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.
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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.
REDUCING CHEMORADIOTHERAPY SAFE FOR SOMERABDOMYOSARCOMAS
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NEW YORK (Reuters Health) Mar 03 - Reducing the use of radiotherapy and eliminating cyclophosphamide has been found safe and effective in some patients with newly diagnosed, low-risk embryonal rhabdomyosarcoma (ERMS).
The findings are the latest from The Intergroup Rhabdomyosarcoma Study Group (IRSG), and were published online February 28th in the Journal of Clinical Oncology.
In previous studies the same researchers who conducted this study found that patients with localized, grossly resected, or gross residual (orbital only) ERMS had 5-year failure-free survival rates of 83% and overall survival rates of 95%. That was using specially designed protocols for low-risk patients established by the IRSG. Those regimens included vincristine and dactinomycin with or without cyclophosphamide and radiation therapy.
The aim of the present study was to see if it was feasible, in a similar cohort of patients, to decrease toxicity by reducing radiotherapy doses and eliminating cyclophosphamide in patients at lowest risk.
The researchers stratified 342 patients by risk. The lower risk group (n=264) included embryonal ectomesenchymoma or ERMS patients categorized as stage 1 group I/IIA, stage 1 group III orbit, or stage 2 group I.
The higher risk group (n=78) included patients with stage 1 group IIB/C, stage I group III nonorbit, stage 2 group II, or stage 3 group I/II ERMS.
The researchers' specific objectives were three-fold:
1. To estimate failure-free survival rates of patients in subgroup A after vincristine and dactinomycin chemotherapy for 45 weeks, plus radiation therapy for patients with residual tumor;
2. To estimate failure-free survival rates of patients in subgroup B after vincristine and dactinomycin plus cyclophosphamide for 45 weeks, plus radiation therapy for patients with residual tumors;
3. And to ascertain local control and failure-free survival rates in three selected groups of patients given radiation therapy doses 5-10 Gy lower than in previous studies: 36 Gy for stage 1 group IIA, 45 Gy for stage 1 group III N0 orbit, and 36 Gy for stages 2/3 group IIA patients.
Estimated 5-year failure-free survival rates were 89% for patients in the lower risk group, and 85% for the higher risk group, after median follow-up of 5.1 years.
For patients with stage 1 group IIA tumors (n=62), estimated 5-year failure-free survival rates were 81%. For patients with group III orbit tumors (n=77), estimated 5-year failure-free survival was 86%.
The study group says 5-year failure-free survival and overall survival were similar to that observed in IRS-III patients, including those that were treated with reduced doses of radiation. Failure-free survival and overall survival were lower, however, than comparable IRS-IV patients that received vincristine and dactinomycin plus cyclophosphamide. Five-year failure-free survival rates were similar among the lower risk and higher risk patients.
Rhabdomyosarcoma is the most common type of soft-tissue sarcoma in children. The annual incidence of the disease in the U.S. is 4.5 cases per 1 million children younger than 14 years. About 250 new cases are diagnosed each year, nearly two thirds being embryonal rhabdomyosarcomas.
The findings are the latest from The Intergroup Rhabdomyosarcoma Study Group (IRSG), and were published online February 28th in the Journal of Clinical Oncology.
In previous studies the same researchers who conducted this study found that patients with localized, grossly resected, or gross residual (orbital only) ERMS had 5-year failure-free survival rates of 83% and overall survival rates of 95%. That was using specially designed protocols for low-risk patients established by the IRSG. Those regimens included vincristine and dactinomycin with or without cyclophosphamide and radiation therapy.
The aim of the present study was to see if it was feasible, in a similar cohort of patients, to decrease toxicity by reducing radiotherapy doses and eliminating cyclophosphamide in patients at lowest risk.
The researchers stratified 342 patients by risk. The lower risk group (n=264) included embryonal ectomesenchymoma or ERMS patients categorized as stage 1 group I/IIA, stage 1 group III orbit, or stage 2 group I.
