Abstract
The results of a large randomized trial conducted in Spain suggest that adjuvant therapy with docetaxel plus doxorubicin and cyclophosphamide should be the standard of care for node-positive breast cancer.
The results of a study published in a recent issue of the New England Journal of Medicine showed that docetaxel increased both overall and disease-free survival compared to flurouracil, another commonly used chemotherapeutic agent.
The researchers randomly assigned a total of 1491 women with node-positive breast cancer to receive six cycles of either docetaxel or flurouracil, in combination with two other anticancer drugs: doxorubicin and cyclophosophamine. Treatment was initiated 60 days after the women had undergone surgery to remove the cancer.
Women receiving docetaxel plus doxorubicin and cyclophosophamine (TAC) had 5-year survival rates of 87%, compared with 81% for those receiving flurouracil plus doxorubicin and cyclophosophamine (FAC). In addition, those treated with TAC had a 28% reduction in relapse rate, with a 75% disease-free survival rate after five years, compared to 68% for women receiving FAC. The study “clearly shows that six cycles of the TAC combination is superior to six cycles of the FAC combination” enthused study author Dr Miguel Martin. Dr John Mackey of the Cross Cancer Institute in Edmonton, Canada, added “there's no group of patients that didn't benefit, so you can't pick out someone who's not a winner from the new treatment.”
The study showed, however, that docetaxel was associated with an increased risk of some serious side-effects. Neutropenia (grade 3 or 4) occurred in 65.5% of patients in the TAC group, compared to 49.3% of those in the FAC group, leading to an increased risk of infection. Researchers also noted an increase in diarrhea and mouth sores. An earlier French study was halted when 3 women died from complications caused by this drug combination. Reduced tolerability and a lack of evidence in women over 70 “cannot be minimized”, stated Dr Edith Perez of the Mayo Clinic on Jackson, Florida, in her accompanying editorial.
TAC has yet to be tested against another commonly used regimen, doxorubin and cyclophosphophamide followed by paclitaxel. However, the study authors wrote that docetaxel “does not interfere with the pharmacokinetics of doxorubicin, indicating that, unlike paclitaxel, it may not exacerbate doxorubicin-related cardiotoxicity”.
Despite the increased side-effects the study authors are confident that the benefits in terms of survival will outweigh the risks. “We have a reasonable new therapeutic option that can improve the likelihood of cure of node-positive breast cancer patients” stated Dr Martin.
Dr Perez concluded that “On the basis of the available data, one can consider TAC to be a standard of care, as is the dose-dense regimen of doxorubicin and cyclophosphamide followed by paclitaxel, for patients with resected node-positive breast cancer.”
Testosterone patch effective for hypoactive sexual desire disorder
In a 24-week double-blind, multicenter, phase III trial, researchers demonstrated that a testosterone patch improved sexual satisfaction and desire and decreased personal distress in a sample of 533 women.
In a report published in the May issue of Obstetrics & Gynecology, John E Buster and colleagues commented “Studies involving testosterone therapy in the form of oral preparations, intramuscular injections, and subcutaneous implants have demonstrated significant improvement in sexual desire in postmenopausal women. However, many of these studies included small sample sizes and were of short duration, warranting large-scale, longer-term trials of testosterone therapy in women.”
The Investigation of Natural Testosterone In Menopausal women Also Taking Estrogen in Surgically Menopausal women (INTIMATE SM 2) study aimed to elucidate the safety and efficacy of testosterone therapy for the treatment of hypoactive sexual desire disorder. The women, who had undergone surgical menopause, were randomized to receive a placebo or a 300 μm per day testosterone patch.
Adverse events were rare and generally mild, and the authors are satisfied that the patch was well-tolerated.
in brief…
Yaffe K, Krueger K, Cummings SR, Blackwell T et al., Am. J. Psychiatry 162(4), 683–690 (2005).
