Raloxifene Shown to be as Effective as Tamoxifen in Preventing Invasive Breast Cancer
Initial results of the Study of Tamoxifen and Raloxifene, or STAR, show that the drug raloxifene, currently used to prevent and treat osteoporosis in postmenopausal women, works as well as tamoxifen in reducing breast cancer risk for postmenopausal women at increased risk of the disease. In STAR, both drugs reduced the risk of developing invasive breast cancer by about 50 percent. In addition, within the study, women who were prospectively and randomly assigned to take raloxifene daily, and who were followed for an average of about four years, had 36 percent fewer uterine cancers and 29 percent fewer blood clots than the women who were assigned to take tamoxifen. Uterine cancers, especially endometrial cancers, are a rare but serious side effect of tamoxifen. Both tamoxifen and raloxifene are known to increase a woman's risk of blood clots.
STAR, one of the largest breast cancer prevention clinical trials ever conducted, enrolled 19,747 postmenopausal women who were at increased risk of the disease. Participants were randomly assigned to receive either 60 mg of raloxifene (Evista®) or 20 mg of tamoxifen (Nolvadex®) daily for five years. The trial is coordinated by the National Surgical Adjuvant Breast and Bowel Project (NSABP), a network of cancer research professionals, and is sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health.
"This optimistic news from STAR is a significant step in breast cancer prevention," said John E. Niederhuber, M.D., currently providing leadership at NCI. "These results, once again, demonstrate the critical importance of clinical trials in our efforts to establish evidence-based practices."
"In 1998, the landmark Breast Cancer Prevention Trial showed that tamoxifen could reduce the risk of invasive breast cancer in premenopausal and postmenopausal women by nearly 50 percent," said Norman Wolmark, M.D., NSABP chairman. "Today, we can tell you that for postmenopausal women at increased risk of breast cancer, raloxifene is just as effective, without some of the serious side effects known to occur with tamoxifen."
Women taking either drug had equivalent numbers of strokes, heart attacks, and bone fractures. Both raloxifene and tamoxifen are known to protect bone health; it is estimated that half a million postmenopausal women are currently taking raloxifene by prescription to prevent or treat osteoporosis. Additionally, the initial results from STAR suggest that raloxifene does not increase the risk of developing a cataract, as tamoxifen does."Although no drugs are without side effects, tamoxifen and raloxifene are vital options for women who are at increased risk of breast cancer and want to take action," said Leslie Ford, M.D., associate director for clinical research in NCI's Division of Cancer Prevention. "For many women, raloxifene's benefits will outweigh its risks in a way that tamoxifen's benefits do not.
" The STAR researchers also tracked known menopausal side effects that occur with both drugs and monitored the participants' quality of life. The data show that side effects of both drugs were mild to moderate in severity, and quality of life was the same for both drugs.Participants in STAR are now receiving information about which drug they were taking. Women assigned to raloxifene will continue to be provided with the drug until they have completed five years of treatment. Those women assigned to tamoxifen can choose to continue taking tamoxifen or to receive raloxifene to complete their five years of treatment.
Study details include:
STAR enrolled 19,747 women. This data analysis is based on the 19,471 women for whom complete study information was available. The numbers of invasive breast cancers in both groups of women were statistically equivalent. Among the 9,745 women in the raloxifene group, 167 developed invasive breast cancer, compared to 163 of 9,726 women in the tamoxifen group. More than half of the women who joined STAR had had a hysterectomy and, therefore, were not at risk of uterine cancer. For those women with a uterus, 36 of 4,732 who were assigned to take tamoxifen developed uterine cancers (mainly endometrial cancer) compared to 23 of 4,712 women who were assigned to take raloxifene. In STAR, women in the raloxifene group had 29 percent fewer deep vein thromboses (blood clots in a major vein) and pulmonary embolisms (blood clots in the lung) than women in the tamoxifen group. Specifically, 87 of 9,726 women in the tamoxifen group had a deep vein thrombosis compared to 65 of 9,745 women taking raloxifene. In addition, 54 of 9,726 women taking tamoxifen developed pulmonary embolisms compared to 35 of 9,745 women taking raloxifene. The number of strokes occurring in both groups of women was statistically equivalent: 53 of 9,726 women in the tamoxifen group and 51 of 9,745 women in the raloxifene group had a stroke during the trial. There was no difference in deaths from strokes: 6 of 9,726 women in the tamoxifen group and 4 of 9,745 women in the raloxifene group died from this event. Women at increased risk of stroke (those with uncontrolled hypertension or uncontrolled diabetes, or a history of stroke, transient ischemic attack, or atrial fibrillation) were not eligible to participate in STAR. While tamoxifen has been shown to reduce, by half, the incidence of lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS), raloxifene did not have an effect on these diagnoses. (LCIS and DCIS are sometimes called noninvasive breast cancers.) Of the 9,726 women taking tamoxifen, 57 developed LCIS or DCIS, compared to 81 of 9,745 taking raloxifene. This result confirms data reported in 2004 in a large study of raloxifene, the Continued Outcomes Relevant to Evista (or CORE Trial). Women who participated in STAR were postmenopausal, at least 35 years old, and had an increased risk of breast cancer as determined by their age, family history of breast cancer, personal medical history, age at first menstrual period, and age at first live birth. Before participating in the study, the women were instructed about the potential risks and benefits of tamoxifen and raloxifene and then were asked to sign an informed consent document. STAR investigators will present additional data at the 42nd annual meeting of the American Society for Clinical Oncology (ASCO) from June 2-6, 2006, in Atlanta, Ga. "This is an important and long awaited trial," said Sandra J. Horning, M.D., president of ASCO, "and we look forward to further discussion and analysis at the ASCO annual meeting that will address the observed differences in toxicity and prevention of non-invasive breast cancers with the two treatment approaches." A manuscript is also being submitted to a peer-reviewed journal for publication. The maker of tamoxifen, AstraZeneca Pharmaceuticals, Wilmington, Del., and the maker of raloxifene, Eli Lilly and Company, Indianapolis, Ind., provided their drugs and matching placebos for the trial without charge to participants. Eli Lilly and Company also gave NSABP support to defray recruitment costs at the participating centers and to help local investigators conduct the study.