The higher risk group (n=78) included patients with stage 1 group IIB/C, stage I group III nonorbit, stage 2 group II, or stage 3 group I/II ERMS.
The researchers' specific objectives were three-fold:
1. To estimate failure-free survival rates of patients in subgroup A after vincristine and dactinomycin chemotherapy for 45 weeks, plus radiation therapy for patients with residual tumor;
2. To estimate failure-free survival rates of patients in subgroup B after vincristine and dactinomycin plus cyclophosphamide for 45 weeks, plus radiation therapy for patients with residual tumors;
3. And to ascertain local control and failure-free survival rates in three selected groups of patients given radiation therapy doses 5-10 Gy lower than in previous studies: 36 Gy for stage 1 group IIA, 45 Gy for stage 1 group III N0 orbit, and 36 Gy for stages 2/3 group IIA patients.
Estimated 5-year failure-free survival rates were 89% for patients in the lower risk group, and 85% for the higher risk group, after median follow-up of 5.1 years.
For patients with stage 1 group IIA tumors (n=62), estimated 5-year failure-free survival rates were 81%. For patients with group III orbit tumors (n=77), estimated 5-year failure-free survival was 86%.
The study group says 5-year failure-free survival and overall survival were similar to that observed in IRS-III patients, including those that were treated with reduced doses of radiation. Failure-free survival and overall survival were lower, however, than comparable IRS-IV patients that received vincristine and dactinomycin plus cyclophosphamide. Five-year failure-free survival rates were similar among the lower risk and higher risk patients.
Rhabdomyosarcoma is the most common type of soft-tissue sarcoma in children. The annual incidence of the disease in the U.S. is 4.5 cases per 1 million children younger than 14 years. About 250 new cases are diagnosed each year, nearly two thirds being embryonal rhabdomyosarcomas.
INTERMITTENT ANDROGEN SUPPRESSION AS EFFECTIVE AS CONTINUOUS TREATMENT FOR PROSTATE CANCER
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Intergroup trial shows that intermittent androgen suppression is non-inferior to continuous androgen deprivation in men with PSA recurrence after radical therapy
In men with PSA recurrence after radical radiotherapy, intermittent androgen suppression has been suggested by phase II trials to improve quality of life (QoL) but effects on survival were unknown. In the NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/UK intercontinental CRUKE/01/013 randomized phase III trial, investigators compared intermittent androgen suppression vs continuous androgen deprivation to test for non-inferiority with respect to overall survival.
Eligible men had rising PSA > 3.0 ng/ml more than one year after radical radiotherapy, either initial or salvage, for localized prostate cancer. Patients could receive up to 1 year of neo/adjuvant androgen deprivation therapy. Stratification factors were time since radical radiotherapy, initial PSA, prior radical prostatectomy and prior androgen deprivation therapy. Intermittent androgen suppression was delivered for 8 months in each cycle with restart when PSA reached >10 ng/ml off treatment. Primary endpoint was overall survival; secondary endpoints included time to hormone refractory state, QoL, cholesterol/HDL/LDL, duration of treatment/non-treatment intervals, time to testosterone and potency recovery. The independent Data and Safety Monitoring Committee recommended halting the trial after a planned interim analysis demonstrated that a pre-specified stopping boundary for non-inferiority was crossed.
Investigators randomized 1,386 patients, 690 to intermittent and 696 to continuous androgen deprivation. Arms were balanced for important baseline factors. Median follow up was 6.9 years. Intermittent androgen suppression patients completed a median of 2 x 8 month cycles. A total of 524 deaths were observed (268 on intermittent vs 256 on continuous androgen deprivation). Median overall survival was 8.8 vs 9.1 years on intermittent and continuous androgen deprivation arms, respectively (p=0.009). The intermittent androgen suppression arm had more disease related (122 vs 97) and fewer unrelated (134 vs 146) deaths. Time to the hormone refractory state was statistically significantly improved on the intermittent androgen suppression arm (p=0.024). Intermittent androgen suppression patients had reduced hot flashes, but otherwise there was no evidence of differences in adverse events, including myocardial events or osteoporotic fractures.
