October 1, 2010 — A steady improvement in survival from breast cancer over the past 6 decades has been shown in a review of records from the University of Texas M.D. Anderson Cancer Center in Houston.
The review shows a "dramatic shift in the natural history of the disease," said Aman Buzdar MD, professor of medicine and breast medical oncology at M.D. Anderson.
"If patients are appropriately managed, they have a much better chance of surviving breast cancer today than they would have had 20, 30, or even 10 years ago, because therapies are constantly evolving and improving," he added.
Dr. Buzdar was speaking last week at an American Society for Clinical Oncology presscast; the data were presented at the 2010 Breast Cancer Symposium, in Washington, DC, on October 2, 2010.
"This is an elegant review of patient records from a single institution that shows major improvements in breast cancer survival over recent years," said Jennifer Obel, MD, from the NorthShore University Health System in Evanston, Illinois, who was moderating the presscast.
Although these data come from a single institution, both Dr. Buzdar and Dr. Obel said that the improvements in survival should be generalizable to other institutions and to the community.
Review of Past 60 Years
Dr. Buzdar and colleagues examined records dating back to 1944 for nearly 57,000 breast cancer patients, of whom 12,809 had initial therapy at M.D. Anderson. Patients were divided into 3 general cancer stages — local, regional, and distant (with metastases) — and 10-year survival rates were calculated.
Improvements in survival were seen at each cancer stage, and in some cases the shift was dramatic, Dr. Buzdar noted.
For example, among women with regional breast cancer in 1944 to 1954, only 16.2% were still alive 10 years later, compared with 74% in the most recent decade (1995 to 2004) analyzed.
The improvements are due to a number of factors, Dr. Buzdar said, including earlier diagnosis and the combined modality approach to treatment, where systemic therapy is offered to women at high risk for recurrence, even though the initial presentation of the disease is local.
Ten-Year Survival Rates by Stage of Breast Cancer
Decade Local, % Regional, % Distant, % Overall survival, % (n)
1944–54 55 16 3 25 (410)
1955–64 56 24 4 30 (1449)
1965–74 59 29 5 35 (1387)
1975–84 72 47 7 49 (1983)
1985–94 79 57 11 62 (2927)
1995–2004 86 74 22 77 (4653)
These data show that only 1 in 4 women were still alive after 10 years in the 1950s, whereas 3 in 4 women in recent years were, said Dr. Obel. "Care of breast cancer patients has evolved at a rapid pace," she added.
The 2010 Breast Cancer Symposium is cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the American Society of Clinical Oncology, the American Society of Radiation Oncology, the National Consortium of Breast Centers, the Society of Surgical Oncology, and Susan G. Komen for the Cure.
2010 Breast Cancer Symposium: Abstract 172. Presented October 2, 2010.
Τρίτη 5 Οκτωβρίου 2010
OUT OF HOSPITAL HYPOTHERMIA FOR CARDIAC ARREST
October 4, 2010 (Las Vegas, Nevada) — When emergency medical services added induced hypothermia with cold saline to standard postresuscitation care, the survival rate of patients with a return of spontaneous circulation in the field nearly doubled, according to a study presented here at the American College of Emergency Physicians 2010 Scientific Assembly.
Researchers evaluated the hospital discharge summaries of survivors of out-of-hospital return of spontaneous circulation before and after the introduction of a new protocol for therapeutic hypothermia.
According to their results, overall survival before the protocol was implemented was 17.2%, whereas after it was implemented, overall survival was 28.8%, with an adjusted odds ratio of 1.9 (95% confidence interval [CI], 1.2 - 3.1).
Importantly, survival rates improved from the before to the after groups for all initial rhythms, including ventricular fibrillation (VF)/ventricular tachycardia (VT) (41.8% vs 54.5%), pulseless electrical activity (PEA) (4.4% vs 16.1%), and asystole (3.8% vs 10.1%). The best survival outcomes were seen for VF/VT, which had an adjusted odds ratio of 8.6 (95% CI, 5.5 - 13.3).
"It was very encouraging that we saw a trend toward an improvement in survival in each rhythm," said Brent Myers, MD, a coauthor on the study and medical director for the Wake County EMS System, headquartered in Raleigh, North Carolina.
Even more encouraging, he said, was the finding that there were no statistically significant differences in the before and after groups in the proportion of patients with a good neurologic outcome. Previous studies have indicated that patients at risk for ischemic brain injuries might have better outcomes if treated with therapeutic hypothermia.
"The outcome measure for the study was primarily discharge from the hospital, but the more important question is whether the [Pittsburgh Cerebral Performance Categories] scores at the time of discharge indicated that the patient was neurologically intact," he said.
"At the time of discharge, 3 of 4 patients in both arms were neurologically intact, but we just doubled the survival rate in the hypothermia group and still had a very robust number of patients who left the hospital," he said. "So we were very happy that these individuals were not left in a persistent vegetative state."
The study comprised 227 patients in the before group and 413 in the after group; baseline characteristics were similar in both groups, including mean age (65.9% vs 65.2%), male sex (52.1% vs 59.6%), mean response interval from 911 call to first arriving unit (5.6 vs 5.6 minutes), and VF/VT rhythm (35.0% vs 38.4%).
Dr. Myers noted that, contrary to some assumptions, age did not strongly affect the chance of survival with therapeutic hypothermia.
"We found in the odds ratio of survival that age does affect survival, but the decrease in survival is small," he noted, adding that increasing age was not significantly associated with survival.
According to Brian J. O'Neil, MD, moderator of the session, the study offers some impressive survival statistics for therapeutic hypothermia.
"I wasn't surprised with the VF/VT patients, but I was very surprised with the recovery rate of the PEA and asystole patients, he said. "These are among the best outcomes in the country."
He said hospitals might have various reasons for not establishing a therapeutic hypothermia protocol, but the benefits clearly outweigh the costs.
"I have heard all of the reasons, including [that it is] too much of a capital expenditure and too labor-intensive, but they are weak arguments," said Dr. O'Neil, associate chair of research and director of basic science research at Wayne State University School of Medicine, in Detroit, Michigan.
"Ice and cooling blankets cost nothing and the cost and labor to care for nursing home patients makes these arguments short-sighted."
Dr. Myers has disclosed no relevant financial relationships, although one member of the research team was on the Physio-Control EMS Fellowship during the project. Dr. O'Neil reports receiving grant support and being on the speakers board for Medivance, maker of the Arctic Sun therapeutic temperature management product.
American College of Emergency Physicians (ACEP) 2010 Scientific Assembly: Abstract 13. Presented September 28, 2010.
Researchers evaluated the hospital discharge summaries of survivors of out-of-hospital return of spontaneous circulation before and after the introduction of a new protocol for therapeutic hypothermia.
According to their results, overall survival before the protocol was implemented was 17.2%, whereas after it was implemented, overall survival was 28.8%, with an adjusted odds ratio of 1.9 (95% confidence interval [CI], 1.2 - 3.1).
Importantly, survival rates improved from the before to the after groups for all initial rhythms, including ventricular fibrillation (VF)/ventricular tachycardia (VT) (41.8% vs 54.5%), pulseless electrical activity (PEA) (4.4% vs 16.1%), and asystole (3.8% vs 10.1%). The best survival outcomes were seen for VF/VT, which had an adjusted odds ratio of 8.6 (95% CI, 5.5 - 13.3).
"It was very encouraging that we saw a trend toward an improvement in survival in each rhythm," said Brent Myers, MD, a coauthor on the study and medical director for the Wake County EMS System, headquartered in Raleigh, North Carolina.
Even more encouraging, he said, was the finding that there were no statistically significant differences in the before and after groups in the proportion of patients with a good neurologic outcome. Previous studies have indicated that patients at risk for ischemic brain injuries might have better outcomes if treated with therapeutic hypothermia.
"The outcome measure for the study was primarily discharge from the hospital, but the more important question is whether the [Pittsburgh Cerebral Performance Categories] scores at the time of discharge indicated that the patient was neurologically intact," he said.
"At the time of discharge, 3 of 4 patients in both arms were neurologically intact, but we just doubled the survival rate in the hypothermia group and still had a very robust number of patients who left the hospital," he said. "So we were very happy that these individuals were not left in a persistent vegetative state."
The study comprised 227 patients in the before group and 413 in the after group; baseline characteristics were similar in both groups, including mean age (65.9% vs 65.2%), male sex (52.1% vs 59.6%), mean response interval from 911 call to first arriving unit (5.6 vs 5.6 minutes), and VF/VT rhythm (35.0% vs 38.4%).
Dr. Myers noted that, contrary to some assumptions, age did not strongly affect the chance of survival with therapeutic hypothermia.
"We found in the odds ratio of survival that age does affect survival, but the decrease in survival is small," he noted, adding that increasing age was not significantly associated with survival.
According to Brian J. O'Neil, MD, moderator of the session, the study offers some impressive survival statistics for therapeutic hypothermia.
"I wasn't surprised with the VF/VT patients, but I was very surprised with the recovery rate of the PEA and asystole patients, he said. "These are among the best outcomes in the country."
He said hospitals might have various reasons for not establishing a therapeutic hypothermia protocol, but the benefits clearly outweigh the costs.
"I have heard all of the reasons, including [that it is] too much of a capital expenditure and too labor-intensive, but they are weak arguments," said Dr. O'Neil, associate chair of research and director of basic science research at Wayne State University School of Medicine, in Detroit, Michigan.
"Ice and cooling blankets cost nothing and the cost and labor to care for nursing home patients makes these arguments short-sighted."
Dr. Myers has disclosed no relevant financial relationships, although one member of the research team was on the Physio-Control EMS Fellowship during the project. Dr. O'Neil reports receiving grant support and being on the speakers board for Medivance, maker of the Arctic Sun therapeutic temperature management product.
American College of Emergency Physicians (ACEP) 2010 Scientific Assembly: Abstract 13. Presented September 28, 2010.
Δευτέρα 4 Οκτωβρίου 2010
A CHEAP COMBINATION TREATMENT FOR HER2+ BREAST CANCER
NATIONAL HARBOR, Md. -- Almost 80% of patients with HER2-positive metastatic breast cancer had responses or stable disease in a small preliminary study of a chemotherapy-targeted therapy combination as first-line treatment.
Eight of 18 patients had objective responses with the combination of trastuzumab (Herceptin), bevacizumab (Avastin), and docetaxel (Taxotere), and six others had prolonged stable disease. Median time to progression exceeded one year.
The regimen was generally well tolerated, including no increased risk of cardiotoxicity, according to a presentation here at the American Society of Clinical Oncology's Breast Cancer Symposium.
"The study is ongoing, so these data must be considered preliminary, but the combination has shown promising activity thus far," Bhuvaneswari Ramaswamy, MD, of Ohio State University in Columbus, told MedPage Today. "If the results continue to be favorable, eventually we would like to see this combination evaluated in a randomized trial."