Raloxifene, a selective estrogen receptor modulator, is under investigation as a potential preventive treatment for osteoporosis in postmenopausal women. However, it has also been postulated to have an effect on cognitive impairment. In this randomized, placebo-controlled trial 5386 postmenopausal women were given either 60 or 120 mg raloxifene per day and cognitive impairment was assessed by clinical and cognitive evaluations, including brain scans and laboratory tests in those showing signs of dementia. The results showed that 120 mg/day of raloxifene resulted in a 33% lower risk of minor cognitive impairment and somewhat reduced risks of major cognitive impairment and Alzheimer's disease.
Almstedt Shoepe H, Snow CM: Osteoporos. Int. (2005) [Epub ahead of print]
High peak bone mass in youth is a primary strategy to prevent osteoporosis in later life. This study aimed to assess the effect of oral contraceptives on bone mineral density in young women aged 18–25 years, with or without a history of oral contraceptive use. In a cross-sectional analysis of 98 women, those using oral contraceptives had a significantly lower bone mineral density than controls at the spine, femoral neck, greater trochanter, total hip, and whole body, indicating that oral contraceptives may compromise bone health in young women.
Jenkins AD, Ramondetta LM, Sun C et al.: Gynecol. Oncol. 97(3), 840–844 (2005).
This Phase II IRB-approved trial investigated the efficacy and safety of capectabine in 23 women with inoperable, recurrent, or metastatic squamous cell cervical cancer. While capectabine was well-tolerated, none of the women showed a partial or complete response or increased quality of life, indicating that it is not suitable as a single agent in a poor-prognosis cervical cancer population.
Drug to prevent mother-to-child HIV transmission may be more likely to induce resistance than first thought
Three new studies, published in the Journal of Infectious Diseases, suggest that drug resistance after a single dose of nevirapine may be both more common and longer lasting than previously thought, and occur more frequently in those infected with HIV-1 subtype C.
Single-dose nevirapine is given to HIV-infected mothers during delivery, with a second dose given to the child at birth. It is highly effective, cutting the rate of HIV transmission in half, and is relatively cost-effective, making it the drug of choice in many developing countries.
The first study, by researchers at the Centers for Disease Control and Prevention, USA, used a new, more sensitive assay to detect resistance mutations in HIV-1 samples isolated from 50 mothers before and after treatment with nevirapine. Compared with previous estimates of 40% resistance, the investigators showed that resistance emerged in at least 65% of the women.
The second study utilized the more sensitive assays to determine the persistence of drug resistance in nine mothers and five infants. The study, conducted by a group from John Hopkins University, showed that resistance could persist for a year or more. Standard sequencing techniques could not detect resistance at 1-year follow up.
The third study was carried out by the same group at John Hopkins and aimed to determine the relationship between HIV-1 subtype, which varies geographically, and rate of resistance. Those infected with subtype C had a higher frequency of resistance mutations (69%) than those with subtype A or D (19 and 36%, respectively).
Future research is likely to focus on whether this resistance might compromise the use of nevirapine in a second pregnancy or the subsequent anti-HIV treatment of the mother and infant.
Women's brains more vulnerable to alcohol-related damage
Female alcoholics suffer brain damage faster than their male counterparts, suggests neuroimaging research by Karl Mann and his team, at the University of Heidelberg, Germany.
By scanning the brains of 34 male and 42 female age-matched alcoholics, plus healthy controls, using computed tomography, the researchers hoped to shed light on the rather neglected subject of gender differences in alcohol dependence.
The results, reported in Alcoholism: Clinical and Experimental Research, showed that the alcohol-dependent women had similar levels of brain atrophy and brain-volume reduction as the men, despite having been alcoholics for, on average, half as long.
“These results corroborate previous studies that have found other gender-related consequences of alcohol, such as cognitive deficits, alcoholic cardiomyopathy, myopathy of skeletal muscle, and alcoholic liver disease - all of which occur earlier in women than in men despite a significantly shorter exposure to alcohol” reported Professor Mann.
