patient population.
he new findings were presented in a poster here at the 32nd Annual San Antonio Breast Cancer Symposium by George Perkins, MD, from the Department of Radiation Oncology at the University of Texas M.D. Anderson Cancer center in Houston.

"While mucinous breast cancer is thought to be a disease with a favorable prognosis, our study is the first to identify it as one associated with significant multifocal presentation, which is a potentially unfavorable aspect," he said.

"In recent years, there has been an overall trend toward minimization of treatment for women with this subtype, because these mucinous tumors are considered to have an extremely favorable prognosis," Dr. Perkins explained in an interview. In particular, there has been a trend away from using whole-breast irradiation in these patients, so some patients receive no radiation at all, whereas others are treated with partial breast irradiation, he explained.

"Our study shows that that about one third of these women have more than a solitary lesion. This disease may be more multicentric than previously thought, and this is the first time that this has been reported," he said. These new findings suggest that undertreatment may be a "significant hazard for patients," he added.

It is important that the pendulum does not swing too far.

"You have to be very careful about offering no treatment or minimized treatment," he said. "In an era where there is a concern about overtreatment, it is important that the pendulum does not swing too far so that we are undertreating."

Claudine Issacs, MD, director of the Clinical Breast Cancer Program at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, who moderated a press conference at which the findings were highlighted, added: "Partial-breast irradiation is an investigational treatment and should not be offered as a standard of care."

Large Series of Rare Tumor Type

Mucinous tumors are diagnosed in about 2% of all breast cancer patients, but they are more common in older women. This subtype is found in about 8% to 10% of women 70 or years or older, but in fewer than 0.5% of those 35 years or younger.

The M.D. Anderson team reviewed the charts of 264 patients diagnosed with a pure mucinous carcinoma from 1965 to 2005; the median age was 57 years, and median follow-up was 14 years. "This is one of the largest single-institution experiences with a relatively uncommon subtype, and it has a significant long-term follow-up of patients," Dr. Perkins said.

The favorable prognosis is apparent from the long-term follow-up, as shown in the table below.

Outcome After Long-Term Follow-Up

Outcome	5 Years	10 Years	15 Years
Overall survival rate (%)	95	97	97
Distant metastases-free survival rate (9%)	88	95	94
Local regional control rate (%)	83	92	85

On initial examination, only 10% of these women had a multicentric/multifocal presentation. However, a detailed pathology review revealed a 38% rate of multicentric/multifocal disease after resection, which surprised the team, Dr. Perkins explained.

"We had previously been surprised by the decreasing age at presentation in this population, and by the regression of favorable outcomes toward the lower outcomes of other common breast cancer subtypes over time," he explained in a statement. "This reinforces our commitment to interdisciplinary care and true personalized patient treatment in this variant," he said.

There needs to be a move away from "the assumption that it may not matter which treatment approach is taken because this is a favorable disease," he added.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract 4117. Presented December 12, 2009.

DEAR GOD!

Ann Oncol. 2009 Dec 17. [Epub ahead of print]

Economic evaluation of docetaxel-gemcitabine versus vinorelbine-cisplatin combination as front-line treatment of patients with advanced/metastatic non-small-cell lung cancer in Greece: a cost-minimization analysis.

Maniadakis N, Fragoulakis V, Pallis AG, Simou E, Georgoulias V.

Department of Health Services Management, National School of Public Health, Athens.

BACKGROUND: An economic evaluation was undertaken, alongside a randomized phase III study, to assess docetaxel-gemcitabine (DG) relative to vinorelbine-cisplatin (VC) combination as front-line treatment of patients with advanced/metastatic non-small-cell lung cancer. METHODS: No differences were found in efficacy, thus a cost-minimization analysis was carried out. Treatment cost accounts for the administration of first- and second-line chemotherapy, for concomitant medications, for laboratory and biochemical examinations, and for hospitalizations due to adverse events. Unit prices used reflect 2008 and are common among National Health Service hospitals in Greece. RESULTS: The mean total cost of therapy in the DG group [euro14045, 95% uncertainty interval (UI) euro12628-euro15390], was significantly higher than in the VC group (euro8143, 95% UI euro7314-euro9067). CONCLUSIONS: Even though the combination VC has similar effectiveness compared with DG in patients with metastatic lung cancer, it is associated with a lower overall treatment cost and hence, it is preferable from an economic perspective. However, it should be noted that although VC is associated with lower cost, it is also more toxic than DG regimen, a significant parameter that should be considered in clinical decisions.