HER2-positive breast cancers often have increased expression of vascular endothelial growth factor (VEGF). The combination of trastuzumab and the VEGF inhibitor bevacizumab has demonstrated activity in preclinical and clinical studies, including a 54% response rate in a small phase II study of first-line therapy for metastatic breast cancer, said Ramaswamy. However, cardiotoxicity complicated treatment in almost 40% of the cases.
Docetaxel has demonstrated single-agent activity in breast cancer, and has proven to be safe and effective in combination with either trastuzumab or bevacizumab.
Thus, the clinical history of the three drugs in breast cancer provided a strong rationale for using them in combination, Ramaswamy added.
To evaluate the combination, investigators enrolled patients with previously untreated HER2-positive metastatic breast cancer. Eligibility criteria included HER2 overexpression by immunohistochemistry (3+) or fluorescence in situ hybridization, normal left ventricular ejection fraction (LVEF), and no brain metastases.
All patients received six cycles of the three-drug combination, at which point docetaxel could be discontinued at physician discretion. Patients continued to receive the targeted therapies until disease progression or development of unacceptable toxicity. LVEF was assessed after every three cycles of therapy.
Ramaswamy reported data on the first 18 patients enrolled in the ongoing trial, including 16 patients evaluable for response. Grade 3-4 hematologic toxicity consisted of one case of neutropenia and two each of febrile neutropenia (one fatal) and infection.
Grade 3-4 nonhematologic toxicity consisted of one case each of nausea, vomiting, thrombosis, nephrotic syndrome, vision disturbance, fatigue, upper respiratory tract infection, and anorexia, and two cases of excessive tearing of the eyes.
One patient had an asymptomatic decline in LVEF and one had wound dehiscence.
Ramaswamy reported that eight patients had partial responses and six others had stable disease, resulting in a clinical benefit rate of 77.7% (14 of 18). Of 16 patients included in a survival analysis, median progression-free survival was 55.9 weeks. Six patients progressed or died.
Three patients had stable disease for more than six months, including one patient who has remained stable for more than two years while continuing targeted therapy.
Ramaswamy said accrual for the study continues at her institution and at the University of Pittsburgh. Data from correlational studies of circulating tumor cells and circulating endothelial cells will be reported at a later date, she said.
Eight of 18 patients had objective responses with the combination of trastuzumab (Herceptin), bevacizumab (Avastin), and docetaxel (Taxotere), and six others had prolonged stable disease. Median time to progression exceeded one year.
The regimen was generally well tolerated, including no increased risk of cardiotoxicity, according to a presentation here at the American Society of Clinical Oncology's Breast Cancer Symposium.
"The study is ongoing, so these data must be considered preliminary, but the combination has shown promising activity thus far," Bhuvaneswari Ramaswamy, MD, of Ohio State University in Columbus, told MedPage Today. "If the results continue to be favorable, eventually we would like to see this combination evaluated in a randomized trial."
HER2-positive breast cancers often have increased expression of vascular endothelial growth factor (VEGF). The combination of trastuzumab and the VEGF inhibitor bevacizumab has demonstrated activity in preclinical and clinical studies, including a 54% response rate in a small phase II study of first-line therapy for metastatic breast cancer, said Ramaswamy. However, cardiotoxicity complicated treatment in almost 40% of the cases.
Docetaxel has demonstrated single-agent activity in breast cancer, and has proven to be safe and effective in combination with either trastuzumab or bevacizumab.
Thus, the clinical history of the three drugs in breast cancer provided a strong rationale for using them in combination, Ramaswamy added.
To evaluate the combination, investigators enrolled patients with previously untreated HER2-positive metastatic breast cancer. Eligibility criteria included HER2 overexpression by immunohistochemistry (3+) or fluorescence in situ hybridization, normal left ventricular ejection fraction (LVEF), and no brain metastases.
All patients received six cycles of the three-drug combination, at which point docetaxel could be discontinued at physician discretion. Patients continued to receive the targeted therapies until disease progression or development of unacceptable toxicity. LVEF was assessed after every three cycles of therapy.
Ramaswamy reported data on the first 18 patients enrolled in the ongoing trial, including 16 patients evaluable for response. Grade 3-4 hematologic toxicity consisted of one case of neutropenia and two each of febrile neutropenia (one fatal) and infection.
Grade 3-4 nonhematologic toxicity consisted of one case each of nausea, vomiting, thrombosis, nephrotic syndrome, vision disturbance, fatigue, upper respiratory tract infection, and anorexia, and two cases of excessive tearing of the eyes.
One patient had an asymptomatic decline in LVEF and one had wound dehiscence.
Ramaswamy reported that eight patients had partial responses and six others had stable disease, resulting in a clinical benefit rate of 77.7% (14 of 18). Of 16 patients included in a survival analysis, median progression-free survival was 55.9 weeks. Six patients progressed or died.
Three patients had stable disease for more than six months, including one patient who has remained stable for more than two years while continuing targeted therapy.
Ramaswamy said accrual for the study continues at her institution and at the University of Pittsburgh. Data from correlational studies of circulating tumor cells and circulating endothelial cells will be reported at a later date, she said.
SURGERY FOR HIGH RISK PROSTATE CANCER?
October 1, 2010 — Radical prostatectomy should be a treatment option for men with high-risk prostate cancer, according to a study presented yesterday at the 84th Annual Meeting of the North Central Section of the American Urological Association, held in Chicago, Illinois.
In a retrospective analysis of the 1238 men who underwent surgery and the 344 treated with external-beam radiation plus hormone therapy, the cancer-specific survival rate was 92%.
Median follow-up for the men treated with surgery was 10.2 years, and for those treated with external-beam radiation plus hormone therapy was 6 years.
"Our results do not suggest that surgery is for all men with high-risk prostate cancer, but it should be discussed as a treatment option," said lead author Stephen Boorjian, MD, a urologist at the Mayo Clinic in Rochester, Minnesota.
"The optimal treatment for high-risk disease continues to be debated," added Dr. Boorjian. However, surgery has not been favored, even by urologists, he told Medscape Medical News.
"The bias for the nonsurgical treatment of high-risk prostate cancer is multidisciplinary," said Dr. Boorjian, adding that he is unaware of any "pathologic basis" for this "therapeutic nihilism."
Another prostate cancer expert interviewed by Medscape Medical News believes there is an optimal treatment for high-risk prostate cancer.
Mark Scholz, MD, a medical oncologist at the Prostate Cancer Research Institute in Los Angeles, California, advises men with high-risk disease to have "state-of-the-art [intensity-modulated radiation therapy] with at least 7800 rads, along with hormone blockade for at least 18 months."
"Men with high-risk disease who elect to undergo surgery all too often have positive margins and need radiation anyway. Why should the poor souls be subjected to both surgery and radiation?" he asked.
Hormone Therapy for the "Weak and Feeble"?
The new study was a collaboration by investigators from the Mayo Clinic and those from the Fox Chase Cancer Center in Philadelphia, Pennsylvania. The former provided data on surgery patients and the latter provided data on radiation patients.
High-risk disease was defined according to National Comprehensive Cancer Network criteria: a prostate-specific antigen (PSA) score of 20 or higher, a biopsy Gleason score of 8 to 10, and a clinical stage of T3 or greater.
Of the 1847 patients with aggressive prostate cancer involved in the study from 1988 to 2004, 1238 underwent surgery and 609 were treated with radiation therapy. Of the 609 receiving external-beam radiation therapy, 344 also received androgen-deprivation therapy (for an average of 22.8 months).
Researchers analyzed their cancer-specific and overall survival rates. Although the cancer-specific survival rate was equal for the 2 groups of patients, the overall survival rates were not.
The overall survival rate was 77% for surgery, and was significantly better (P < .001) than radiation plus hormone therapy (67%) or radiation alone (52%).
In a press statement, Dr. Boorjian discussed the overall survival differences and the role of hormone therapy.
"Patients with radiation and hormone therapy were 50% more likely to die than patients who had surgery," he said. "This was true even after controlling for patient age, comorbidities, and features of the tumors. These results suggest that the use of hormone therapy in patients who received radiation therapy may have had adverse health consequences."
But when asked if hormone therapy adversely affected overall survival, Dr. Scholz, who was not involved in this study, objected strenuously.
"No. Absolutely not!," he said. "The difference is due to subjective differences between the 2 groups. Uncontrolled-for factors are always operative in the retrospective selection of men for surgery vs radiation. Healthier, stronger men get surgery, while weaker, more feeble men get radiation. This is always seen in these retrospective comparisons."
Dr. Scholz defended the use of hormone therapy in general for prostate cancer.
"There is no convincing evidence that hormone blockade shortens life or causes excess heart attacks if weight gain is attended to and blood sugar levels are kept in check," he said. "Hormone blockade extends life in randomized trials, both disease-specific and overall survival. The only studies that show shorter survival are retrospective comparisons in large insurance databases that can't control for the selection biases of physicians who reserve hormone blockade for the 'weak and feeble'," he explained.
Dr. Boorjian admitted that further study is needed to determine if hormone therapy was a factor in the differences seen in overall survival.
Notable Study
Dr. Boorjian also emphasized a number of strengths of the study.
First, compared with past studies that have looked at surgery and radiation, it has a large number of patients, and they are exclusively high-risk patients. Previous studies that have compared the 2 modalities have been for "all comers," with low numbers of high-risk patients, observed Dr. Boorjian. Also, there is longer-term follow-up in this study than in past efforts.
Funding for the study was provided by the National Cancer Institute. The authors have disclosed no relevant financial relationships.
84th Annual Meeting of the North Central Section of the American Urological Association. Abstract 19. Presented September 30, 2010
In a retrospective analysis of the 1238 men who underwent surgery and the 344 treated with external-beam radiation plus hormone therapy, the cancer-specific survival rate was 92%.
Median follow-up for the men treated with surgery was 10.2 years, and for those treated with external-beam radiation plus hormone therapy was 6 years.
"Our results do not suggest that surgery is for all men with high-risk prostate cancer, but it should be discussed as a treatment option," said lead author Stephen Boorjian, MD, a urologist at the Mayo Clinic in Rochester, Minnesota.
"The optimal treatment for high-risk disease continues to be debated," added Dr. Boorjian. However, surgery has not been favored, even by urologists, he told Medscape Medical News.
"The bias for the nonsurgical treatment of high-risk prostate cancer is multidisciplinary," said Dr. Boorjian, adding that he is unaware of any "pathologic basis" for this "therapeutic nihilism."
Another prostate cancer expert interviewed by Medscape Medical News believes there is an optimal treatment for high-risk prostate cancer.
