In a randomized, double-blind phase 2 study, an intravaginal probiotic composed of Lactobacillus crispatus CTV-05 (Lactin-V, Osel Inc) reduced the rate of recurrent urinary tract infection (rUTI) in UTI-prone women by roughly one half, which compares favorably with historical data on antimicrobial prophylaxis, the researchers say.
They add that larger trials are warranted to see whether use of vaginal Lactobacillus could replace long-term antimicrobial preventive treatments in women susceptible to rUTI.
The study was published online April 15 and in the May 15 print issue of Clinical Infectious Diseases.
UTIs are common in women and frequently recur, Ann Stapleton, MD, from the University of Washington in Seattle, and colleagues note in their report. It has been shown, they add, that women with rUTIs often have alterations in vaginal microbiota, including depletion of lactobacilli.
A phase 1 study of Lactobacillus crispatus CTV-05 showed that the probiotic can be given as a vaginal suppository with minimal adverse effects to healthy women with a history of rUTI. In the phase 2 study, 100 premenopausal women (median age, 21 years) with a history of rUTI received antimicrobials for acute UTI and then were randomly assigned to receive eitherLactobacillus crispatus CTV-05 or placebo vaginal suppository gelatin capsules administered once daily for 5 days, followed by once weekly for 10 weeks.
"We found that Lactin-V reduced the risk of rUTI approximately as effectively as antimicrobial prophylaxis, achieved high-level vaginal colonization in most women, and was well tolerated," Dr. Stapleton and colleagues report.
According to the investigators, culture-confirmed rUTI occurred in 7 (15%) of 48 of women who received Lactobacillus crispatus CTV-05 compared with 13 (27%) of 48 women who received placebo (relative risk [RR], .5; 95% confidence interval [CI], .2 - 1.2).
A high level of vaginal colonization with L crispatus throughout follow-up was associated with a significant reduction in rUTI only among women receiving Lactobacillus crispatus CTV-05 (RR for Lactin-V, .07; RR for placebo, 1.1; P < .01).
The safety profile of the probiotic mirrored that seen in the phase 1 study. Adverse effects were reported by 56% of women receiving Lactobacillus crispatus CTV-05 and 50% of those receiving placebo. The most common adverse effects included vaginal discharge or itching or moderate abdominal discomfort.
A novel aspect of this study, the authors say, is the application of quantitative polymerase chain reaction to assess vaginal microbiota after UTI. This enabled them to define sentinel changes in vaginal microbiota with or without the Lactobacillus crispatus CTV-05 probiotic.
Using quantitative polymerase chain reaction to assess L crispatus colonization in women in both study groups, the researchers say, allowed them to distinguish the natural recovery of the vaginal microbiota after UTI, as may have potentially occurred in the placebo group, from specific effects attributable to the probiotic.
What was "striking," the investigators add, was that placebo-treated women often had high concentrations of vaginal L crispatus during follow-up, yet this failed to protect them from rUTI (RR, 1.1; 95% CI, .4 - 3.1). In contrast, women who received Lactobacillus crispatus CTV-05 and achieved high colonization were protected from rUTI (RR, .07; 95% CI, .02 - .3; P < .01).
"Lactin-V after treatment for acute UTI," they conclude, "confers a significant advantage over repopulation of the vaginal microbiota with endogenous L. crispatus."
"Ongoing studies in our group are directed at understanding the mechanisms of protection in vivo and optimizing this prophylactic regimen," they note.
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BRCA2 MUTATION LINKED TO BETTER SURVIVAL IN OVARIAN CANCER PATIENTS
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Ovarian cancer patients with the BRCA2 gene mutation are more likely to survive their disease than those with the BRCA1 mutation and those without either mutation.
After adjustment for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest nonsignificant survival advantage (hazard ratio [HR], 0.84; P = .12). However, BRCA2 carriers showed a marked improvement in survival, compared with noncarriers (HR, 0.57; P = 6 ×10–4).