One in five youth with diabetes has already developed two or more additional risk factors for premature heart disease.
The issue of Diabetes Care also includes new treatment guidelines developed by the
American Diabetes Association to help physicians choose the most appropriate therapies for lowering blood glucose levels in people with type 2 diabetes.
Overall roughly 20 percent of young people with diabetes (92% in those with type 2 and 14% in those with type 1) experience at least two additional cardiovascular disease risk factors, according to a new study sponsored by the Centers for Disease Control and Prevention, and the National Institutes of Health. As is the case among adults, CVD risk factors were higher among minority and ethnic groups than they were among non-Hispanic whites. They were also higher among girls.
The researchers recommended better weight, lipid, and blood pressure control in youth with diabetes to prevent or delay the development of cardiovascular disease as they grow up.
Management of hyperglycemia in type 2 diabetes is extremely important, especially given the increased prevalence of this disease. Studies have shown that maintaining blood glucose levels as close to the nondiabetic range as possible helps to prevent the serious complications of type 2 diabetes, such as eye and kidney disease and nerve damage. Lowering blood glucose levels has also been shown to prevent heart disease in people with type 1 diabetes.
To help physicians select the most appropriate and effective therapies for lowering blood glucose levels, the American Diabetes Association has published in this month's Diabetes Care a consensus statement describing the treatment of elevated blood glucose. The guidelines urge physicians to make "normal" glycemic levels a goal for most patients (i.e. an A1C level less than 6.1 percent, with any A1C greater than or equal to 7% a call to adjust therapy); to first attempt to lower blood glucose levels with lifestyle interventions and the drug metformin; to add any one of three classes of medications if glycemic levels are not quickly achieved; to use insulin therapy when other treatment options do not result in patients achieving their target goals; and to initiate and adjust interventions rapidly to lower glycemic levels to target, with adjustments usually no less frequent than every three months.
With the emergence of many different medications for the treatment of type 2 diabetes in recent years, these recommendations set a precedent in the treatment of diabetes by providing health care providers with a specific treatment algorithm to determine the most appropriate intervention for their patients with type 2. "The consensus panel believes that the algorithm we describe can be easily implemented," said Dr. David M. Nathan, the Chair of the Panel. He added, "We have recommended that clinicians use the generic drug metformin in combination with lifestyle changes immediately upon diagnosis, and that only three other drug classes are necessary for most patients, should metformin plus lifestyle intervention prove insufficient. Also, it's no longer acceptable to delay the initiation and adjustment of glucose-lowering therapy when metabolic goals are not being met."
Researchers identify potential ovarian cancer stem cells
Massachusetts General Hospital (MGH) researchers have identified potential ovarian cancer stem cells, which may be behind the difficulty of treating these tumors with standard chemotherapy.
Understanding more about the stem-like characteristics of these cells could lead to new approaches to treating ovarian cancer, which kills more than 16,000 U.S. women annually and is their fifth most common cause of cancer death.
We feel these stem-like cancer cells may be resistant to traditional chemotherapy and could be responsible for the ultimately fatal drug-resistant recurrence that is characteristic of ovarian cancer," says Paul Szotek, MD, of the MGH Pediatric Surgical Research Laboratories, first author of the PNAS report. "We believe this likely is the first time stem-like cells have been found in models of ovarian cancer and in cells associated with human ovarian cancer."