The authors, who presented results at the fourth annual Genitourinary Cancers Symposium (17-19 February 2011, Orlando, USA), concluded that in men with PSA recurrence after radical radiotherapy, intermittent androgen suppression, given as described herein, is non-inferior to continuous androgen deprivation with respect to the overall survival.
The Genitourinary Cancers Symposium was co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology and the Society of Urologic Oncology.
Eligible men had rising PSA > 3.0 ng/ml more than one year after radical radiotherapy, either initial or salvage, for localized prostate cancer. Patients could receive up to 1 year of neo/adjuvant androgen deprivation therapy. Stratification factors were time since radical radiotherapy, initial PSA, prior radical prostatectomy and prior androgen deprivation therapy. Intermittent androgen suppression was delivered for 8 months in each cycle with restart when PSA reached >10 ng/ml off treatment. Primary endpoint was overall survival; secondary endpoints included time to hormone refractory state, QoL, cholesterol/HDL/LDL, duration of treatment/non-treatment intervals, time to testosterone and potency recovery. The independent Data and Safety Monitoring Committee recommended halting the trial after a planned interim analysis demonstrated that a pre-specified stopping boundary for non-inferiority was crossed.
Investigators randomized 1,386 patients, 690 to intermittent and 696 to continuous androgen deprivation. Arms were balanced for important baseline factors. Median follow up was 6.9 years. Intermittent androgen suppression patients completed a median of 2 x 8 month cycles. A total of 524 deaths were observed (268 on intermittent vs 256 on continuous androgen deprivation). Median overall survival was 8.8 vs 9.1 years on intermittent and continuous androgen deprivation arms, respectively (p=0.009). The intermittent androgen suppression arm had more disease related (122 vs 97) and fewer unrelated (134 vs 146) deaths. Time to the hormone refractory state was statistically significantly improved on the intermittent androgen suppression arm (p=0.024). Intermittent androgen suppression patients had reduced hot flashes, but otherwise there was no evidence of differences in adverse events, including myocardial events or osteoporotic fractures.
The authors, who presented results at the fourth annual Genitourinary Cancers Symposium (17-19 February 2011, Orlando, USA), concluded that in men with PSA recurrence after radical radiotherapy, intermittent androgen suppression, given as described herein, is non-inferior to continuous androgen deprivation with respect to the overall survival.
The Genitourinary Cancers Symposium was co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology and the Society of Urologic Oncology.
5 health reasons to not quit coffee
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I really like coffee. The morning ritual of brewing a cup, the smell that perks me up before I take a sip and, of course, the flavor all make it my favorite beverage aside from water (water’s delicious!). As a registered dietitian and a nutrition editor for EatingWell Magazine, I know that coffee is fine in moderation. It has lots of antioxidants and is low in calories if you don’t load it up with cream and sugar. Nonetheless, I always feel slightly guilty about drinking it—you know, in a “it’s so good, it must be bad” kind of way.
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Which is why I’m always delighted to hear of new reasons that coffee is good for your health...and there are plenty! Over 18,000 studies on coffee have been published in the past few decades, revealing these benefits, many of which Joyce Hendley wrote about in the March/April issue of EatingWell Magazine:
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1. It protects your heart: Moderate coffee drinkers (1 to 3 cups/day) have lower rates of stroke than noncoffee drinkers, an effect linked to coffee’s antioxidants. Coffee has more antioxidants per serving than blueberries, making it the biggest source of antioxidants in American diets. All those antioxidants may help suppress the damaging effect of inflammation on arteries. Immediately after drinking it, coffee raises your blood pressure and heart rate, but over the long term, it actually may lower blood pressure as coffee’s antioxidants activate nitric acid, widening blood vessels.
2. It diverts diabetes: Those antioxidants (chlorogenic acid and quinides, specifically) play another role: boosting your cells’ sensitivity to insulin, which helps regulate blood sugar. In fact, people who drink 4 or more cups of coffee each day may have a lower risk of developing type 2 diabetes, according to some studies. Other studies have shown that caffeine can blunt the insulin-sensitivity boost, so if you do drink several cups a day, try mixing in decaf occasionally.