The data were presented here at the American Association for Cancer Research 102nd Annual Meeting.
"This is the first solid evidence that BRCA2 carriers show a distinct clinical course from BRCA1 carriers," said lead author Kelly Bolton, MPhil, a predoctoral candidate at the National Cancer Institute.
"Our findings don't have any immediate impact on clinical practice, but they do have important implications for both clinical prediction and trial design — particularly for clinical trials," explained Ms. Bolton.
The next step is to try to understand the mechanism driving these survival differences. "There is some evidence from in vitro work and some retrospective clinical studies that suggest that response to chemotherapy may be different between carriers and noncarriers," she said. "There could also be biological differences that exist that we are not yet aware of between BRCA1 andBRCA2 carriers and noncarriers that are driving this association."
Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in about 10% to 15% of ovarian cancer patients, but are quite uncommon in the general population. Both genes play key roles in DNA damage repair, but appear to have distinct, although often complementary, functions, Ms. Bolton pointed out. Breast and ovarian cancer risks differ between the 2 carrier groups, and mutation-specific effects have been suggested for both.
Possible Treatment Implications
Survival among ovarian cancer patients is quite variable, noted Ellen Goode, PhD, associate professor of epidemiology at the Mayo Clinic in Rochester, Minnesota. "BRCA1 and BRCA2 are 2 genes that increase the risk of ovarian cancer."
"But what hasn't been definitively shown until now is that once you have ovarian cancer, if you are a carrier of one of these genes, that will affect your survival," she told Medscape Medical News. Dr. Goode was not involved in the study.
This study shows that there is a difference in outcome that could lead to variables in treatment. "It could be that we need more tailored chemotherapy, depending on BRCA status," she said.
It is still premature to consider testing all ovarian cancer patients for BRCA status, explained Dr. Goode, but it should be considered on an individual basis. "Testing for BRCA is very expensive, so it is not something that is feasible on a large scale," she said.
"If a woman has a family history of the disease and has already been tested, it is probably something that should be taken into account at this point," she added.
"In terms of chemotherapy regimens, a good next analysis would be to stratify women by carrier status," said Dr. Goode. "In the future, I think that this information will prove useful in terms of treatment."
Survival Advantage for BRCA2 Carriers
In this study, Ms. Bolton and colleagues conducted a large multicenter study to investigate the impact of germline BRCA1 andBRCA2 mutations on ovarian cancer survival.
The cohort consisted of 3531 women with invasive epithelial ovarian cancer, of whom 1178 were BRCA1 carriers, 367 were BRCA2carriers, and 1986 were noncarriers. The team analyzed survival-time data obtained from 24 studies conducted in the United States, Europe, Israel, and Asia. The main analysis excluded patients who had not or who were likely to have not received platinum-based therapy.
BRCA1 and BRCA2 carriers were more likely than noncarriers to present with advanced-stage disease, high-grade tumors, and serous disease. The authors also observed that BRCA1 carriers tended to be younger than noncarriers at diagnosis (P = 2 × 10–9), and that BRCA2 carriers were slightly older at diagnosis (P = .002).
In terms of tumor stage, grade, and histology, there was no difference between BRCA1 and BRCA2 carriers, but there was a difference in age at diagnosis (P = 2 × 10–14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from noncarriers in overall survival (BRCA1 HR, 1.02; P = .77; BRCA2 HR, 0.89; P = .36). However, after adjustment for baseline characteristics, differences in the 3 groups emerged. For noncarriers, 5-year survival was 36%, for BRCA1 carriers it was 46%, and for BRCA2 carriers it was 61%.
The survival differences that were observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemosensitivity, the authors note.
After adjustment for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest nonsignificant survival advantage (hazard ratio [HR], 0.84; P = .12). However, BRCA2 carriers showed a marked improvement in survival, compared with noncarriers (HR, 0.57; P = 6 ×10–4).