Mark Scholz, MD, a medical oncologist at the Prostate Cancer Research Institute in Los Angeles, California, advises men with high-risk disease to have "state-of-the-art [intensity-modulated radiation therapy] with at least 7800 rads, along with hormone blockade for at least 18 months."
"Men with high-risk disease who elect to undergo surgery all too often have positive margins and need radiation anyway. Why should the poor souls be subjected to both surgery and radiation?" he asked.
Hormone Therapy for the "Weak and Feeble"?
The new study was a collaboration by investigators from the Mayo Clinic and those from the Fox Chase Cancer Center in Philadelphia, Pennsylvania. The former provided data on surgery patients and the latter provided data on radiation patients.
High-risk disease was defined according to National Comprehensive Cancer Network criteria: a prostate-specific antigen (PSA) score of 20 or higher, a biopsy Gleason score of 8 to 10, and a clinical stage of T3 or greater.
Of the 1847 patients with aggressive prostate cancer involved in the study from 1988 to 2004, 1238 underwent surgery and 609 were treated with radiation therapy. Of the 609 receiving external-beam radiation therapy, 344 also received androgen-deprivation therapy (for an average of 22.8 months).
Researchers analyzed their cancer-specific and overall survival rates. Although the cancer-specific survival rate was equal for the 2 groups of patients, the overall survival rates were not.
The overall survival rate was 77% for surgery, and was significantly better (P < .001) than radiation plus hormone therapy (67%) or radiation alone (52%).
In a press statement, Dr. Boorjian discussed the overall survival differences and the role of hormone therapy.
"Patients with radiation and hormone therapy were 50% more likely to die than patients who had surgery," he said. "This was true even after controlling for patient age, comorbidities, and features of the tumors. These results suggest that the use of hormone therapy in patients who received radiation therapy may have had adverse health consequences."
But when asked if hormone therapy adversely affected overall survival, Dr. Scholz, who was not involved in this study, objected strenuously.
"No. Absolutely not!," he said. "The difference is due to subjective differences between the 2 groups. Uncontrolled-for factors are always operative in the retrospective selection of men for surgery vs radiation. Healthier, stronger men get surgery, while weaker, more feeble men get radiation. This is always seen in these retrospective comparisons."
Dr. Scholz defended the use of hormone therapy in general for prostate cancer.
"There is no convincing evidence that hormone blockade shortens life or causes excess heart attacks if weight gain is attended to and blood sugar levels are kept in check," he said. "Hormone blockade extends life in randomized trials, both disease-specific and overall survival. The only studies that show shorter survival are retrospective comparisons in large insurance databases that can't control for the selection biases of physicians who reserve hormone blockade for the 'weak and feeble'," he explained.
Dr. Boorjian admitted that further study is needed to determine if hormone therapy was a factor in the differences seen in overall survival.
Notable Study
Dr. Boorjian also emphasized a number of strengths of the study.
First, compared with past studies that have looked at surgery and radiation, it has a large number of patients, and they are exclusively high-risk patients. Previous studies that have compared the 2 modalities have been for "all comers," with low numbers of high-risk patients, observed Dr. Boorjian. Also, there is longer-term follow-up in this study than in past efforts.
Funding for the study was provided by the National Cancer Institute. The authors have disclosed no relevant financial relationships.
84th Annual Meeting of the North Central Section of the American Urological Association. Abstract 19. Presented September 30, 2010
Σάββατο 2 Οκτωβρίου 2010
A BREAKTHROUGH ADVANCE FOR THE TREATMENT OF REFRACTORY HODGKIN LYMPHOMA
LOS ANGELES (Reuters) Sep 27 - A robust 75% of Hodgkin's lymphoma patients in a pivotal trial responded to an experimental drug being developed by Seattle Genetics, the company said on Monday.
Results of the phase III trial -- involving 102 patients with relapsed or refractory disease -- clear the way for a first-half 2011 application for U.S. regulatory approval of the drug, called brentuximab vedotin.
Seattle Genetics said the trial also showed that patients who responded to brentuximab did so for a median of more than six months.
The company said additional details of the trial would be presented within the next few weeks. It said the 75% figure included complete and partial responders (whose tumor burden shrank at least 50%).
"We are extremely excited with these results," said Clay Siegall, chief executive officer of Seattle Genetics. "Brentuximab vedotin has the potential to be the first targeted therapy ever approved for Hodgkin lymphoma."
The drug links an anti-CD30 monoclonal antibody with a chemotherapy drug called monomethyl auristatin E. It targets CD30-expressing tumor cells in patients with Hodgkin's lymphoma, several types of T-cell lymphomas and other hematologic malignancies.
Brentuximab vedotin has been granted orphan drug designation by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of Hodgkin's lymphoma and anaplastic large cell lymphoma and has been granted fast track designation by the FDA for Hodgkin's lymphoma.
Seattle Genetics said the safety profile of the drug during the trial was "generally consistent with prior clinical trial experience."
The company, which is developing brentuximab with Japan's Takeda Pharmaceutical Co Ltd, expects to announce within the next few weeks results from another trial of patients with anaplastic large-cell lymphoma.
In the current trial, all patients had already undergone autologous stem cell transplant. Seattle Genetics is also studying the drug as an initial treatment for Hodgkin's lymphoma.
Results of the phase III trial -- involving 102 patients with relapsed or refractory disease -- clear the way for a first-half 2011 application for U.S. regulatory approval of the drug, called brentuximab vedotin.
Seattle Genetics said the trial also showed that patients who responded to brentuximab did so for a median of more than six months.
The company said additional details of the trial would be presented within the next few weeks. It said the 75% figure included complete and partial responders (whose tumor burden shrank at least 50%).
"We are extremely excited with these results," said Clay Siegall, chief executive officer of Seattle Genetics. "Brentuximab vedotin has the potential to be the first targeted therapy ever approved for Hodgkin lymphoma."
The drug links an anti-CD30 monoclonal antibody with a chemotherapy drug called monomethyl auristatin E. It targets CD30-expressing tumor cells in patients with Hodgkin's lymphoma, several types of T-cell lymphomas and other hematologic malignancies.
Brentuximab vedotin has been granted orphan drug designation by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of Hodgkin's lymphoma and anaplastic large cell lymphoma and has been granted fast track designation by the FDA for Hodgkin's lymphoma.
Seattle Genetics said the safety profile of the drug during the trial was "generally consistent with prior clinical trial experience."
The company, which is developing brentuximab with Japan's Takeda Pharmaceutical Co Ltd, expects to announce within the next few weeks results from another trial of patients with anaplastic large-cell lymphoma.
In the current trial, all patients had already undergone autologous stem cell transplant. Seattle Genetics is also studying the drug as an initial treatment for Hodgkin's lymphoma.
IGF-1R OVEREXPREESION GOOD PROGNOSTIC FACTOR IN TRIPLE NEGATIVE BREAST CANCER
September 30, 2010 — Triple-negative breast cancer accounts for only a small proportion of breast cancer cases, but it is difficult to treat and might have a more aggressive clinical course than other forms of the disease.
According to data presented at the 4th American Association for Cancer Research International Conference on Molecular Diagnostics in Cancer Therapeutic Development, in Denver, Colorado, insulin-like growth-factor 1 receptor (IGF-1R) is overexpressed and amplified in a subset of triple-negative breast cancer patients.
This finding suggests that IGF-IR is a potential therapeutic target, explained study coauthor Agnieszka K. Witkiewicz, MD, associate professor of pathology at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania.
The researchers found that IGF-1R was overexpressed in 25% of cases, and a significant association was observed between IGF-1R protein expression and IGF1R gene amplification (P < .001). In patients 55 years and younger, a high IGF-1R score was associated with prolonged survival (hazard ratio, 0.13; 95% confidence interval, 0.02 - 1.00; P = .050).
During a presscast, Dr. Witkiewicz explained that even though triple-negative breast cancer accounts for only 15% to 20% of patients with the disease, it leads to half of all breast cancer deaths. Estrogen-receptor-positive breast cancer mortality has declined over the past decade, but the same is not true for triple-negative disease.
"This is one of the subsets that is most challenging to treat," said Dr. Witkiewicz. "It is more common in young women, more common in African American women, and is characterized by an aggressive course."
Therefore, there is a significant need for a better understanding of the pathogenesis of triple-negative breast cancer and a need to identify new molecular targets for treatment, she added.
IGF-1R has been known to play a major role in cancer cell proliferation, survival, and resistance to treatment in a number of human malignancies, including breast cancer, the authors write. It is also a target of several investigational drugs, both in clinical and preclinical development.
However, the authors note, there have been no systematic studies of IGF-1R expression in triple-negative breast cancer.
High Expression Equated the Better Survival
In the current study, Dr. Witkiewicz and colleagues evaluated IGF-1R expression in 99 women with triple-negative breast cancer. Immunohistochemistry was used to evaluate IGF-1R protein expression, which was scored according to standardized criteria originally developed for HER2 disease. In addition, chromogenic in situ hybridization for the IGF1R gene was performed on 35 cases.
A tumor was interpreted as positive for gene amplification when the ratio of the IGF1R gene signal to the chromosome 15 signal was 2.2 or higher; for the purpose of statistical analysis, the expression of IGF-1R was classified as low (0 to 2) or high (3).
The authors observed that IGF-1R expression was high in 29 of 99 (29%) cases and correlated with negative lymph nodes (P = .03). Gene amplification was seen is 8 of 35 cases (23%). Low IGF-1R expression was associated with lymph node metastases (P = .033); conversely, high IGF-1R expression was associated with a tumor size that was borderline significantly smaller (P = 0.080).
The authors note that there was no statistically significant association between IGF-1R expression and grade or race.
However, patient age played a role, Dr. Witkiewicz pointed out. "In patients older than 65 years, there was no difference in survival between patients with low and high IGF-1R expression," she said. "But in patients younger than 65, those with high IGF-1R expression had longer survival than those with low expression."
The longest survival was seen in younger patients with high IGF-1R expression, and the poorest survival was seen in older patients (>55 years) with low IGF-1R expression.
"For now, we know that it is there and we know it is a marker of better prognosis," said Dr. Witkiewicz. "The next step is to learn if triple-negative breast cancer patients benefit from targeting IGF-1R."
Program chair Gordon B. Mills, MD, PhD, from the Department of Systems Biology at the University of Texas M.D. Anderson Cancer Center, in Houston, noted that, based on earlier iterations of this conference and the contributions of many members of the community, "we have developed a pathway to the development of molecular diagnostics and biomarkers."
"Importantly, we have a much better concept of the limitations, challenges, and hurdles that need to be overcome for the implementation of molecular diagnostics," he told Medscape Medical News.