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3. Your liver loves it: OK, so the research here is limited, but it looks like the more coffee people drink, the lower their incidence of cirrhosis and other liver diseases. One analysis of nine studies found that every 2-cup increase in daily coffee intake reduced liver cancer risk by 43 percent. Again, it’s those antioxidants—chlorogenic and caffeic acids—and caffeine that might prevent liver inflammation and inhibit cancer cells.
4. It boosts your brain power: Drinking between 1 and 5 cups a day (admittedly a big range) may help reduce risk of dementia and Alzheimer’s disease, as well as Parkinson’s disease, studies suggest. Those antioxidants may ward off brain cell damage and help the neurotransmitters involved in cognitive function to work better.
5. It helps your headaches: And not just the withdrawal headaches caused by skipping your daily dose of caffeine! Studies show that 200 milligrams of caffeine—about the amount in 16 ounces of brewed coffee—provides relief from headaches, including migraines. Exactly how caffeine relieves headaches isn’t clear. But scientists do know that caffeine boosts the activity of brain cells, causing surrounding blood vessels to constrict. One theory is that this constriction helps to relieve the pressure that causes the pain, says Robert Shapiro, M.D., Ph.D., associate professor of neurology and director of the Headache Clinic at the University of Vermont Medical School.
Now, that’s not to say that coffee doesn’t have any pitfalls—it does. Some people are super-sensitive to caffeine and get jittery or anxious after drinking coffee; habitual coffee drinkers usually develop a tolerance to caffeine that eliminates this problem (but they then need the caffeine to be alert and ward off withdrawal headaches). Coffee can also disturb sleep, especially as people age. Cutting some of the caffeine and drinking it earlier in the day can curb this effect. Lastly, unfiltered coffee (like that made with a French press) can raise LDL cholesterol, so use a filter for heart health.
But if you like coffee and you can tolerate it well, enjoy it...without the guilt.
ENDOMETRIAL CANCER SURVIVAL BETTER UNDER SPECIAL CARE
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Women with high-risk endometrial cancer who were treated by gynecological oncologists had significantly better survival than patients not receiving such care, but the same study found that in the United States, only about 20% of women with endometrial cancer are treated by these specialists.
The findings are published online in the Journal of Clinical Oncology.
"The survival benefit associated with care by a gynecologic oncologist may be explained by their better understanding of the disease process, resulting in more accurate staging, followed by adjuvant treatment if indicated," the authors explain. However, they and an outside commentator point out that the superior survival could be attributed to a "stage migration" effect.
Deaths Are Increasing
The study is important, say the researchers, because the number of annual deaths from endometrial cancer has doubled over the past 20 years.
As far as they are aware, it is the first large population-based study to evaluate the influence of subspecialty care on patients with endometrial cancer.
The team, led by John Chan, MD, from the University of California San Francisco, analyzed data on 18,338 women with endometrial cancer from 1988 to 2005, obtained from the Medicare and Surveillance, Epidemiology and End Results (SEER) database.
They found that 21.4% of these women received care from gynecologic oncologists.
Compared with the remaining women, the women who received care from gynecologic oncologists were older, had more lymph nodes removed, presented with more advanced cancer (stages III to IV), had higher-grade tumors, and were more likely to receive chemotherapy for advanced disease.
They were also more likely to undergo staging procedures with lymph node assessment and to receive chemotherapy.
They showed significantly better survival rates for high-risk disease.
For women with stage II to IV disease who received care from a gynecologic oncologist, 5-year disease-specific survival was 79%, compared with 73% for women who didn't receive such care (P = .001). The difference was even greater for women with advanced-stage disease (stage III to IV), where the 5-year disease-specific survival was 72%, compared with 64% (P < .001).
However, there was no difference in survival rates for women with early, stage I and grade 1 cancers. All of them had "excellent" overall survival, the researchers note, with a 5-year disease-specific survival of 95%.