The data were presented here at the American Association for Cancer Research 102nd Annual Meeting.
"This is the first solid evidence that BRCA2 carriers show a distinct clinical course from BRCA1 carriers," said lead author Kelly Bolton, MPhil, a predoctoral candidate at the National Cancer Institute.
"Our findings don't have any immediate impact on clinical practice, but they do have important implications for both clinical prediction and trial design — particularly for clinical trials," explained Ms. Bolton.
The next step is to try to understand the mechanism driving these survival differences. "There is some evidence from in vitro work and some retrospective clinical studies that suggest that response to chemotherapy may be different between carriers and noncarriers," she said. "There could also be biological differences that exist that we are not yet aware of between BRCA1 andBRCA2 carriers and noncarriers that are driving this association."
Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in about 10% to 15% of ovarian cancer patients, but are quite uncommon in the general population. Both genes play key roles in DNA damage repair, but appear to have distinct, although often complementary, functions, Ms. Bolton pointed out. Breast and ovarian cancer risks differ between the 2 carrier groups, and mutation-specific effects have been suggested for both.
Possible Treatment Implications
Survival among ovarian cancer patients is quite variable, noted Ellen Goode, PhD, associate professor of epidemiology at the Mayo Clinic in Rochester, Minnesota. "BRCA1 and BRCA2 are 2 genes that increase the risk of ovarian cancer."
"But what hasn't been definitively shown until now is that once you have ovarian cancer, if you are a carrier of one of these genes, that will affect your survival," she told Medscape Medical News. Dr. Goode was not involved in the study.
This study shows that there is a difference in outcome that could lead to variables in treatment. "It could be that we need more tailored chemotherapy, depending on BRCA status," she said.
It is still premature to consider testing all ovarian cancer patients for BRCA status, explained Dr. Goode, but it should be considered on an individual basis. "Testing for BRCA is very expensive, so it is not something that is feasible on a large scale," she said.
"If a woman has a family history of the disease and has already been tested, it is probably something that should be taken into account at this point," she added.
"In terms of chemotherapy regimens, a good next analysis would be to stratify women by carrier status," said Dr. Goode. "In the future, I think that this information will prove useful in terms of treatment."
Survival Advantage for BRCA2 Carriers
In this study, Ms. Bolton and colleagues conducted a large multicenter study to investigate the impact of germline BRCA1 andBRCA2 mutations on ovarian cancer survival.
The cohort consisted of 3531 women with invasive epithelial ovarian cancer, of whom 1178 were BRCA1 carriers, 367 were BRCA2carriers, and 1986 were noncarriers. The team analyzed survival-time data obtained from 24 studies conducted in the United States, Europe, Israel, and Asia. The main analysis excluded patients who had not or who were likely to have not received platinum-based therapy.
BRCA1 and BRCA2 carriers were more likely than noncarriers to present with advanced-stage disease, high-grade tumors, and serous disease. The authors also observed that BRCA1 carriers tended to be younger than noncarriers at diagnosis (P = 2 × 10–9), and that BRCA2 carriers were slightly older at diagnosis (P = .002).
In terms of tumor stage, grade, and histology, there was no difference between BRCA1 and BRCA2 carriers, but there was a difference in age at diagnosis (P = 2 × 10–14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from noncarriers in overall survival (BRCA1 HR, 1.02; P = .77; BRCA2 HR, 0.89; P = .36). However, after adjustment for baseline characteristics, differences in the 3 groups emerged. For noncarriers, 5-year survival was 36%, for BRCA1 carriers it was 46%, and for BRCA2 carriers it was 61%.
The survival differences that were observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemosensitivity, the authors note.
Welding And Parkinson's, Can Fumes Lead To The Disease?
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Fumes produced by welding contain manganese. Manganese is a chemical element that, even at low levels, has been linked to neurologic problems, including Parkinson's disease-like symptoms. New research suggests that workers exposed to welding fumes may be at risk for developing brain damage in an area of the brain also affected inParkinson's disease.