"Currently, the outcome for triple-negative breast cancer is poor, at least in part because of the lack of novel targets for therapy," he told Medscape Medical News. Dr. Witkiewicz and colleagues have demonstrated that IGF-1R is overexpressed in triple-negative breast cancer, warranting studies to validate IGF-1R as a target for therapy," he said.
4th American Association for Cancer Research International Conference on Molecular Diagnostics in Cancer Therapeutic Development (AACR-MDCTD): Abstract A29. Presented September 28, 2010.
According to data presented at the 4th American Association for Cancer Research International Conference on Molecular Diagnostics in Cancer Therapeutic Development, in Denver, Colorado, insulin-like growth-factor 1 receptor (IGF-1R) is overexpressed and amplified in a subset of triple-negative breast cancer patients.
This finding suggests that IGF-IR is a potential therapeutic target, explained study coauthor Agnieszka K. Witkiewicz, MD, associate professor of pathology at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania.
The researchers found that IGF-1R was overexpressed in 25% of cases, and a significant association was observed between IGF-1R protein expression and IGF1R gene amplification (P < .001). In patients 55 years and younger, a high IGF-1R score was associated with prolonged survival (hazard ratio, 0.13; 95% confidence interval, 0.02 - 1.00; P = .050).
During a presscast, Dr. Witkiewicz explained that even though triple-negative breast cancer accounts for only 15% to 20% of patients with the disease, it leads to half of all breast cancer deaths. Estrogen-receptor-positive breast cancer mortality has declined over the past decade, but the same is not true for triple-negative disease.
"This is one of the subsets that is most challenging to treat," said Dr. Witkiewicz. "It is more common in young women, more common in African American women, and is characterized by an aggressive course."
Therefore, there is a significant need for a better understanding of the pathogenesis of triple-negative breast cancer and a need to identify new molecular targets for treatment, she added.
IGF-1R has been known to play a major role in cancer cell proliferation, survival, and resistance to treatment in a number of human malignancies, including breast cancer, the authors write. It is also a target of several investigational drugs, both in clinical and preclinical development.
However, the authors note, there have been no systematic studies of IGF-1R expression in triple-negative breast cancer.
High Expression Equated the Better Survival
In the current study, Dr. Witkiewicz and colleagues evaluated IGF-1R expression in 99 women with triple-negative breast cancer. Immunohistochemistry was used to evaluate IGF-1R protein expression, which was scored according to standardized criteria originally developed for HER2 disease. In addition, chromogenic in situ hybridization for the IGF1R gene was performed on 35 cases.
A tumor was interpreted as positive for gene amplification when the ratio of the IGF1R gene signal to the chromosome 15 signal was 2.2 or higher; for the purpose of statistical analysis, the expression of IGF-1R was classified as low (0 to 2) or high (3).
The authors observed that IGF-1R expression was high in 29 of 99 (29%) cases and correlated with negative lymph nodes (P = .03). Gene amplification was seen is 8 of 35 cases (23%). Low IGF-1R expression was associated with lymph node metastases (P = .033); conversely, high IGF-1R expression was associated with a tumor size that was borderline significantly smaller (P = 0.080).
The authors note that there was no statistically significant association between IGF-1R expression and grade or race.
However, patient age played a role, Dr. Witkiewicz pointed out. "In patients older than 65 years, there was no difference in survival between patients with low and high IGF-1R expression," she said. "But in patients younger than 65, those with high IGF-1R expression had longer survival than those with low expression."
The longest survival was seen in younger patients with high IGF-1R expression, and the poorest survival was seen in older patients (>55 years) with low IGF-1R expression.
"For now, we know that it is there and we know it is a marker of better prognosis," said Dr. Witkiewicz. "The next step is to learn if triple-negative breast cancer patients benefit from targeting IGF-1R."
Program chair Gordon B. Mills, MD, PhD, from the Department of Systems Biology at the University of Texas M.D. Anderson Cancer Center, in Houston, noted that, based on earlier iterations of this conference and the contributions of many members of the community, "we have developed a pathway to the development of molecular diagnostics and biomarkers."
"Importantly, we have a much better concept of the limitations, challenges, and hurdles that need to be overcome for the implementation of molecular diagnostics," he told Medscape Medical News.
"Currently, the outcome for triple-negative breast cancer is poor, at least in part because of the lack of novel targets for therapy," he told Medscape Medical News. Dr. Witkiewicz and colleagues have demonstrated that IGF-1R is overexpressed in triple-negative breast cancer, warranting studies to validate IGF-1R as a target for therapy," he said.
4th American Association for Cancer Research International Conference on Molecular Diagnostics in Cancer Therapeutic Development (AACR-MDCTD): Abstract A29. Presented September 28, 2010.
ENDORECTAL MRI OF LIMITED VALUE FOR PREDICTING T3 PROSTATE CANCER
NEW YORK (Reuters Health) Sep 28 - Endorectal MRI has little clinical value for predicting pT3 (locally invasive) prostate cancer preoperatively, researchers report in the August 26th BJU International online.
Some earlier studies reported endorectal MRI to have a sensitivity and specificity exceeding 90% for detecting T3 disease, but these included all patients who presented for prostatectomy and generally involved academic radiologists specialized in MRI or the genitourinary system.
Dr. Jonathan S. Brajtbord and colleagues from The Mount Sinai Medical Center, New York, evaluated the accuracy of endorectal MRI in predicting the presence of extracapsular extension and seminal vesicle invasion in 1161 men who underwent robotic-assisted laparoscopic prostatectomy. Endorectal MRI results were available for 179 of these patients.
MRIs were ordered on selected higher risk patients and performed at both private imaging centers and academic institutions, investigators say, thereby better reflecting the current practice environment in the USA than previous study designs did.
Eighty-one of 110 patients with histopathologically organ-confined disease (74%) were correctly diagnosed as such on endorectal MRI, whereas only 30 of 69 patients with pT3 disease (43%) were correctly predicted by endorectal MRI.
These figures result in an overall accuracy of 64%, with an overall sensitivity of 43% and specificity of 73% for diagnosing pT3 disease. Positive predictive value of endorectal MRI was 50% and negative predictive value was 67%.
The positive predictive value of 50% is "equivalent to a coin toss," the authors say. "This demonstrates that endorectal MRI has a limited ability to preoperatively predict seminal vesicle invasion and extracapsular extension, and a positive test does not reliably indicate the presence of extraprostatic disease."
Results were similar when locally advanced tumors were stratified by extracapsular extension and seminal vesicle invasion, and when the analysis was limited to high-risk patients.
Moreover, sensitivity and specificity rates were similar at academic and non-academic centers.
According to the researchers, "The Prostate-Specific Antigen Best Practice Statement of 2009 states that it is 'generally unnecessary' for patients with a PSA score of 25 or less to undergo radiological staging by CT or MRI."
"The data obtained in the present study support this recommendation," the authors conclude.
"It should be noted that improvements in MRI technology currently being investigated have shown promise over standard endorectal MRI," they add. "Such improvements may improve preoperative staging, although, at this time, the endorectal MRI does not appear to be of much clinical utility."
BJU Intl. Posted online August 26, 2010. Abstract
Some earlier studies reported endorectal MRI to have a sensitivity and specificity exceeding 90% for detecting T3 disease, but these included all patients who presented for prostatectomy and generally involved academic radiologists specialized in MRI or the genitourinary system.
Dr. Jonathan S. Brajtbord and colleagues from The Mount Sinai Medical Center, New York, evaluated the accuracy of endorectal MRI in predicting the presence of extracapsular extension and seminal vesicle invasion in 1161 men who underwent robotic-assisted laparoscopic prostatectomy. Endorectal MRI results were available for 179 of these patients.
MRIs were ordered on selected higher risk patients and performed at both private imaging centers and academic institutions, investigators say, thereby better reflecting the current practice environment in the USA than previous study designs did.
Eighty-one of 110 patients with histopathologically organ-confined disease (74%) were correctly diagnosed as such on endorectal MRI, whereas only 30 of 69 patients with pT3 disease (43%) were correctly predicted by endorectal MRI.
These figures result in an overall accuracy of 64%, with an overall sensitivity of 43% and specificity of 73% for diagnosing pT3 disease. Positive predictive value of endorectal MRI was 50% and negative predictive value was 67%.
The positive predictive value of 50% is "equivalent to a coin toss," the authors say. "This demonstrates that endorectal MRI has a limited ability to preoperatively predict seminal vesicle invasion and extracapsular extension, and a positive test does not reliably indicate the presence of extraprostatic disease."
Results were similar when locally advanced tumors were stratified by extracapsular extension and seminal vesicle invasion, and when the analysis was limited to high-risk patients.
Moreover, sensitivity and specificity rates were similar at academic and non-academic centers.
According to the researchers, "The Prostate-Specific Antigen Best Practice Statement of 2009 states that it is 'generally unnecessary' for patients with a PSA score of 25 or less to undergo radiological staging by CT or MRI."
"The data obtained in the present study support this recommendation," the authors conclude.
"It should be noted that improvements in MRI technology currently being investigated have shown promise over standard endorectal MRI," they add. "Such improvements may improve preoperative staging, although, at this time, the endorectal MRI does not appear to be of much clinical utility."
BJU Intl. Posted online August 26, 2010. Abstract
SLNB IS SAFE-BIGGEST TRIAL ANNOUNCED
September 28, 2010 — In women with breast cancer and clinically negative lymph nodes, a less invasive approach to lymph node surgery provides the same survival and regional control as a more aggressive approach.
This is the most definitive word to date on the subject of sentinel lymph node (SLN) biopsy vs axillary lymph node dissection (ALND) in these women, according to the authors of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial.
The results from this study, the largest-ever randomized surgical trial of breast cancer, which were presented earlier this year at the American Society of Clinical Oncology annual meeting, were published online September 20 in the Lancet Oncology.
The trial enrolled 5611 women with invasive breast cancer, and randomly assigned them to either SLN biopsy plus ALND or to SLN biopsy alone (with ALND only if the SLNs were positive).
SLN surgery is the "highly targeted removal of the lymph nodes that receive direct drainage from a solid tumor in the breast," explain the study authors, led by David Krag, MD, from the University of Vermont in Burlington.
Anytime that SNL surgery is performed without follow-up ALND, there is the chance that there is residual disease in the nonsentinel nodes, according to an editorial that accompanies the study.
"It is of crucial importance to ascertain whether the finite proportion of patients with residual disease in nonsentinel nodes have impaired overall survival," writes editorialist John Benson, MD, from Cambridge University Teaching Hospitals Trust in the United Kingdom.
There was a slight difference in survival among patients assigned to SLN biopsy plus ALND and those assigned to SLN alone. But the difference was not statistically significant and, thus, could have been due to chance.