"This is an important paper, as it suggests that patients with more advanced endometrial cancer who are managed by gynecologic oncologists experience a superior outcome," said Maurie Markman MD, vice president of patient care services and national director for medical oncology at Cancer Treatment Centers for America, in Philadelphia, Pennsylvania.
"However, one must be cautious in the interpretation of the data, as 'stage migration' may be playing an important role," Dr. Markman added. This would have the effect of making it appear that patients with more advanced disease have a superior outcome when managed by a gynecologic oncologist, when in fact it is possible that the process of being seen by a gynecologic oncologist and undergoing a more extensive staging procedure results in patients being upstaged (e.g., from stage I to stage II or stage II to stage III), he explained.
The authors concur. In a subset analysis, they found that after adjusting for the effect of surgical staging in women with stage III disease, care by a gynecologic oncologist was no longer associated with an improvement in survival (84.6% vs 84.4%; P = .6).
"The result of this subset analysis suggests that the effect of gynecologic oncologist care may be partially attributed to the comprehensive staging procedures and subsequent guidance to appropriate therapy for improving survival," they write.
However, for women with stage III to IV disease, the benefit of gynecologic oncologist care might be associated not only with comprehensive surgical staging, but also with cytoreduction of metastatic disease, Dr. Chan and colleagues note. They found that, in a subset of 1689 stage IV patients, care from a gynecologic oncologist improved survival from 52% to 63%, suggesting that cytoreductive surgery might play a role in the survival advantage.
Another factor that might be at play is that care by a gynecologic oncologist might be associated with better screening and early detection of other malignancies, the authors suggest. They cite a previous study (Am J Obstet Gynecol. 2008;198:86.e1-86.e8), which found that patients with endometrial cancer who were cared for by gynecologic oncologists were more likely to receive mammography and colorectal cancer screening, compared with a matched group of women with no history of cancer cared for by primary care providers.
The authors have disclosed no relevant financial relationships. Dr. Markman reports serving as a director, officer, partner, employee, advisor, consultant, or trustee for Boehringer Ingelheim Pharmaceuticals, Genentech, Amgen, Celgene, and Hana Biosciences; and a as speaker or a member of a speakers bureau for Eli Lilly.
The findings are published online in the Journal of Clinical Oncology.
"The survival benefit associated with care by a gynecologic oncologist may be explained by their better understanding of the disease process, resulting in more accurate staging, followed by adjuvant treatment if indicated," the authors explain. However, they and an outside commentator point out that the superior survival could be attributed to a "stage migration" effect.
Deaths Are Increasing
The study is important, say the researchers, because the number of annual deaths from endometrial cancer has doubled over the past 20 years.
As far as they are aware, it is the first large population-based study to evaluate the influence of subspecialty care on patients with endometrial cancer.
The team, led by John Chan, MD, from the University of California San Francisco, analyzed data on 18,338 women with endometrial cancer from 1988 to 2005, obtained from the Medicare and Surveillance, Epidemiology and End Results (SEER) database.
They found that 21.4% of these women received care from gynecologic oncologists.
Compared with the remaining women, the women who received care from gynecologic oncologists were older, had more lymph nodes removed, presented with more advanced cancer (stages III to IV), had higher-grade tumors, and were more likely to receive chemotherapy for advanced disease.
They were also more likely to undergo staging procedures with lymph node assessment and to receive chemotherapy.
They showed significantly better survival rates for high-risk disease.
For women with stage II to IV disease who received care from a gynecologic oncologist, 5-year disease-specific survival was 79%, compared with 73% for women who didn't receive such care (P = .001). The difference was even greater for women with advanced-stage disease (stage III to IV), where the 5-year disease-specific survival was 72%, compared with 64% (P < .001).
However, there was no difference in survival rates for women with early, stage I and grade 1 cancers. All of them had "excellent" overall survival, the researchers note, with a 5-year disease-specific survival of 95%.
"This is an important paper, as it suggests that patients with more advanced endometrial cancer who are managed by gynecologic oncologists experience a superior outcome," said Maurie Markman MD, vice president of patient care services and national director for medical oncology at Cancer Treatment Centers for America, in Philadelphia, Pennsylvania.