Brad A. Racette, MD, with Washington University School of Medicine in St. Louis and a Fellow with the American Academy of Neurology stated:
Almost everyone is exposed to small amounts of manganese, a naturally occurring substance in our air, soil, water and food, daily. If kept in check, the body is able to control manganese levels by expelling extra amounts, but if the intake becomes too great, it can become overwhelming and cause a variety of health problems, including permanent nervous system damage.
What makes manganese so dangerous is that the current safety levels may not be adequate, so people may be taking in dangerous levels of this compound that almost no one is aware of.
The study involved 20 welders with no symptoms of Parkinson's disease, 20 people with Parkinson's disease who were not welders and 20 people who were not welders and did not have Parkinson's.
The welders were recruited from two Midwest shipyards and one metal fabrication company. All participants were given brain PET and MRI scans, motor skills tests and examined by a neurologist who specializes in movement disorders. The welders had an average of 30,000 hours of lifetime welding exposure. Their average manganese levels were found to be two times the upper limits of normal.
Scientists found that welders had an average 11.7% reduction in a marker of dopamine in one area of the brain on PET scans as compared to people who did not weld. Dopamine is a chemical messenger that helps nerve cells communicate and is decreased in specific brain regions in people with Parkinson's disease. The welders' motor skills test scores also showed mild movement difficulties that were about half of that found in the early Parkinson's disease patients.
Racette continues:
Perhaps most concerning is that permanent damage to the nervous system may occur after exposure to manganese levels that the Environmental Protection Agency (EPA) has noted as safe.
W. R. Wayne Martin, MD from University of Alberta in Edmonton, Alberta, Canada and also a member of the American Academy of Neurology adds:
Brad A. Racette, MD, with Washington University School of Medicine in St. Louis and a Fellow with the American Academy of Neurology stated:
"There are over one million workers who perform welding as part of their job functions in the United States. If a link between neurotoxic effects and these fumes were proven, it would have a substantial public health impact for the U.S. workforce and economy."
Almost everyone is exposed to small amounts of manganese, a naturally occurring substance in our air, soil, water and food, daily. If kept in check, the body is able to control manganese levels by expelling extra amounts, but if the intake becomes too great, it can become overwhelming and cause a variety of health problems, including permanent nervous system damage.
What makes manganese so dangerous is that the current safety levels may not be adequate, so people may be taking in dangerous levels of this compound that almost no one is aware of.
The study involved 20 welders with no symptoms of Parkinson's disease, 20 people with Parkinson's disease who were not welders and 20 people who were not welders and did not have Parkinson's.
The welders were recruited from two Midwest shipyards and one metal fabrication company. All participants were given brain PET and MRI scans, motor skills tests and examined by a neurologist who specializes in movement disorders. The welders had an average of 30,000 hours of lifetime welding exposure. Their average manganese levels were found to be two times the upper limits of normal.
Scientists found that welders had an average 11.7% reduction in a marker of dopamine in one area of the brain on PET scans as compared to people who did not weld. Dopamine is a chemical messenger that helps nerve cells communicate and is decreased in specific brain regions in people with Parkinson's disease. The welders' motor skills test scores also showed mild movement difficulties that were about half of that found in the early Parkinson's disease patients.
Racette continues:
"While these changes in the brain and dopamine dysfunction may be an early marker of neuron death related to welding exposure, the damage appeared to be different from those of people with full-fledged Parkinson's disease. MRI scans also revealed brain changes in welders that were consistent with manganese deposits in the brain."
Perhaps most concerning is that permanent damage to the nervous system may occur after exposure to manganese levels that the Environmental Protection Agency (EPA) has noted as safe.