The 8-year Kaplan–Meier estimates for overall survival were 91.8% (95% confidence interval [CI], 90.4 - 93.3) for SLN biopsy plus ALND and 90.3% (95% CI, 88.8 - 91.8) for SLN biopsy alone.
The new data vindicate the "contemporary practice of SLN biopsy and provide support for a reduction in extent of axillary surgery for most patients with breast cancer," writes Dr. Benson.
However, this is not the final word on the subject — more follow-up is needed, says Dr. Benson.
For instance, there were more regional recurrences with SLN biopsy alone (14 vs 8 events). "Low volume axillary disease might arguably be clinically relevant if it translates into overall survival differences with longer-term follow-up," he points out.
However, the study authors placed a different emphasis on these data.
Dr. Krag and his coauthors say the results confirm the low rate of regional node recurrences after SLN surgery. Furthermore, the trial shows that in patients with negative SLNs, "the number of regional node recurrences does not differ significantly between patients who have axillary dissection or SLN resection only," they write.
"SLN surgery represents the next major step in reducing the extent of surgical procedures to treat breast cancer," the authors conclude, citing breast-conserving surgery as the previous major step.
Adverse Effect Advantage Too
In the editorial, Dr. Benson points out that this study is a step forward in understanding how SLN influences outcomes in clinical node-negative breast cancer, where disease in the nodes cannot be palpably detected in the clinic.
"Most published data on [SLN] biopsy come from validation studies in which clinically node-negative patients have undergone SLN biopsy and then immediate complete [ALND]," he writes.
What's been missing is comparative data for SLN biopsy alone without concomitant ALND, he adds.
There are actually 5 randomized controlled trials currently comparing SLN biopsy with conventional ALND in clinically node-negative patients. Notably, 3 of the trials have the exact same design: SLN biopsy plus ALND vs SLN biopsy alone. But the NSABP B-32 trial is the biggest.
In the B-32 trial, which is taking place at 80 centers in Canada and the United States, SLN biopsy was done in the more than 5000 patients with a blue dye and radioactive tracer, note the authors.
Previously reported results from the B-32 trial showed that morbidity related to range of motion, edema, pain, and sensory defects is lower in the SLN group than in the ALND group (J Clin Oncol. 2010;28:3929-3936; J Surg Oncol 2010;102:111-118).
This is key because the whole point of SLN surgery is to reduce morbidity.
However, as Dr. Krag and colleagues point out, SLN surgery is not without complications. There is a small increase over baseline of extremity edema and functional and neurologic deficits, they note.
The authors have disclosed no relevant financial relationships.
Lancet Oncol. Published online September 20, 2010. Abstract, Abstract
This is the most definitive word to date on the subject of sentinel lymph node (SLN) biopsy vs axillary lymph node dissection (ALND) in these women, according to the authors of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial.
The results from this study, the largest-ever randomized surgical trial of breast cancer, which were presented earlier this year at the American Society of Clinical Oncology annual meeting, were published online September 20 in the Lancet Oncology.
The trial enrolled 5611 women with invasive breast cancer, and randomly assigned them to either SLN biopsy plus ALND or to SLN biopsy alone (with ALND only if the SLNs were positive).
SLN surgery is the "highly targeted removal of the lymph nodes that receive direct drainage from a solid tumor in the breast," explain the study authors, led by David Krag, MD, from the University of Vermont in Burlington.
Anytime that SNL surgery is performed without follow-up ALND, there is the chance that there is residual disease in the nonsentinel nodes, according to an editorial that accompanies the study.
"It is of crucial importance to ascertain whether the finite proportion of patients with residual disease in nonsentinel nodes have impaired overall survival," writes editorialist John Benson, MD, from Cambridge University Teaching Hospitals Trust in the United Kingdom.
There was a slight difference in survival among patients assigned to SLN biopsy plus ALND and those assigned to SLN alone. But the difference was not statistically significant and, thus, could have been due to chance.
The 8-year Kaplan–Meier estimates for overall survival were 91.8% (95% confidence interval [CI], 90.4 - 93.3) for SLN biopsy plus ALND and 90.3% (95% CI, 88.8 - 91.8) for SLN biopsy alone.
The new data vindicate the "contemporary practice of SLN biopsy and provide support for a reduction in extent of axillary surgery for most patients with breast cancer," writes Dr. Benson.
However, this is not the final word on the subject — more follow-up is needed, says Dr. Benson.
For instance, there were more regional recurrences with SLN biopsy alone (14 vs 8 events). "Low volume axillary disease might arguably be clinically relevant if it translates into overall survival differences with longer-term follow-up," he points out.
However, the study authors placed a different emphasis on these data.
Dr. Krag and his coauthors say the results confirm the low rate of regional node recurrences after SLN surgery. Furthermore, the trial shows that in patients with negative SLNs, "the number of regional node recurrences does not differ significantly between patients who have axillary dissection or SLN resection only," they write.
"SLN surgery represents the next major step in reducing the extent of surgical procedures to treat breast cancer," the authors conclude, citing breast-conserving surgery as the previous major step.
Adverse Effect Advantage Too
In the editorial, Dr. Benson points out that this study is a step forward in understanding how SLN influences outcomes in clinical node-negative breast cancer, where disease in the nodes cannot be palpably detected in the clinic.
"Most published data on [SLN] biopsy come from validation studies in which clinically node-negative patients have undergone SLN biopsy and then immediate complete [ALND]," he writes.
What's been missing is comparative data for SLN biopsy alone without concomitant ALND, he adds.
There are actually 5 randomized controlled trials currently comparing SLN biopsy with conventional ALND in clinically node-negative patients. Notably, 3 of the trials have the exact same design: SLN biopsy plus ALND vs SLN biopsy alone. But the NSABP B-32 trial is the biggest.
In the B-32 trial, which is taking place at 80 centers in Canada and the United States, SLN biopsy was done in the more than 5000 patients with a blue dye and radioactive tracer, note the authors.
Previously reported results from the B-32 trial showed that morbidity related to range of motion, edema, pain, and sensory defects is lower in the SLN group than in the ALND group (J Clin Oncol. 2010;28:3929-3936; J Surg Oncol 2010;102:111-118).
This is key because the whole point of SLN surgery is to reduce morbidity.
However, as Dr. Krag and colleagues point out, SLN surgery is not without complications. There is a small increase over baseline of extremity edema and functional and neurologic deficits, they note.
The authors have disclosed no relevant financial relationships.
Lancet Oncol. Published online September 20, 2010. Abstract, Abstract
IMMUNOTHERAPY FOR HIGH RISK NEUROBLASTOMA
September 30, 2010 — An immunotherapy combination improved cure rates by 20%, compared with standard treatment, in children with high-risk neuroblastoma, according to a new multicenter study published in the September 30 issue of the New England Journal of Medicine.
The study was stopped early because of the effectiveness of the experimental regimen.
"We expect these findings will change clinical practice, setting a new gold standard of treatment for this often-deadly disease," said John M. Maris, MD, a coauthor of the study, in a press statement. He is from the Children's Hospital of Philadelphia, Pennsylvania, and is chair of the neuroblastoma committee of the Children's Oncology Group, the cooperative multicenter research organization that sponsored the study.
The newly published data were first presented at the American Society of Clinical Oncology annual meeting in 2009, and were reviewed in detail by Medscape Medical News at the time.
In the 226-patient study, the rate of event-free survival at 2 years was 46% ± 5% for patients randomized to isotretinoin, the standard therapy, and 66% ± 5% for the patients randomized to immunotherapy — 3 biologic agents in combination with isotretinoin (P = .01).
The immunotherapy consisted of the monoclonal antibody ch14.18, plus 2 cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-2.
Event-free survival is the key outcome in this setting because, as the authors note, "children with recurrent or progressive disease are rarely cured."
The rate of overall survival at 2 years was 75% ± 5% for standard therapy and 86% ± 4% for immunotherapy (P = .02). The median duration of follow-up was 2.1 years.
The need for an alternative treatment in this setting is pressing, according to the authors. "More than half the patients receiving standard therapy have a relapse and ultimately die from the tumor," they write.
More Details
The case for using immunotherapy in this setting partially stems from preclinical and preliminary clinical data that indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when the antibody is combined with either GM-CSF or IL-2, explain the study authors, who were led by Alice L. Yu, MD, PhD, from the University of California, San Diego.
In the study, the randomization, in a 1:1 ratio, took place only in patients with high-risk neuroblastoma who responsed to induction therapy and stem-cell transplantation.
The standard therapy consisted of 6 cycles of isotretinoin, and the experimental immunotherapy consisted of 6 cycles of isotretinoin and 5 concomitant cycles of ch14.18 in combination with alternating GM-CSF and IL-2.
A total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively.
When 61% of the number of expected events was observed, the study was stopped because it met the efficacy criteria, the authors report.
The immunotherapy regimen produced more treatment-related clinical toxic effects.
The effects in the immunotherapy group included, most importantly, pain, hypotension, capillary leak syndrome, and hypersensitivity reactions; there were relatively few toxic effects with standard therapy. Pain of grade 3 or 4 was observed in 52% of patients (during 25% of 598 cycles of immunotherapy).
The National Cancer Institute (NCI) was the sponsor of the study and provided the ch14.18 monoclonal antibody. Bayer provided the GM-CSF. Neither the NCI nor Bayer had a role in the study design or analysis.
N Engl J Med. 2010;363:1324-1334.
The study was stopped early because of the effectiveness of the experimental regimen.
"We expect these findings will change clinical practice, setting a new gold standard of treatment for this often-deadly disease," said John M. Maris, MD, a coauthor of the study, in a press statement. He is from the Children's Hospital of Philadelphia, Pennsylvania, and is chair of the neuroblastoma committee of the Children's Oncology Group, the cooperative multicenter research organization that sponsored the study.
The newly published data were first presented at the American Society of Clinical Oncology annual meeting in 2009, and were reviewed in detail by Medscape Medical News at the time.
In the 226-patient study, the rate of event-free survival at 2 years was 46% ± 5% for patients randomized to isotretinoin, the standard therapy, and 66% ± 5% for the patients randomized to immunotherapy — 3 biologic agents in combination with isotretinoin (P = .01).
The immunotherapy consisted of the monoclonal antibody ch14.18, plus 2 cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-2.
Event-free survival is the key outcome in this setting because, as the authors note, "children with recurrent or progressive disease are rarely cured."
The rate of overall survival at 2 years was 75% ± 5% for standard therapy and 86% ± 4% for immunotherapy (P = .02). The median duration of follow-up was 2.1 years.
The need for an alternative treatment in this setting is pressing, according to the authors. "More than half the patients receiving standard therapy have a relapse and ultimately die from the tumor," they write.
More Details
The case for using immunotherapy in this setting partially stems from preclinical and preliminary clinical data that indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when the antibody is combined with either GM-CSF or IL-2, explain the study authors, who were led by Alice L. Yu, MD, PhD, from the University of California, San Diego.