Moderate exercise lowers breast cancer death rate
A study published recently in the Journal of the American Medical Association followed 2987 women diagnosed with breast cancer for up to 18 years. The women were part of the Nurses Health Study (NHS), a Harvard-based study tracking the lifestyle and health of almost 122,000 nurses.
“Physical activity has been shown to decrease the incidence of breast cancer, but the effect on recurrence or survival after a breast cancer diagnosis is not known” stated the study authors.
Exercise equivalent to walking for 3–5 hours a week can reduce breast cancer patients' risk of death by 50%, according to researchers at Brigham and Women's Hospital, MA, USA.
While 3–5 hours per week spent walking at a moderate pace produced the optimum benefit, even 1 hour of walking cut the risk of death by 20%. No additional benefit was found in those who exercised for over 5 hours a week.
The greatest benefits were seen in women with estrogen-receptive tumors, supporting the theory that exercise may fight breast cancer by reducing body fat and consequently lowering ovarian hormone levels.
Another recent study, conducted by researchers at Penn State University, USA, suggests that exercise may also help the immune system to recover after chemotherapy. The study divided a total of 49 breast cancer patients who had recently completed post-surgery chemotherapy into exercise and control groups.
The exercise group, who exercised for 60–90 mins three-times a week under the supervision of trainers, showed improvements in immune function and decreased levels of inflammatory markers, as well as increased quality of life scores, at 3 and 6 months follow up.
Many breast cancer experts already advise their patients on the benefits of exercise. As the lead author of the Brigham study, Dr Michelle Holmes, points out, “There is not a lot to lose from being physically active and perhaps a lot to gain”.
Successful birth following ovary transplant
A report published in the New England Journal of Medicine has described a successful pregnancy and birth following an operation to transplant ovarian tissue between identical twin sisters. This is the first instance of a successful birth resulting from ovarian transplantation between women.
The recipient, an otherwise healthy 23-year old woman, had undergone premature menopause at the age of 14. After two unsuccessful cycles of in vitro fertilization using eggs donated by her twin, the woman received a transplant of cortical ovarian tissue. The tissue, removed from the fertile twin by minilaproscopy, was sutured to both of the infertile twin's ovaries.
Within 3 months, the recipient's gonadotropin and estrogen levels were normal and she was menstruating. She conceived naturally in her second menstrual cycle and has now given birth to a healthy-seeming baby girl.
The authors of this study hope that it will support the viability of ovarian tranplantation, concluding that “The demonstration that ovarian function can be restored and that natural conception and successful pregnancy can be achieved after transplantation of ovarian tissue may have broader implications for preserving fertility in young women, such as those who require potentially sterilizing treatment for cancer”.
Researchers announce potential of nonsteroidal agent as a once-daily oral contraceptive
A novel nonsteroidal progesterone receptor agonist, tanaproget, has shown an acceptable safety profile in a preliminary clinical trial in 46 women.
Tanaproget works by inhibiting ovulation and decreasing cervical mucus. The investigators were hopeful that it might avoid some of the side effects of steroidal oral contraceptives, for example bloating, weight gain and changes in lipid and coagulation factors.
Dr Jody Bapst of Wyeth Research in Collegeville, USA, suggested that “A nonsteroidal oral contraceptive may reduce the common side effects of oral contraceptives and make this a more acceptable and tolerable option for many women, including current nonusers”.
To assess the dosage required for contraceptive efficacy the women's hormone levels were monitored, follicular development and rupture were documented by transvaginal ultrasonography and daily cervical mucus scores were graded.
The results, announced at the 53th Annual Clinical Meeting of the American College of Obstetricians and Gynecologists on the 10th June 2005, revealed that a dose of 0.3 mg was sufficient to completely suppress ovulation and 0.03 mg was enough to decrease cervical mucus scores.
Whilst no serious adverse events or abnormal trends in hormone levels were reported, common side-effects included headaches, abdominal pain, intramenstrual spotting and follicular cyst formation.
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