Abstract
Standard adjuvant chemotherapy may improve survival among older women with breast cancer
A recent study published in the New England Journal of Medicine provides much needed insight into optimal treatment strategies for older women with breast cancer.
Despite the fact that the risk of getting breast cancer increases with age and, in the USA, most deaths related to breast cancer occur in women aged 65 years or older, women in this category are under-represented in clinical trails. In addition, breast cancer in older women is not always managed in accordance with treatment guidelines.
With the aim of addressing this discrepancy, researchers randomly assigned a total of 633 patients with stage I, II, IIIA or IIIB breast cancer to either standard chemotherapy (326 patients; consisting of cyclophosphamide, methotrexate and fluorouracil) or cyclophosphamide plus doxorubicin, or capecitabine (307 patients), an oral fluorouracil prodrug often preferred by many patients over intravenous chemotherapy. Endocrine therapy was also recommended after chemotherapy for patients with hormone receptor-positive tumors. Approximately two-thirds of the patients were 70 years of age or older, and approximately 5% were aged 80 years or older.
The trial was halted following the enrollment of the 600th patient, when an interim analysis revealed that conventional regimens were likely to be superior to capecitabine with a longer follow-up period.
At 1-year follow-up beyond enrollment of the final patient, the hazard ratio for recurrence or death was 2.09 for patients receiving capecitabine versus conventional therapy. Patients treated with capecitabine also had a mortality hazard ratio of 1.85 versus their standard adjuvant therapy counterparts. The 3-year relapse-free survival was 68% with capecitabine, compared with 85% for standard therapy. An overall survival of 86% was reported for patients receiving capecitabine, whereas the rate observed for patients treated with standard chemotherapy was 91%. Two patients taking capecitabine died owing to treatment side effects; no deaths were reported in the group receiving standard chemotherapy.
However, in women with hormone receptor-positive cancer, which constituted two thirds of the study's participants, the efficacy of standard therapy and capecitabine was quite similar. Lead researcher Hyman Muss stated that, “It would be reasonable for these women to select capecitabine over standard chemotherapy, but my bias would still be to pick the standard right now.”
The results also demonstrated older women to be capable of tolerating adjuvant chemotherapy almost as well as their younger counterparts, a notable finding given that older women are more likely to be treated with lower doses of chemotherapy than younger women.
The authors concluded that such data “are part of a developing body of evidence that choice of adjuvant chemotherapy really matters in older women.”
Source: Muss HB, Berry DA, Cirrincione CT et al.: Adjuvant chemotherapy in older women with early-stage breast cancer. N. Engl. J. Med. 360(20), 2055–2065 (2009).
Potential pharmacogenetic interaction may improve the treatment of women suffering from polycystic ovary syndrome
A team investigating resistance to clomiphene citrate (CC) treatment for polycystic ovary syndrome have identified a genetic variant that almost doubles the risk for resistance to the drug.
“…a subset of patients are resistant to [clomiphene citrate] and the mechanisms of this resistance are as yet unknown.”
Clomiphene citrate is commonly used as a treatment for polycystic ovary syndrome, an endocrine disorder that can lead to reproductive difficulties and anovulatory infertility in women of reproductive age. The drug binds to estrogen receptors, specifically in the hypothalamus, which results in the release of increased amounts of luteinizing hormone and follicle-stimulating hormone (FSH), which are then hoped to stimulate ovulation. The drug is highly successful; however, a subset of patients are resistant to the drug and the mechanisms of this resistance are as yet unknown. The study's researchers investigated whether polymorphisms in the gene encoding for the FSH receptor influenced resistance to the drug.
They performed a retrospective study, examining 193 patients suffering from polycystic ovary syndrome who were being treated through ovulation induction at the Obstetrics and Gynecology Department of the VU University Medical Center, The Netherlands, measuring their response to CC and their FSH receptor genotype. Patients homozygous for the Ser680Ser-polymorphism were almost doubly likely to be resistant to the drug (28%) than heterozygotes Asn/Ser (14%) or wildtype Asn/Asn (15%). Whilst they had looked at other potential influences on CC resistance, when they performed a multivariate logistic regression analysis, only basal FSH levels and FSH receptor genotype predicted ovulation when corrected for a number of variables.
“These results show that there is a significant influence of pharmacogenetic factors in ovulation induction,” commented Annelies Overbeek, first author on the study, who also stressed that, owing to the retrospective nature of the study, there were nongenetic risk factors previously identified to affect CC response that could not be evaluated.
“It might be very interesting to perform a multicenter study in which this particular polymorphism and other genes can be looked at to evaluate the outcome of ovulation induction and in which the abovementioned other risk factors can be taken into account. We are currently collaborating with other centers in The Netherlands to put this into effect,” explained Overbeek.
“It might be possible to predict whether or not a therapy will be successful, and this might save precious time, especially in infertility patients.”
“Exploring these and other pathways may allow tailored therapy for each patient in the near future. It might be possible to predict whether or not a therapy will be successful, and this might save precious time, especially in infertility patients.” With thanks to Dr Overbeek for her comments.
Source: Overbeek A, Kuijper EA, Hendriks ML et al.: Clomiphene citrate resistance in relation to follicle-stimulating hormone receptor Ser680Ser-polymorphism in polycystic ovary syndrome. Hum. Reprod. 1(1), 1–7 (2009).
in brief…
Kado DM, Lui LY, Ensrud KE, Fink HA, Karlamangla AS, Cummings SR: Ann. Intern. Med. 150(10), 681–687 (2009).