In the study, the randomization, in a 1:1 ratio, took place only in patients with high-risk neuroblastoma who responsed to induction therapy and stem-cell transplantation.
The standard therapy consisted of 6 cycles of isotretinoin, and the experimental immunotherapy consisted of 6 cycles of isotretinoin and 5 concomitant cycles of ch14.18 in combination with alternating GM-CSF and IL-2.
A total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively.
When 61% of the number of expected events was observed, the study was stopped because it met the efficacy criteria, the authors report.
The immunotherapy regimen produced more treatment-related clinical toxic effects.
The effects in the immunotherapy group included, most importantly, pain, hypotension, capillary leak syndrome, and hypersensitivity reactions; there were relatively few toxic effects with standard therapy. Pain of grade 3 or 4 was observed in 52% of patients (during 25% of 598 cycles of immunotherapy).
The National Cancer Institute (NCI) was the sponsor of the study and provided the ch14.18 monoclonal antibody. Bayer provided the GM-CSF. Neither the NCI nor Bayer had a role in the study design or analysis.
N Engl J Med. 2010;363:1324-1334.
HRT PROMOTION OR CAUSE OF BREAST CANCER?
September 24, 2010 — A dramatic decrease in use of hormone replacement therapy (HRT) during a 2-year period in Canada coincided with lower breast cancer incidence, mirroring what happened in the United States, according to a new study published online September 23 in the Journal of the National Cancer Institute.
The use of HRT, once favored for treating the symptoms of menopause, decreased in the wake of a 2002 report of results from the Women's Health Initiative clinical trial that found that the treatment came with an increased risk for breast cancer, stroke, and myocardial infarction.
In Canada, the proportion of women aged 50 to 69 years who reported using combined HRT — estrogen and progestin — declined from 12.7% in 2002 to 4.9% in 2004, according to the study. The incidence of breast cancer in this age group declined 9.6% during that period, even as mammography rates remained steady.
"The results support the hypothesized link between the use of [HRT] and invasive breast cancer incidence and indicate that the sharp decline in breast cancer incidence in 2002 is likely explained by the concurrent decline in the use of [HRT] among Canadian women," write lead author Prithwish De, PhD, an epidemiologist with the Canadian Cancer Society, and colleagues.
The Canadian researchers note the same trend in the United States, pointing to an 11.8% decline in invasive breast cancer between 2001 and 2004 for women aged 50 to 69 years, as reported by the US Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. During this time, prescriptions for estrogen–progestin and conjugated equine estrogen declined from 60 million to slightly more than 20 million.
Does HRT Promote Rather Than Cause Breast Cancer?
After taking a 2-year dip, the incidence of breast cancer in Canada began to rise again in 2005, except for women aged 40 to 49 years. The Canadian researchers attempt to make sense of this reversal, surmising that such a rebound might be expected "if occult hormone-sensitive tumors were merely slowed by the withdrawal of [HRT,] rather than prevented by it."
If this is true, "[HRT] may be thought to act as a promoter rather than as a putative cause of breast cancer," Dr. Prithwish and colleagues write.
Another statistical wrinkle in the link between HRT and breast cancer is that the incidence of breast cancer among older women had started to decline in 1998, 4 years before the Women's Health Initiative report sounded its alarms about HRT. The authors try to explain that, too. Published research in the late 1990s that downplayed the cardiovascular benefit of HRT may have dampened enthusiasm for the treatment, they write. In addition, an upswing in mammography rates may have caused the number of detectable cases of breast cancer to reach a saturation point.
The authors acknowledge several limitations to their research. Because the study was ecological in design, it looks at trends only at a population level, they write. Self-reported use of HRT is subject to recall bias and does not reflect how long or how frequently women took these hormones. And the authors could not confirm whether changes in breast cancer incidence primarily involved estrogen receptor–positive tumors, because receptor status is not routinely gathered at the national level for Canadian patients with the disease.
The study was conducted with author contributions in-kind. The authors have disclosed no relevant financial relationships.
J Natl Cancer Inst. Published online September 23, 2010. Abstract
The use of HRT, once favored for treating the symptoms of menopause, decreased in the wake of a 2002 report of results from the Women's Health Initiative clinical trial that found that the treatment came with an increased risk for breast cancer, stroke, and myocardial infarction.
In Canada, the proportion of women aged 50 to 69 years who reported using combined HRT — estrogen and progestin — declined from 12.7% in 2002 to 4.9% in 2004, according to the study. The incidence of breast cancer in this age group declined 9.6% during that period, even as mammography rates remained steady.
"The results support the hypothesized link between the use of [HRT] and invasive breast cancer incidence and indicate that the sharp decline in breast cancer incidence in 2002 is likely explained by the concurrent decline in the use of [HRT] among Canadian women," write lead author Prithwish De, PhD, an epidemiologist with the Canadian Cancer Society, and colleagues.
The Canadian researchers note the same trend in the United States, pointing to an 11.8% decline in invasive breast cancer between 2001 and 2004 for women aged 50 to 69 years, as reported by the US Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. During this time, prescriptions for estrogen–progestin and conjugated equine estrogen declined from 60 million to slightly more than 20 million.
Does HRT Promote Rather Than Cause Breast Cancer?
After taking a 2-year dip, the incidence of breast cancer in Canada began to rise again in 2005, except for women aged 40 to 49 years. The Canadian researchers attempt to make sense of this reversal, surmising that such a rebound might be expected "if occult hormone-sensitive tumors were merely slowed by the withdrawal of [HRT,] rather than prevented by it."
If this is true, "[HRT] may be thought to act as a promoter rather than as a putative cause of breast cancer," Dr. Prithwish and colleagues write.
Another statistical wrinkle in the link between HRT and breast cancer is that the incidence of breast cancer among older women had started to decline in 1998, 4 years before the Women's Health Initiative report sounded its alarms about HRT. The authors try to explain that, too. Published research in the late 1990s that downplayed the cardiovascular benefit of HRT may have dampened enthusiasm for the treatment, they write. In addition, an upswing in mammography rates may have caused the number of detectable cases of breast cancer to reach a saturation point.
The authors acknowledge several limitations to their research. Because the study was ecological in design, it looks at trends only at a population level, they write. Self-reported use of HRT is subject to recall bias and does not reflect how long or how frequently women took these hormones. And the authors could not confirm whether changes in breast cancer incidence primarily involved estrogen receptor–positive tumors, because receptor status is not routinely gathered at the national level for Canadian patients with the disease.
The study was conducted with author contributions in-kind. The authors have disclosed no relevant financial relationships.
J Natl Cancer Inst. Published online September 23, 2010. Abstract
NEW DATA ADDS TO DEBATE ABOUT MAMMOGRAPHY EFFICIENCY
October 1, 2010 — New data from a large Swedish study show that mammography screening in women aged 40 to 49 years results in a much greater reduction in mortality from breast cancer than has been previously reported.
"This huge study from Sweden should end any debate" over the benefits of regular mammography screening in this age group, said a leading expert on mammography, Daniel Kopans, MD, professor of radiology at Harvard Medical School in Boston, Massachusetts, who was approached for comment. Beginning mammography at age 50 "has never had any scientific basis and should be dropped," he said.
The issue leapt into headlines late last year, when the US Preventive Services Task Force (USPSTF) recommended against regular screening mammography in women 40 to 49 years, in direct contrast to the recommendations from other American authorities. At the time, top mammography experts, including Dr. Kopans, expressed outrage at this recommendation, saying that it would lead to lives being lost to breast cancer.
The experts also question the calculation of benefit by the USPSTF, which estimated a 15% reduction in breast cancer mortality from mammography in women 39 to 49 years of age.
The new data from Sweden found a 26% reduction in breast cancer mortality among the women in the 40 to 49 year age group who were invited for screening, and a 29% reduction in those who actually underwent the screening (not all those who were invited participated).
"This is bigger and better than has been seen in other studies," said Jennifer Obel, MD, from the NorthShore University Health System in Evanston, Illinois.
The new data were outlined by Håkan Jonsson, PhD, associate professor of cancer epidemiology at Umeå University in Sweden, at an American Society of Clinical Oncology (ASCO) presscast for the upcoming Breast Cancer Symposium. The study was published online September 29 in Cancer. Dr. Obel was moderating the presscast, and is on the ASCO Communications Committee.
True-to-Life Study
The Swedish data on women 40 to 49 years represents the "largest epidemiological study of mammography in this age group," Dr. Jonsson told reporters. There were more than 1 million women involved, with an average follow-up of 16 years.
"While this was not a randomized controlled trial, it captured a real-life experience of mammography in this age group . . . [because] of a unique confluence of events," said Dr. Obel.
It came about because of differences in counties in Sweden, Dr. Jonsson explained. When Sweden introduced a nationwide mammography program in 1986, it targeted women 50 to 69 years of age, but it was left up to individual counties to decide whether or not to also invite women 40 to 49 years to be screened.
About half of the counties did so and half did not (the control group). The invitations to screening were issued every 2 years, so from the ages of 40 to 49 years, these women would have undergone about 5 rounds of screening, Dr. Jonsson explained.
During the follow-up period, from 1986 and 2005, there were 619 deaths from breast cancer among the women who had been invited for screening, and 1205 deaths in the control group.
The rate ratio was 0.74 (95% confidence interval [CI], 0.66 - 0.83) for women invited to be screened (i.e., 26% reduction), and 0.71 (95% CI, 0.62 - 0.80) for women who were actually screened (29% reduction).
Dr. Jonsson contrasted these findings with data considered by the USPSTF, which found 448 deaths from breast cancer in the screened group and 625 in the control group, and a 15% reduction in mortality. When asked about the differences between the 2 findings, he said the USSPTF data were based on a meta-analysis of 8 randomized clinical trials, but many of those trials were old, having been conducted more than 20 years ago.
The Swedish data are robust and are "far superior" to the computer models that the USSPTF used, Dr. Kopans explained. They offer "direct proof that the benefit is almost twice as high as the estimate used by the USSPTF," he added.
Mammography in Women 40 to 49 Years of Age
"In this large study, mammography screening for women aged 40 to 49 is clearly shown to be efficient for reducing breast cancer mortality," Dr. Jonsson concluded. The researchers estimated that the number of women that had to be invited to be screened in the 40 to 49 year age group to save 1 life was 1252.
"This study adds to our knowledge of the performance of mammography in this age group," Dr. Obel said. "Many women aged 40 to 49 want unambiguous recommendations," she noted, but the optimum use of this screening continues to be discussed among experts in the field. She recommended that women in this age group discuss the risks and benefits with their doctor to decide "what is best for them individually."