"However, one must be cautious in the interpretation of the data, as 'stage migration' may be playing an important role," Dr. Markman added. This would have the effect of making it appear that patients with more advanced disease have a superior outcome when managed by a gynecologic oncologist, when in fact it is possible that the process of being seen by a gynecologic oncologist and undergoing a more extensive staging procedure results in patients being upstaged (e.g., from stage I to stage II or stage II to stage III), he explained.
The authors concur. In a subset analysis, they found that after adjusting for the effect of surgical staging in women with stage III disease, care by a gynecologic oncologist was no longer associated with an improvement in survival (84.6% vs 84.4%; P = .6).
"The result of this subset analysis suggests that the effect of gynecologic oncologist care may be partially attributed to the comprehensive staging procedures and subsequent guidance to appropriate therapy for improving survival," they write.
However, for women with stage III to IV disease, the benefit of gynecologic oncologist care might be associated not only with comprehensive surgical staging, but also with cytoreduction of metastatic disease, Dr. Chan and colleagues note. They found that, in a subset of 1689 stage IV patients, care from a gynecologic oncologist improved survival from 52% to 63%, suggesting that cytoreductive surgery might play a role in the survival advantage.
Another factor that might be at play is that care by a gynecologic oncologist might be associated with better screening and early detection of other malignancies, the authors suggest. They cite a previous study (Am J Obstet Gynecol. 2008;198:86.e1-86.e8), which found that patients with endometrial cancer who were cared for by gynecologic oncologists were more likely to receive mammography and colorectal cancer screening, compared with a matched group of women with no history of cancer cared for by primary care providers.
The authors have disclosed no relevant financial relationships. Dr. Markman reports serving as a director, officer, partner, employee, advisor, consultant, or trustee for Boehringer Ingelheim Pharmaceuticals, Genentech, Amgen, Celgene, and Hana Biosciences; and a as speaker or a member of a speakers bureau for Eli Lilly.
DENOSUMAB FOR BONE METASTASES
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Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma.
Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, von Moos R, Willenbacher W, Woll PJ, Wang J, Jiang Q, Jun S, Dansey R, Yeh H.Joan Karnell Cancer Center, Philadelphia, PA; Hospital de Santa Maria and Instituto de Medicina Molecular, Lisboa, Portugal; Teaching Hospital Cochin, Paris, France; McGill University Health Centre, Montreal, Canada; Irmandade da Santa Casa de Misericordia de Sao Paulo, Sao Paulo, Brazil; University Hospital Motol, Prague, Czech Republic; University of Torino, Orbassano, Italy; HagaZiekenhuis-Leyenburg, Den Haag, the Netherlands; The Alfred Hospital, Melbourne, Australia; MD Anderson Cancer Center, Houston, TX; Kantonsspital Graubünden, Chur, Switzerland; Medical University of Innsbruck, Innsbruck, Austria; Weston Park Hospital, University of Sheffield, Sheffield, United Kingdom; and Amgen, Thousand Oaks, CA.
Abstract
PURPOSE This study compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA) for delaying or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma. PATIENTS AND METHODS Eligible patients were randomly assigned in a double-blind, double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily supplemental calcium and vitamin D were strongly recommended. The primary end point was time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression). Results Denosumab was noninferior to ZA in delaying time to first on-study SRE (hazard ratio, 0.84; 95% CI, 0.71 to 0.98; P = .0007). Although directionally favorable, denosumab was not statistically superior to ZA in delaying time to first on-study SRE (P = .03 unadjusted; P = .06 adjusted for multiplicity) or time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to 1.04; P = .14). Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred at similarly low rates in both groups. Acute-phase reactions after the first dose occurred more frequently with ZA, as did renal adverse events and elevations in serum creatinine based on National Cancer Institute Common Toxicity Criteria for Adverse Events grading. CONCLUSION Denosumab was noninferior (trending to superiority) to ZA in preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.
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