W. R. Wayne Martin, MD from University of Alberta in Edmonton, Alberta, Canada and also a member of the American Academy of Neurology adds:
"Although this study shows that these workers had dopamine dysfunction in the brain, the study authors could not determine whether this was specifically related to manganese. Will these individuals develop full-fledged Parkinson's disease? We can't answer that question based on the study but more research should be done to explore this possibility."
NEOADJUVANT ANDROGEN DEPRIVATION THERAPY BEFORERADIOTHERAPY HALVES PROSTATE CANCER MORTALITY
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New long-term results confirm the finding that neoadjuvant androgen-deprivation therapy (ADT), combined with radiotherapy, can significantly boost survival in men with locally advanced prostate cancer.
The updated results of the Trans-Tasman Radiation Oncology Group (TROG) 96.01 trial are published online March 25 in the Lancet Oncology.
They show that a large proportion of patients with locally advanced disease can be successfully treated with as little as 6 months of neoadjuvant ADT and a relatively low dose of radiation.
The authors note that at 10 years, neoadjuvant ADT cut the prostate-cancer-specific mortality rate in half, compared with radiation treatment alone (11% vs 22%).
All-cause mortality was also reduced, by about a third, among patients who received both therapies (29% vs 43%).
These results confirm the use of neoadjuvant ADT in this population of prostate cancer patients, explained lead author James W. Denham, MD, director of the Prostate Cancer Trials Group at the University of Newcastle, New South Wales, Australia. "It also gives evidence that the treatment needs to be at least 6 months to have an effect on mortality."
"For men with intermediate-risk cancers, RTOG [Radiation Therapy Oncology Group] 9408 has shown that 4 months of neoadjuvant ADT can improve survival," he told Medscape Medical News.
Earlier Results Confirmed
Dr. Denham and colleagues previously reported 5-year results from this study. They suggested that 6 months of neoadjuvant ADT improved prostate-cancer-specific survival by reducing metastases (Lancet Oncol. 2005;6:841-850). At 10 years, they now find that, compared with radiotherapy alone, the addition of ADT improves event-free survival, decreases the cumulative incidence of prostate-specific antigen (PSA) progression, and decreases distant progression and all-cause and disease-specific mortality.
In this prostate cancer population, neoadjuvant ADT for at least 6 months is the already the standard of care in Australia and New Zealand and a number of centers in other parts of the world, explained Dr. Denham.
He also noted that although a longer duration of ADT after radiation might increase survival slightly, which has been seen in some trials from the RTOG and European Organization for Research and Treatment of Cancer, it comes at a cost — both financially and in terms of toxicity. "A point we make in the article is that the informed treatment-consent process is getting much more rigorous in many countries, and it is getting more difficult to 'persuade' men that the inconvenience and potential prolonged ill effects of long-term ADT are worth the possible additional gains," he said.
"Six months of neoadjuvant ADT and radiation is a very reasonable choice, particularly for men with coexisting medical problems that could be exacerbated by long-term ADT," Dr. Denham added.
Clear Messages for Clinical Practice
In an accompanying editorial, Chris Parker, MD, consultant clinical oncologist from the Royal Marsden Hospital, Sutton, United Kingdom, agrees that these findings strengthen the evidence and send "2 clear messages for current clinical practice."
First off, he writes, is that it offers confirmation that neoadjuvant ADT "significantly reduces mortality after radiotherapy for high-risk prostate cancer, and is a standard of care."
The second point is that it helps to" resolve the uncertainty" regarding the duration of this therapy, and strongly suggests that the duration should be at least 6 months, he notes.
Six Months Superior to 3 Months
The TROG 96.01 study compared radiotherapy alone with 3 or 6 months of neoadjuvant ADT, which was given before and during radiation therapy. In their paper, the authors report, from the 10-year data, the benefits derived from 3 months and 6 months of neoadjuvant ADT.
Their analysis involved 802 men with stage T2b, T2c, T3, and T4 N0M0 prostate cancers. They were randomly assigned to receive radiotherapy alone (n = 270), 3 months of neoadjuvant ADT plus radiotherapy (n = 265), or 6 months of neoadjuvant ADT plus radiotherapy (n = 267).