Currently in the United States, most organizations recommend yearly mammograms beginning at age 40, including the American Cancer Society, the National Comprehensive Cancer Network, the American Medical Association, the American College of Surgeons, and the American College of Obstetricians and Gynecologists.
It is only the USSPTF that does not recommend regular mammography in the 40 to 49 year age group, but recommends screening every 2 years for women 50 to 74 years of age. But there are other countries that also use the age of 50 as the threshold at which to begin mammography screening, such as the United Kingdom.
Dr. Kopans is adamant that the age of 50 as a threshold is scientifically unsupportable, and has no biologic basis. "Data have been used inappropriately to make it appear as if something changes abruptly at the age of 50, when the data, actually, do not show any sudden changes in the parameters of screening at the age of 50, or any other age."
Another expert approached for comment was also in favor of starting mammography at the age of 40. "Virtually all studies that have evaluated, in a scientifically rigorous way, the effectiveness of mammography have shown a benefit in breast cancer mortality in the younger women," said Mark Pearlman, MD, from the University of Michigan in Ann Arbor, who holds the only breast disease fellowship in obstetrics and gynecology in the United States.
The difference with older women is that more breast cancer is detected, so the numbers needed to screen become smaller, he explained. For instance, in the data from the USSPTF, the number needed to screen to detect a single case of breast cancer was 1900 in women aged 40 to 49 and 1300 in women aged 50 to 74, he explained. A similar difference would be expected in the numbers needed to screen to save a life from breast cancer.
Although the same amount of screening will save more lives in the older age group than in the younger age group, Dr. Pearlman emphasized that in younger women, screening "saves more years of life." If you analyze the data in terms of life-years saved, then screening in younger women is actually more efficient than in older women, he added.
While careful not to imply that the life of a younger woman is more valuable than the life of an older woman, he suggested that the implications are different, because younger women are more likely to be mothers and to be managing the lives of several others. "This takes us out of the scientific arena and into socioethical areas" Dr. Pearlman said, "but we need to be aware as a society of the implications of not screening a woman in her 40s."
Strong Support for Starting at Age 40
The new study also drew a strong reactions from the American College of Radiology and several other bodies, all of which support starting screening with mammography at age 40 years.
The American College of Radiology describes the new Swedish data a "landmark" study and said they "confirm that the use of the age of 50 as a threshold for breast cancer screening is scientifically unfounded. Women should begin getting annual mammograms at age 40."
"This study, which looked at the performance of screening mammography as it is actually used, rather than relying on mathematical modeling, shows without a doubt that mammography decreases deaths from breast cancer in women aged 40-49 by nearly one third," said Carol H. Lee, MD, chair of the American College of Radiology Breast Imaging Commission, in a statement. "There is no excuse not to recommend that average risk women begin annual screening mammography at age 40."
Voicing a similar opinion in the same press release was Phil Evans, MD, president of the Society of Breast Imaging. "This study shows that annual mammograms for women 40 and over result in a tremendously significant reduction in the breast cancer death rate," he said. "The age of 50 is an artificial threshold that has no basis in scientific fact. The debate is now over."
A third voice in the same release expressed the same strong opinion.
"It is now time to stop confusing women with conflicting information. Mammography is a lifesaver for women in their 40s," said Gail Lebovic, MD, breast surgeon and president of the American Society of Breast Disease. "What providers need to do now is uniformly confirm for women that they need to start getting annual mammograms beginning at age 40 and work to build on the ability of mammography to detect cancer early, when it is most treatable."
In reaction to the reactions that the debate is ended, the American Cancer Society suggested that discussions should continue. Otis Brawley, MD, chief medical officer from the ACS, said in a statement released to Medscape Medical News, "This has become an incredibly polarized debate. The focus of our discussion really should be how to improve screening technologies so that we prevent as many of the more than 40,000 breast cancer deaths in the US every year as we can. While even the USPSTF says screening women in their 40s is a viable option, and the American Cancer Society says it's effective enough that every woman should be screened starting at age 40, none of us should be completely satisfied. We must support research to find better screening and diagnostic tools and better treatments that would make this current discussion a footnote in cancer history."
The fourth annual Breast Cancer Symposium is cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the American Society of Clinical Oncology, the American Society of Radiation Oncology, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the Susan G. Komen for the Cure.
Cancer. Published online September 29, 2010.
"This huge study from Sweden should end any debate" over the benefits of regular mammography screening in this age group, said a leading expert on mammography, Daniel Kopans, MD, professor of radiology at Harvard Medical School in Boston, Massachusetts, who was approached for comment. Beginning mammography at age 50 "has never had any scientific basis and should be dropped," he said.
The issue leapt into headlines late last year, when the US Preventive Services Task Force (USPSTF) recommended against regular screening mammography in women 40 to 49 years, in direct contrast to the recommendations from other American authorities. At the time, top mammography experts, including Dr. Kopans, expressed outrage at this recommendation, saying that it would lead to lives being lost to breast cancer.
The experts also question the calculation of benefit by the USPSTF, which estimated a 15% reduction in breast cancer mortality from mammography in women 39 to 49 years of age.
The new data from Sweden found a 26% reduction in breast cancer mortality among the women in the 40 to 49 year age group who were invited for screening, and a 29% reduction in those who actually underwent the screening (not all those who were invited participated).
"This is bigger and better than has been seen in other studies," said Jennifer Obel, MD, from the NorthShore University Health System in Evanston, Illinois.
The new data were outlined by Håkan Jonsson, PhD, associate professor of cancer epidemiology at Umeå University in Sweden, at an American Society of Clinical Oncology (ASCO) presscast for the upcoming Breast Cancer Symposium. The study was published online September 29 in Cancer. Dr. Obel was moderating the presscast, and is on the ASCO Communications Committee.
True-to-Life Study
The Swedish data on women 40 to 49 years represents the "largest epidemiological study of mammography in this age group," Dr. Jonsson told reporters. There were more than 1 million women involved, with an average follow-up of 16 years.
"While this was not a randomized controlled trial, it captured a real-life experience of mammography in this age group . . . [because] of a unique confluence of events," said Dr. Obel.
It came about because of differences in counties in Sweden, Dr. Jonsson explained. When Sweden introduced a nationwide mammography program in 1986, it targeted women 50 to 69 years of age, but it was left up to individual counties to decide whether or not to also invite women 40 to 49 years to be screened.
About half of the counties did so and half did not (the control group). The invitations to screening were issued every 2 years, so from the ages of 40 to 49 years, these women would have undergone about 5 rounds of screening, Dr. Jonsson explained.
During the follow-up period, from 1986 and 2005, there were 619 deaths from breast cancer among the women who had been invited for screening, and 1205 deaths in the control group.
The rate ratio was 0.74 (95% confidence interval [CI], 0.66 - 0.83) for women invited to be screened (i.e., 26% reduction), and 0.71 (95% CI, 0.62 - 0.80) for women who were actually screened (29% reduction).
Dr. Jonsson contrasted these findings with data considered by the USPSTF, which found 448 deaths from breast cancer in the screened group and 625 in the control group, and a 15% reduction in mortality. When asked about the differences between the 2 findings, he said the USSPTF data were based on a meta-analysis of 8 randomized clinical trials, but many of those trials were old, having been conducted more than 20 years ago.
The Swedish data are robust and are "far superior" to the computer models that the USSPTF used, Dr. Kopans explained. They offer "direct proof that the benefit is almost twice as high as the estimate used by the USSPTF," he added.
Mammography in Women 40 to 49 Years of Age
"In this large study, mammography screening for women aged 40 to 49 is clearly shown to be efficient for reducing breast cancer mortality," Dr. Jonsson concluded. The researchers estimated that the number of women that had to be invited to be screened in the 40 to 49 year age group to save 1 life was 1252.
"This study adds to our knowledge of the performance of mammography in this age group," Dr. Obel said. "Many women aged 40 to 49 want unambiguous recommendations," she noted, but the optimum use of this screening continues to be discussed among experts in the field. She recommended that women in this age group discuss the risks and benefits with their doctor to decide "what is best for them individually."
Currently in the United States, most organizations recommend yearly mammograms beginning at age 40, including the American Cancer Society, the National Comprehensive Cancer Network, the American Medical Association, the American College of Surgeons, and the American College of Obstetricians and Gynecologists.
It is only the USSPTF that does not recommend regular mammography in the 40 to 49 year age group, but recommends screening every 2 years for women 50 to 74 years of age. But there are other countries that also use the age of 50 as the threshold at which to begin mammography screening, such as the United Kingdom.
Dr. Kopans is adamant that the age of 50 as a threshold is scientifically unsupportable, and has no biologic basis. "Data have been used inappropriately to make it appear as if something changes abruptly at the age of 50, when the data, actually, do not show any sudden changes in the parameters of screening at the age of 50, or any other age."
Another expert approached for comment was also in favor of starting mammography at the age of 40. "Virtually all studies that have evaluated, in a scientifically rigorous way, the effectiveness of mammography have shown a benefit in breast cancer mortality in the younger women," said Mark Pearlman, MD, from the University of Michigan in Ann Arbor, who holds the only breast disease fellowship in obstetrics and gynecology in the United States.
The difference with older women is that more breast cancer is detected, so the numbers needed to screen become smaller, he explained. For instance, in the data from the USSPTF, the number needed to screen to detect a single case of breast cancer was 1900 in women aged 40 to 49 and 1300 in women aged 50 to 74, he explained. A similar difference would be expected in the numbers needed to screen to save a life from breast cancer.
Although the same amount of screening will save more lives in the older age group than in the younger age group, Dr. Pearlman emphasized that in younger women, screening "saves more years of life." If you analyze the data in terms of life-years saved, then screening in younger women is actually more efficient than in older women, he added.
While careful not to imply that the life of a younger woman is more valuable than the life of an older woman, he suggested that the implications are different, because younger women are more likely to be mothers and to be managing the lives of several others. "This takes us out of the scientific arena and into socioethical areas" Dr. Pearlman said, "but we need to be aware as a society of the implications of not screening a woman in her 40s."
Strong Support for Starting at Age 40
The new study also drew a strong reactions from the American College of Radiology and several other bodies, all of which support starting screening with mammography at age 40 years.
The American College of Radiology describes the new Swedish data a "landmark" study and said they "confirm that the use of the age of 50 as a threshold for breast cancer screening is scientifically unfounded. Women should begin getting annual mammograms at age 40."
"This study, which looked at the performance of screening mammography as it is actually used, rather than relying on mathematical modeling, shows without a doubt that mammography decreases deaths from breast cancer in women aged 40-49 by nearly one third," said Carol H. Lee, MD, chair of the American College of Radiology Breast Imaging Commission, in a statement. "There is no excuse not to recommend that average risk women begin annual screening mammography at age 40."