Several recent studies have identified tiny populations of tumor cells that appear to act like stem cells, driving the tumor's ability to grow and spread. If some of these specialized cells escaped destruction by chemotherapy or radiation, the tumor would be able to recur quickly, often in a form resistant to chemotherapy. Similar cancer stem cells have been previously identified in leukemia and breast cancer and in cell lines of central nervous system and gastrointestinal tumors.
Standard treatment for ovarian cancer - surgical removal of all involved tissues followed by chemotherapy - usually appears successful, but treatment-resistant tumors recur in the vast majority of patients, leading to a five-year survival rate of less than 30 percent. Those factors and other observations suggested that cancer stem cells may also be found with ovarian tumors, leading to the current study.
The MGH researchers first examined two mouse ovarian cancer cell lines and identified cells with characteristics of the cancer stem cells found with other tumors. They then observed a small percentage of stem-like cells in human ovarian cancer lines and in cells taken from ascites fluid that had accumulated within the abdomen of several ovarian cancer patients. When mouse ovarian tumor stem-like cells were injected under the skin of mice, they led to the formation of new tumors much faster than did injections of regular tumor cells.
Although the potential ovarian cancer stem cells were less responsive than regular tumor cells to in vitro treatment with the chemotherapy drug doxorubicin, the stem-like cells remained sensitive to repeated treatment with Mullerian Inhibiting Substance (MIS). This protein, important in the normal development of sexual organs, has been studied for its potential to treat several reproductive tumors by Patricia Donahoe, MD, director of the MGH Pediatric Surgical Research Laboratories and senior author of the PNAS study, and David MacLaughlin, PhD, associate director of the labs and a study co-author.
"We feel that non-traditional, possibly innovative approaches will be required to eradicate these stem-like cancer cells and ultimately cure ovarian cancer. With its potential to maintain the ability to inhibit the proliferation of these cells, MIS may play a role in these new therapeutic approaches," Donahoe says. "We intend to keep searching for stem-like cells in patient tumor samples and to study their responsiveness to both chemotherapeutic agents and to novel agents specifically targeted to stem cell as individualized therapy of the future." Donahoe is the Marshall K. Bartlett Professor of Surgery at Harvard Medical School.
Trends in Breast Cancer by Race and Ethnicity: Update 2006
Carol Smigal, MPH, Ahmedin Jemal, DVM, PhD, Elizabeth Ward, PhD, Vilma Cokkinides, PhD, MSPH, Robert Smith, PhD, Holly L. Howe, PhD and Michael Thun, MD, MS
In this article, the American Cancer Society (ACS) provides estimates of new breast cancer cases and deaths in 2006 and describes trends in incidence, mortality, and survival for female breast cancer in the United States. These estimates are based on incidence data from the National Cancer Institute (NCI) and the North American Association of Central Cancer Registries, which includes state data from NCI and the National Program of Cancer Registries of the Centers for Disease Control and Prevention and mortality data from the National Center for Health Statistics for the most recent years available (1975 to 2002).
Trends in incidence vary by age, race, socioeconomic status, and stage. The continuing increase in incidence (all stages combined) is limited to White women age 50 and older; recent trends are stable for African American women age 50 and older and White women under age 50 years and are decreasing for African American women under age 50 years. Although incidence rates (all races combined) are substantially higher for women age 50 and older (375.0 per 100,000 females) compared with women younger than 50 years (42.5 per 100,000 females), approximately 23% of breast cancers are diagnosed in women younger than 50 years because those women represent 73% of the female population. For women age 35 and younger, age-specific incidence rates are slightly higher among African Americans compared with Whites but then cross over so that Whites have substantially higher incidence at all later ages. Among women of all races and ages, breast cancer mortality rates declined at an average rate of 2.3% per year between 1990 and 2002, a trend that reflects progress in both early detection and treatment. However, death rates in African American women remain 37% higher than in Whites, despite lower incidence rates.
Although, in national surveys, approximately 70% of women age 40 years and older report having had a mammogram in the past 2 years, rates vary by race/ethnicity and are markedly lower among women with lower levels of education, without health insurance, and in recent immigrants. Furthermore, a recent study suggests that the true percentage of women having regular mammography is lower than reported in survey data. Encouraging patients age 40 years and older to have annual mammography and clinical breast exam is the single most important step that clinicians can take to reduce suffering and death from breast cancer. Clinicians should also ensure that patients at high risk of breast cancer are identified and offered appropriate referrals and treatment. Continued progress in the control of breast cancer will require sustained and increased efforts to provide high-quality screening, diagnosis, and treatment to all segments of the population.