At 10 years, prostate-cancer-specific mortality was 22% for radiotherapy alone, 18.9% for 3 months of neoadjuvant therapy (hazard ratio [HR], 0.86; P = .398), and 11.4% for 6 months of neoadjuvant ADT (HR, 0.49; P = .0008).
For all-cause mortality at 10 years, the findings were similar: 42.5% for radiotherapy alone, 36.7% for 3 months of neoadjuvant ADT (HR, 0.84; P = .18), and 29.2% for 6 months of neoadjuvant ADT (HR, 0.63; P = .0008).
Conversely, the cumulative incidence of deaths at 10 years not related to prostate cancer were similar in all treatment groups: 20.4% for radiotherapy alone, 17.7% for 3 months of neoadjuvant ADT, and 17.8% for 6 months of neoadjuvant ADT (P > .40 for all paired comparisons).
During the course of the study, 16,562 PSA levels were obtained from the 802 men; the median number of PSA levels per patient was 21 (range, 1 to 43).
Progression of PSA was observed in 508 men. At 10 years, the cumulative incidence of PSA progression was 73.8% for radiotherapy alone, 60.4% for 3 months of neoadjuvant ADT (HR, 0.72; P = .003), and 52.3% for 6 months of neoadjuvant ADT (HR, 0.57; P < .0001).
Progression of the primary tumor was found in 179 men, and progression at distant sites was found in 226 men. The 10-year cumulative incidence of local progression as a first event was 28.2% for radiotherapy alone, 15.7% for 3 months of neoadjuvant ADT (HR, 0.49; P = .0005), and 13.3% for 6 months of neoadjuvant ADT (HR, 0.45; P < .0001).
More Data to Come
The authors note that data from the RTOG 92.02 study showed that patients with high Gleason scores received the most benefit from prolonged ADT, raising the possibility that "the morbidity of long-term androgen deprivation can be restricted to men with the highest risk of progression."
Although subgroup analyses of prostate-cancer-specific mortality data in TROG 96.01 did not support this hypothesis, the authors explain that the interpretation of the trial's pathology data is limited by lack of a centralized histopathologic review.
"We hope that this trial's successor, TROG 03.04 RADAR34 — which investigates adding 12 months of adjuvant ADT, with or without 18 months of zoledronate, to 6-month neoadjuvant ADT and radiotherapy — can help resolve this possibility," they write.
The study was funded by Australian Government National Health, the Medical Research Council, Hunter Medical Research Institute, AstraZeneca, and Schering-Plough. The authors and the editorialist have disclosed no relevant financial relationships.
The updated results of the Trans-Tasman Radiation Oncology Group (TROG) 96.01 trial are published online March 25 in the Lancet Oncology.
They show that a large proportion of patients with locally advanced disease can be successfully treated with as little as 6 months of neoadjuvant ADT and a relatively low dose of radiation.
The authors note that at 10 years, neoadjuvant ADT cut the prostate-cancer-specific mortality rate in half, compared with radiation treatment alone (11% vs 22%).
All-cause mortality was also reduced, by about a third, among patients who received both therapies (29% vs 43%).
These results confirm the use of neoadjuvant ADT in this population of prostate cancer patients, explained lead author James W. Denham, MD, director of the Prostate Cancer Trials Group at the University of Newcastle, New South Wales, Australia. "It also gives evidence that the treatment needs to be at least 6 months to have an effect on mortality."
"For men with intermediate-risk cancers, RTOG [Radiation Therapy Oncology Group] 9408 has shown that 4 months of neoadjuvant ADT can improve survival," he told Medscape Medical News.