Voicing a similar opinion in the same press release was Phil Evans, MD, president of the Society of Breast Imaging. "This study shows that annual mammograms for women 40 and over result in a tremendously significant reduction in the breast cancer death rate," he said. "The age of 50 is an artificial threshold that has no basis in scientific fact. The debate is now over."
A third voice in the same release expressed the same strong opinion.
"It is now time to stop confusing women with conflicting information. Mammography is a lifesaver for women in their 40s," said Gail Lebovic, MD, breast surgeon and president of the American Society of Breast Disease. "What providers need to do now is uniformly confirm for women that they need to start getting annual mammograms beginning at age 40 and work to build on the ability of mammography to detect cancer early, when it is most treatable."
In reaction to the reactions that the debate is ended, the American Cancer Society suggested that discussions should continue. Otis Brawley, MD, chief medical officer from the ACS, said in a statement released to Medscape Medical News, "This has become an incredibly polarized debate. The focus of our discussion really should be how to improve screening technologies so that we prevent as many of the more than 40,000 breast cancer deaths in the US every year as we can. While even the USPSTF says screening women in their 40s is a viable option, and the American Cancer Society says it's effective enough that every woman should be screened starting at age 40, none of us should be completely satisfied. We must support research to find better screening and diagnostic tools and better treatments that would make this current discussion a footnote in cancer history."
The fourth annual Breast Cancer Symposium is cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the American Society of Clinical Oncology, the American Society of Radiation Oncology, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the Susan G. Komen for the Cure.
Cancer. Published online September 29, 2010.
Παρασκευή 1 Οκτωβρίου 2010
LESS CHEMOTHERAPY FOR INTERMEDIATE RISK NEUROBLASTOMA
September 29, 2010 — Less chemotherapy than usual produced excellent outcomes in children with intermediate-risk neuroblastoma, according to a new multicenter study from Australian and American researchers.
The trial used a "substantially reduced" duration of chemotherapy, compared with previously used regimens, as well as reduced doses, and produced a "very high rate of survival," write the study authors in the September 30 issue of the New England Journal of Medicine.
"These data provide support for further reduction in chemotherapy with more refined risk stratification," conclude the authors, led by David Baker, MD, from the Princess Margaret Hospital for Children in Perth, Australia.
A 3-year overall survival estimate of 96% ± 1% (95% confidence interval [CI], 94 - 97) was achieved with a substantial reduction in cytotoxic therapy for the rare disease, which affects the sympathetic nervous system and most commonly develops in the adrenal glands, say the authors, who are all members of the Children's Oncology Group (COG) research collaborative.
The 3-year event-free survival estimate was 88% ± 2% (95% CI, 84 - 90). In intermediate-risk neuroblastoma, 3 years of survival without relapse generally means that a patient is cured, note the authors.
"Our goal was to reduce the level of chemotherapy needed to effectively treat intermediate-risk neuroblastoma patients while maintaining an excellent rate of survival, and that is exactly what we did," said senior coauthor Katherine Matthay, MD, in a press statement. She is from the University of California San Francisco Benioff Children's Hospital.
"This trial will lead to permanent treatment reductions in our protocol for treating this disease and will have a significant impact on the hundreds of children who are diagnosed with neuroblastoma each year," said Dr. Matthay.
Duration of Chemotherapy at Least 40% Less
In 1998, the COG established a system of risk stratification for neuroblastoma that was based on clinical data (the patient's age at diagnosis and the tumor stage) and tumor-derived biologic data (histopathological classification, MYCN oncogene amplification status, and ploidy).
In the COG system, intermediate-risk neuroblastoma was defined as stage 3 or 4 disease without MYCN amplification in an infant, stage 3 disease and favorable histopathological features in a child, and stage 4S disease with a diploid tumor-cell DNA index, unfavorable histopathological features, or both.
The study, which examined children with stages 3, 4, and 4S disease, involved 479 patients, is the largest trial focused on reducing the amount of chemotherapy needed to treat intermediate-risk neuroblastoma.
According to the researchers, they sought to reduce exposure to chemotherapy by at least 40% while maintaining the same 90% survival rate achieved in earlier trials using higher doses.
For instance, in the largest previously published study of treatment for intermediate-risk neuroblastoma (J Clin Oncol. 1998;16:1256-1264), the overall survival estimates among the cohorts with stages 4S, 4, and 3 disease were 92%, 93%, and 100%, respectively, among patients with tumors that had favorable biologic features. However, this outcome was achieved with 9 months of chemotherapy (10 cycles), consisting of cisplatin, doxorubicin, etoposide, and cyclophosphamide, administered in total cumulative doses substantially exceeding those in the current study.
In contrast, the new trial called for only 4 cycles (for patients with tumors with favorable biologic features) or 8 cycles (for unfavorable biologic features). The chemotherapy consisted of carboplatin, etoposide, cyclophosphamide, and doxorubicin, and was administered at 3-week intervals. This treatment was followed by surgical excision of the primary tumor.
The new trial was prospective, uncontrolled, and nonrandomized. The respective 3-year overall survival estimates were 98% ± 1%, 97% ± 3%, and 93% ± 2% for stages 3, 4S, and 4, respectively. Ploidy, but not histopathological features, was a significant predictor of outcome, the authors report.
In the 479 patients, 59 first events were documented: disease progression in 42 patients, death in 14 patients, and secondary leukemia in 3 patients.
The median follow-up time for patients who survived without an event was 5.2 years.
Severe adverse events without disease progression occurred in 10 patients (2.1%). The events were secondary leukemia (3 patients), death from infection (3 patients), and death at surgery (4 patients).
No Chemotherapy in Some Patients
This is not the first time investigators have experimented with reductions in chemotherapy in this setting.
However, as the current study authors point out, because of differences in the staging and risk factors used, and because of the wide variation within studies of cumulative chemotherapy doses, the results cannot be directly compared.
Nevertheless, the overall survival estimates in these studies were "generally similar" to those in the current study, ranging from 87% to 95%, say the authors.
However, interestingly, some of the patients in those studies received no chemotherapy.
"Some groups have successfully used observation alone in selected infants who had stage 4 disease without radiologic evidence of bone involvement or progression; in these groups, the 2-year overall survival estimate was 95%," write the authors.
The study was funded by the National Cancer Institute. The authors have disclosed no relevant financial relationships.
N Engl J Med. 2010;363:1313-1323.
The trial used a "substantially reduced" duration of chemotherapy, compared with previously used regimens, as well as reduced doses, and produced a "very high rate of survival," write the study authors in the September 30 issue of the New England Journal of Medicine.
"These data provide support for further reduction in chemotherapy with more refined risk stratification," conclude the authors, led by David Baker, MD, from the Princess Margaret Hospital for Children in Perth, Australia.
A 3-year overall survival estimate of 96% ± 1% (95% confidence interval [CI], 94 - 97) was achieved with a substantial reduction in cytotoxic therapy for the rare disease, which affects the sympathetic nervous system and most commonly develops in the adrenal glands, say the authors, who are all members of the Children's Oncology Group (COG) research collaborative.
The 3-year event-free survival estimate was 88% ± 2% (95% CI, 84 - 90). In intermediate-risk neuroblastoma, 3 years of survival without relapse generally means that a patient is cured, note the authors.
"Our goal was to reduce the level of chemotherapy needed to effectively treat intermediate-risk neuroblastoma patients while maintaining an excellent rate of survival, and that is exactly what we did," said senior coauthor Katherine Matthay, MD, in a press statement. She is from the University of California San Francisco Benioff Children's Hospital.
"This trial will lead to permanent treatment reductions in our protocol for treating this disease and will have a significant impact on the hundreds of children who are diagnosed with neuroblastoma each year," said Dr. Matthay.
Duration of Chemotherapy at Least 40% Less
In 1998, the COG established a system of risk stratification for neuroblastoma that was based on clinical data (the patient's age at diagnosis and the tumor stage) and tumor-derived biologic data (histopathological classification, MYCN oncogene amplification status, and ploidy).
In the COG system, intermediate-risk neuroblastoma was defined as stage 3 or 4 disease without MYCN amplification in an infant, stage 3 disease and favorable histopathological features in a child, and stage 4S disease with a diploid tumor-cell DNA index, unfavorable histopathological features, or both.
The study, which examined children with stages 3, 4, and 4S disease, involved 479 patients, is the largest trial focused on reducing the amount of chemotherapy needed to treat intermediate-risk neuroblastoma.
According to the researchers, they sought to reduce exposure to chemotherapy by at least 40% while maintaining the same 90% survival rate achieved in earlier trials using higher doses.
For instance, in the largest previously published study of treatment for intermediate-risk neuroblastoma (J Clin Oncol. 1998;16:1256-1264), the overall survival estimates among the cohorts with stages 4S, 4, and 3 disease were 92%, 93%, and 100%, respectively, among patients with tumors that had favorable biologic features. However, this outcome was achieved with 9 months of chemotherapy (10 cycles), consisting of cisplatin, doxorubicin, etoposide, and cyclophosphamide, administered in total cumulative doses substantially exceeding those in the current study.
In contrast, the new trial called for only 4 cycles (for patients with tumors with favorable biologic features) or 8 cycles (for unfavorable biologic features). The chemotherapy consisted of carboplatin, etoposide, cyclophosphamide, and doxorubicin, and was administered at 3-week intervals. This treatment was followed by surgical excision of the primary tumor.
The new trial was prospective, uncontrolled, and nonrandomized. The respective 3-year overall survival estimates were 98% ± 1%, 97% ± 3%, and 93% ± 2% for stages 3, 4S, and 4, respectively. Ploidy, but not histopathological features, was a significant predictor of outcome, the authors report.
In the 479 patients, 59 first events were documented: disease progression in 42 patients, death in 14 patients, and secondary leukemia in 3 patients.
The median follow-up time for patients who survived without an event was 5.2 years.
Severe adverse events without disease progression occurred in 10 patients (2.1%). The events were secondary leukemia (3 patients), death from infection (3 patients), and death at surgery (4 patients).
No Chemotherapy in Some Patients
This is not the first time investigators have experimented with reductions in chemotherapy in this setting.
However, as the current study authors point out, because of differences in the staging and risk factors used, and because of the wide variation within studies of cumulative chemotherapy doses, the results cannot be directly compared.
Nevertheless, the overall survival estimates in these studies were "generally similar" to those in the current study, ranging from 87% to 95%, say the authors.
However, interestingly, some of the patients in those studies received no chemotherapy.
"Some groups have successfully used observation alone in selected infants who had stage 4 disease without radiologic evidence of bone involvement or progression; in these groups, the 2-year overall survival estimate was 95%," write the authors.
The study was funded by the National Cancer Institute. The authors have disclosed no relevant financial relationships.
N Engl J Med. 2010;363:1313-1323.
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