A Consensus Update by the American Cancer Society and US Multi-Society Task Force on Colorectal Cancer
Douglas K. Rex, MD, Charles J. Kahi, MD, MSc, Bernard Levin, MD, Robert A. Smith, PhD, John H. Bond, MD, Durado Brooks, MD, MPH, Randall W. Burt, MD, Tim Byers, MD, MPH, Robert H. Fletcher, MD, MSc, Neil Hyman, MD, David Johnson, MD, Lynne Kirk, MD, David A. Lieberman, MD, Theodore R. Levin, MD, Michael J. O’Brien, MD, MPH, Clifford Simmang, MD, Alan G. Thorson, MD and Sidney J. Winawer, MD
Patients with resected colorectal cancer are at risk for recurrent cancer and metachronous neoplasms in the colon. This joint update of guidelines by the American Cancer Society (ACS) and US Multi-Society Task Force on Colorectal Cancer addresses only the use of endoscopy in the surveillance of these patients. Patients with endoscopically resected Stage I colorectal cancer,
II surgically resected Stage
III cancers, and Stage
IV cancer resected for cure (isolated hepatic or pulmonary metastasis) are candidates for endoscopic surveillance.
The colorectum should be carefully cleared of synchronous neoplasia in the perioperative period. In nonobstructed colons, colonoscopy should be performed preoperatively. In obstructed colons, double contrast barium enema or computed tomography colonography should be done preoperatively, and colonoscopy should be performed 3 to 6 months after surgery. These steps complete the process of clearing synchronous disease.
After clearing for synchronous disease, another colonoscopy should be performed in 1 year to look for metachronous lesions. This recommendation is based on reports of a high incidence of apparently metachronous second cancers in the first 2 years after resection. If the examination at 1 year is normal, then the interval before the next subsequent examination should be 3 years. If that colonoscopy is normal, then the interval before the next subsequent examination should be 5 years. Shorter intervals may be indicated by associated adenoma findings (see Postpolypectomy Surveillance Guideline).
Shorter intervals are also indicated if the patient’s age, family history, or tumor testing indicate definite or probable hereditary nonpolyposis colorectal cancer. Patients undergoing low anterior resection of rectal cancer generally have higher rates of local cancer recurrence, compared with those with colon cancer. Although effectiveness is not proven, performance of endoscopic ultrasound or flexible sigmoidoscopy at 3- to 6-month intervals for the first 2 years after resection can be considered for the purpose of detecting a surgically curable recurrence of the original rectal cancer.
URINE TEST MAY IMPROVE DETECTION OF BLADDER CANCER RECURRENCE
"A test like the NMP22 assay, which is accurate and easy to administer, I believe, will help identify and treat patients earlier, when they have a better chance for a good outcome," said lead study author H. Barton Grossman, MD, Professor and Deputy Chairperson of the MD Anderson Cancer Center Urology Department.
The study involved 668 patients with a history of bladder cancer who were being followed up for recurrences at 23 clinical in nine US states. Each participant gave a voided urine sample before undergoing cystoscopy. Part of the urine sample was used for traditional cytology, and some was used for the BladderChek test. The researchers compared the detection rates of each method alone and of each urine test combined with cystoscopy. The test’s manufacturer, Matritech, Inc., was involved in designing, funding, and reviewing the study.
Bladder cancer was diagnosed in 103 patients. Cystoscopy was the most accurate test, finding 94 of those cancers (sensitivity = 91%) on its own. The BladderChek test alone found only 51 cancers, but those included eight of the nine cancers missed by cystoscopy. BladderChek combined with cystoscopy found 102 of the 103 cancers (sensitivity = 99%), significantly more than cystoscopy alone (P = 0.005).
Urine cytology also improved the performance of cystoscopy, but not by a statistically significant amount (P = 0.08). It found only three of the nine cancers cystoscopy missed. Together, the two tests found 97 of 103 cancers (sensitivity = 94%). Urine cytology alone found just 12 cancers.
That’s unusually poor performance for urine cytology, especially because many of the missed lesions were high-grade, said Samuel Cohen, MD, PhD, Professor of Oncology and Chair of Pathology and Microbiology at the University of Nebraska Medical Center and a member of the panel that wrote the bladder cancer treatment guidelines for the National Comprehensive Cancer Network. He was not involved in the study.
"I think these data are very interesting, especially given the size of the study and because they were using routine practice," he said. "I was a little concerned that the cytology results were so poor. That’s lower than I’ve seen in routine labs."
The study authors attribute their poor results for urine cytology to variability caused by using multiple facilities rather than a single facility to interpret the samples. And they say the BladderChek test offers several advantages over urine cytology beyond the difference in sensitivity seen in this study.
Chief among them, the BladderChek test can be done in a doctor’s office and requires no special equipment or training. Results are typically available in less than an hour. By contrast, urine cytology requires a specialized lab analysis, and results may take days to be returned. The BladderChek test is also less expensive than urine cytology, the authors say. Because of its weak ability to detect cancer when used alone, Grossman says the BladderChek test should only be used in conjunction with cystoscopy, not as a replacement for that procedure.