Earlier Results Confirmed
Dr. Denham and colleagues previously reported 5-year results from this study. They suggested that 6 months of neoadjuvant ADT improved prostate-cancer-specific survival by reducing metastases (Lancet Oncol. 2005;6:841-850). At 10 years, they now find that, compared with radiotherapy alone, the addition of ADT improves event-free survival, decreases the cumulative incidence of prostate-specific antigen (PSA) progression, and decreases distant progression and all-cause and disease-specific mortality.
In this prostate cancer population, neoadjuvant ADT for at least 6 months is the already the standard of care in Australia and New Zealand and a number of centers in other parts of the world, explained Dr. Denham.
He also noted that although a longer duration of ADT after radiation might increase survival slightly, which has been seen in some trials from the RTOG and European Organization for Research and Treatment of Cancer, it comes at a cost — both financially and in terms of toxicity. "A point we make in the article is that the informed treatment-consent process is getting much more rigorous in many countries, and it is getting more difficult to 'persuade' men that the inconvenience and potential prolonged ill effects of long-term ADT are worth the possible additional gains," he said.
"Six months of neoadjuvant ADT and radiation is a very reasonable choice, particularly for men with coexisting medical problems that could be exacerbated by long-term ADT," Dr. Denham added.
Clear Messages for Clinical Practice
In an accompanying editorial, Chris Parker, MD, consultant clinical oncologist from the Royal Marsden Hospital, Sutton, United Kingdom, agrees that these findings strengthen the evidence and send "2 clear messages for current clinical practice."
First off, he writes, is that it offers confirmation that neoadjuvant ADT "significantly reduces mortality after radiotherapy for high-risk prostate cancer, and is a standard of care."
The second point is that it helps to" resolve the uncertainty" regarding the duration of this therapy, and strongly suggests that the duration should be at least 6 months, he notes.
Six Months Superior to 3 Months
The TROG 96.01 study compared radiotherapy alone with 3 or 6 months of neoadjuvant ADT, which was given before and during radiation therapy. In their paper, the authors report, from the 10-year data, the benefits derived from 3 months and 6 months of neoadjuvant ADT.
Their analysis involved 802 men with stage T2b, T2c, T3, and T4 N0M0 prostate cancers. They were randomly assigned to receive radiotherapy alone (n = 270), 3 months of neoadjuvant ADT plus radiotherapy (n = 265), or 6 months of neoadjuvant ADT plus radiotherapy (n = 267).
At 10 years, prostate-cancer-specific mortality was 22% for radiotherapy alone, 18.9% for 3 months of neoadjuvant therapy (hazard ratio [HR], 0.86; P = .398), and 11.4% for 6 months of neoadjuvant ADT (HR, 0.49; P = .0008).
For all-cause mortality at 10 years, the findings were similar: 42.5% for radiotherapy alone, 36.7% for 3 months of neoadjuvant ADT (HR, 0.84; P = .18), and 29.2% for 6 months of neoadjuvant ADT (HR, 0.63; P = .0008).
Conversely, the cumulative incidence of deaths at 10 years not related to prostate cancer were similar in all treatment groups: 20.4% for radiotherapy alone, 17.7% for 3 months of neoadjuvant ADT, and 17.8% for 6 months of neoadjuvant ADT (P > .40 for all paired comparisons).
During the course of the study, 16,562 PSA levels were obtained from the 802 men; the median number of PSA levels per patient was 21 (range, 1 to 43).
Progression of PSA was observed in 508 men. At 10 years, the cumulative incidence of PSA progression was 73.8% for radiotherapy alone, 60.4% for 3 months of neoadjuvant ADT (HR, 0.72; P = .003), and 52.3% for 6 months of neoadjuvant ADT (HR, 0.57; P < .0001).
Progression of the primary tumor was found in 179 men, and progression at distant sites was found in 226 men. The 10-year cumulative incidence of local progression as a first event was 28.2% for radiotherapy alone, 15.7% for 3 months of neoadjuvant ADT (HR, 0.49; P = .0005), and 13.3% for 6 months of neoadjuvant ADT (HR, 0.45; P < .0001).