Although it has been speculated that hyperkyphosis, or ‘dowager's hump’, may be associated with earlier mortality, previous studies have not controlled for vertebral fractures, a disease that is often silent. Researchers studied a total of 610 women aged 67–93 years for both spinal curvature and presence of vertebral fractures and found that hyperkyphosis predicts an increased risk of death in older white women, independent of both spinal osteoporosis and severity of vertebral fractures. The study also found that women with previous vertebral fractures and increasing degrees of spinal curvature were at increased risk of mortality from hyperkyphosis, irrespective of age, smoking, spinal bone-mineral density or the number and severity of spinal fractures. The study warrants the acceptance of hyperkyphosis as a clinically important finding; the study's investigators emphasize that hyperkyphosis is often associated with poor health and should be recognized as a multifactorial health condition in older individuals.
Champney KP, Frederick PD, Bueno H: Heart 95(11), 895–899 (2009).
Younger women are known to have a higher mortality than man of similar age following a myocardial infarction (MI); however, whether this relationship varies between ST-elevation MI (STEMI) and non-STEMI (NSTEMI) types is unknown. Researchers of this study accordingly conducted a retrospective cohort study of 126,172 STEMI and 235,257 NSTEMI patients from hospitals participating in the US National Registry of Myocardial Infarction. Investigators found that a younger age was associated with a greater risk for in-hospital mortality in both STEMI and NSTEMI women; female NSTEMI patients aged 50 years and younger were at 68% greater risk, while the risk was 56% for female STEMI patients of the same age group. By contrast, older women fare just as well, if not better, than older men following a MI; although women aged 50–59, 60–69 and 70–79 years had a 78, 45 and 8%, greater risk for death, respectively, compared with men, there was no increased risk for women between the ages of 80–89 years.
New surgical technique offers hope for cervical cancer patients
Patients with early-stage cervical cancer may benefit from a new surgical technique that minimizes the complications associated with a radical hysterectomy, with reduced morbidity and risk of local tumor recurrence, compared with traditional methods.
Carcinoma of the uterine cervix is the second most frequent cancer affecting women worldwide. Researchers of the University of Leipzig, Germany, noted that cervical cancer tends to spread locally within the Müllerian compartment for relatively long phases, prompting them to develop a new, more highly targeted technique. Total mesometrial resection (TMMR) involves complete removal of the Müllerian compartment, except its distal part, specifically removing the Fallopian tubes and uterus, the proximal and middle vagina, sparing the pelvic autonomic nerves. By contrast, usual treatment for early-stage disease patients involves radical hysterectomy and radiotherapy.
Researchers in this study assessed the effectiveness of TMMR in 212 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB, IIA and selected IIB cervical cancer between 1999 and 2008.
Recurrence-free survival of subjects was 94%, with a 5-year survival rate of 96% with low treatment-related disease. The 63% of patients with high-risk histopathologic factors had an overall recurrence rate of 5%; by contrast, the overall recurrence rate observed in similar patients treated with traditional radical hysterectomy is 28%. Only ten patients experienced recurrence at a median follow-up period of 41 months. A total of 63% of patients did not experience any treatment-related complications.
The results provide evidence that early cervical cancer is confined to the Müllerian compartment. According to the authors, surgical resection of this area appears to be essential for pelvic tumour control, as they comment that, “Based on historical controls, TMMR without adjuvant radiation has the potential to improve survival by 15–20%.” Further evaluation of the technique with multi-institutional controlled trials is necessary to validate the study's results.
Source: Höckel M, Horn LC, Manthey N: Resection of the embryologically defined uterovaginal (Müllerian) compartment and pelvic control in patients with cervical cancer: a prospective analysis. Lancet Oncol. DOI:10.1016/S1470–2045(09)70100–70107 (2009) (Epub ahead of print).
Improved perinatal outcomes observed in obese expectant mothers participating in a nutritionally monitored trial
Reinforcing the recent guideline changes with regard to gestational weight gain recommendations, a study published in the Journal of the National Medical Association revealed that obese women who gained little or no weight during pregnancy had better outcomes than obese women who gained more weight.
The US Institute of Medicine and the National Research Council recently updated their guidelines to recommend that obese expectant mothers should aim to gain approximately 11–20 lbs during pregnancy; a reduction from the minimum weight gain of 15 lbs recommended since 1990. A team of researchers led by Yvonne Thornton, from New York Medical College, USA, divided 232 obese women with a BMI of over 30 who were pregnant with a single fetus between 8 and 12 weeks of gestation into two study groups. A control group was advised to ‘eat to appetite’ and an intervention group was given nutritional counseling and was told to keep a food diary while they were placed on a diet limiting calorie intake to between 2000 and 3500 per day, depending on their prepregnancy weight.
At the end of pregnancy, the average weight gain of obese women in the control group was 31 lbs, compared with an 11 lb average weight gain in women in intervention group. A total of 23 extremely obese women actually lost weight during their pregnancy.
Women in the intervention group also had fewer cesarean sections, lower rates of gestational diabetes and hypertension, and fewer women delivered newborns weighing more than 10 lb. There were no growth-restricted babies in either group.
“Women who are obese when beginning a pregnancy are, by definition, unhealthy,” noted Thornton. “To say that they should gain even more weight is counterintuitive, and our study bears that out.”
However, the authors do not advocate a one-size-fits-all weight gain figure for obese expectant mothers. Thornton adds, “We need to focus on making these women healthier by getting them to eat a well-balanced diet, similar to the types of moderate calorie-restricted diets that women with gestational diabetes are put on with no ill effects.”
Sources: Thornton YS, Smarkola C, Kopacz SM, Ishoof SB: Perinatal outcomes in nutritionally monitored obese pregnant women: a randomized clinical trial. J. Natl Med. Assoc. 101(6) 569–577 (2009). The National Research Council (http://sites.nationalacademies.org)