More Data to Come
The authors note that data from the RTOG 92.02 study showed that patients with high Gleason scores received the most benefit from prolonged ADT, raising the possibility that "the morbidity of long-term androgen deprivation can be restricted to men with the highest risk of progression."
Although subgroup analyses of prostate-cancer-specific mortality data in TROG 96.01 did not support this hypothesis, the authors explain that the interpretation of the trial's pathology data is limited by lack of a centralized histopathologic review.
"We hope that this trial's successor, TROG 03.04 RADAR34 — which investigates adding 12 months of adjuvant ADT, with or without 18 months of zoledronate, to 6-month neoadjuvant ADT and radiotherapy — can help resolve this possibility," they write.
The study was funded by Australian Government National Health, the Medical Research Council, Hunter Medical Research Institute, AstraZeneca, and Schering-Plough. The authors and the editorialist have disclosed no relevant financial relationships.
BELIMUMAB: A NEW DRUG FOR LUPUS
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The US Food and Drug Administration (FDA) has approved the use of belimumab (Benlysta, Human Genome Sciences and GlaxoSmithKline) in combination with standard therapies to treat active autoantibody-positive systematic lupus erythematosus.
This is the first lupus drug to be approved since 1955, when the FDA approved hydroxychloroquine (Plaquenil) and corticosteroids. In 1948, aspirin was approved to treat lupus.
Belimumab is a B-lymphocyte stimulator protein inhibitor that is thought to decrease the amount of abnormal B cells, which is hypothesized to be a mechanism of action in lupus.
The safety and effectiveness of belimumab was demonstrated in 2 clinical trials that randomized a total of 1684 patients to receive either belimumab or placebo in combination with standard therapy. Treatment with belimumab plus standard therapy reduced disease activity and possibly decreased the number of severe flares and steroid use.
Patients with active lupus that involved the kidneys or central nervous system and those who were previously treated with a B-cell-targeted therapy or intravenous cyclophosphamide were excluded from participating in the trials.
Study participants of African American or African descent did not significantly respond to belimumab. Additional studies will be conducted to definitively determine the safety and efficacy of belimumab in this population.
Common adverse effects reported with belimumab include nausea, diarrhea, fever, and infusion-site reactions. It is suggested that patients be treated with an antihistamine prior to a belimumab infusion.
A greater number of deaths and serious infections were reported in patients treated with belimumab than in those treated with placebo. Live vaccines should not be administered during treatment with belimumab.
It is estimated that lupus afflicts up to 1.5 million Americans, and it disproportionately affects black women.
This is the first lupus drug to be approved since 1955, when the FDA approved hydroxychloroquine (Plaquenil) and corticosteroids. In 1948, aspirin was approved to treat lupus.
Belimumab is a B-lymphocyte stimulator protein inhibitor that is thought to decrease the amount of abnormal B cells, which is hypothesized to be a mechanism of action in lupus.
The safety and effectiveness of belimumab was demonstrated in 2 clinical trials that randomized a total of 1684 patients to receive either belimumab or placebo in combination with standard therapy. Treatment with belimumab plus standard therapy reduced disease activity and possibly decreased the number of severe flares and steroid use.
Patients with active lupus that involved the kidneys or central nervous system and those who were previously treated with a B-cell-targeted therapy or intravenous cyclophosphamide were excluded from participating in the trials.
Study participants of African American or African descent did not significantly respond to belimumab. Additional studies will be conducted to definitively determine the safety and efficacy of belimumab in this population.
Common adverse effects reported with belimumab include nausea, diarrhea, fever, and infusion-site reactions. It is suggested that patients be treated with an antihistamine prior to a belimumab infusion.
A greater number of deaths and serious infections were reported in patients treated with belimumab than in those treated with placebo. Live vaccines should not be administered during treatment with belimumab.
It is estimated that lupus afflicts up to 1.5 million Americans, and it disproportionately affects black women.
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