April 29 2010 — New research suggests that it might be possible to identify which women with ductal carcinoma in situ (DCIS) are likely to go on to develop invasive breast cancer and which women are at very low risk.
The finding, published online April 28 in the Journal of the National Cancer Institute, could prevent overtreatment of DCIS, say the researchers.
"As much as 44% of patients with DCIS may not require any further treatment, and can rely instead on surveillance," said lead author Karla Kerlikowske, MD, professor of medicine, epidemiology and biostatistics at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.
There is a growing concern in the breast cancer community that, currently, DCIS is being overtreated, as previously reported by Medscape Oncology.
However, until now, there has been no way to predict which women with DCIS are at risk of developing invasive breast cancer. They are all "lumped together into one risk group," Dr. Kerlikowske said in a statement.
The new study shows that this risk can be quantified using 2 factors — detection of a breast lump by palpation and the high expression of 43 biomarkers.
This is an exciting and powerful beginning, to be able to predict which precancers will lie dormant and which will lead to invasive cancers,'' said colleague and coauthor Thea Tlsty, PhD, professor of pathology at the Helen Diller Family Comprehensive Cancer Center. "For the first time, we've identified the group of patients at the lowest risk and the group at highest risk of developing invasive cancer. It's a big step forward.''
"Thought-Provoking" Study
Describing the study as "thought-provoking" in an accompanying editorial, Craig Allred, MD, from Washington University School of Medicine in St. Louis, Missouri, said that these new results — if validated in other studies — could lead to optimization of current therapy in certain settings.
The current standard of care for most patients with DCIS is lumpectomy followed by radiation, but these new results suggest that adjuvant radiation could be withheld from patients with low-risk DCIS as defined by the study, he noted.
However, as the researchers themselves acknowledge, Dr. Allred concludes that "there is still much to learn before translating these results to routine clinical practice."
This study was statistically underpowered, and some of the results with biomarkers were "somewhat mystifying." Dr. Allred notes.
In addition, the women with DCIS in this study were treated with a lumpectomy only, but this is rarely the case today, because most women also have adjuvant radiation, and those with estrogen-positive disease are also prescribed tamoxifen for 5 years, he points out.
So, in addition to independent validation, "it will be critical to determine whether the results of this study are influenced by adjuvant radiation and hormonal therapy," he adds.
Two Factors Were Predictive
In the study, Dr. Kerlikowske and colleagues followed the medical histories of 1162 women, 40 years and older, who were diagnosed with DCIS and treated with lumpectomy only. They found that 2 factors predicted invasive cancer developing within 8 years of the DCIS diagnosis — the method by which it was detected and the expression of several biomarkers.
The team found that a breast lump that was diagnosed as DCIS was more predictive of a high risk of subsequent invasive cancer than DCIS diagnosed by mammography.
In addition, women with DCIS lesions that express high levels of 3 biomarkers — p16, cyclooxygenase (COX)-2, and Ki67 — were more likely to develop invasive cancer after their initial DCIS diagnosis, the team reported.
The team found that women with initial DCIS lesions that had both of these factors (i.e., were detected by palpation and had high expression of p16, COX-2, and Ki67) were at high risk of developing subsequent invasive cancer (but not subsequent DCIS). Just over a quarter of the women in their study (27.6%) fell into this category.
But many women (44.1%) did not demonstrate either of these 2 factors, and were categorized as having a low risk of developing subsequent invasive cancer.
Using both of these factors could be useful in stratifying a woman's risk of subsequent invasive cancer and help her decide whether she should undergo adjuvant therapies, the researchers conclude.
"Women choose their treatment based on their level of concern of developing invasive cancer,'' Dr. Kerlikowske explained. "DCIS is noninvasive, so women do not die of it. Their real concern arises if they develop invasive cancer and the cancer spreads.''
The researchers have disclosed no relevant financial relationships.
J Natl Cancer Inst. 2010;102:585-587, 627-637.
Σάββατο 1 Μαΐου 2010
123-MIBG DETECTS NEUROBLASTOMA AND PHEOCHROMOCYTOMA
NEW YORK (Reuters Health) Apr 22 - 123I-mIBG scintigraphy is highly sensitive and specific for neuroblastoma and pheochromocytoma, according to a meta-analysis published online April 14th in The Journal of Clinical Endocrinology & Metabolism.
Patients with these tumors have been assessed with radiolabelled meta-iodobenzylguanidine (mIBG) for more than 20 years, lead author Dr. Arnold F. Jacobson told Reuters Health by e-mail. The 123I isotope was approved in Europe and Japan more than 10 years ago and in the US in 2008. The International Neuroblastoma Risk Group includes 123I-mIBG imaging in its recommendations for assessing children with neuroblastoma, Dr. Jacobson said.
He and his colleagues at GE Healthcare, Princeton, New Jersey, performed their meta-analysis "to provide companion and comparison data" to results of a randomized trial published last year. The results of the meta-analysis (and the prospective trial) are consistent with clinical experience, he said.
They included 22 studies (but not last year's randomized trial). Seven studies with 223 patients focused on the diagnostic performance of 123I-mIBG as an imaging agent for neuroblastoma, and 15 studies with 395 patients focused on pheochromocytoma.
Mean quality scores were 85% for the neuroblastoma articles and 76% for the pheochromocytoma articles.
The combined sensitivity of 123I-mIBG for detecting neuroblastoma was 97% and for detecting pheochromocytoma was 96%.
The combined specificity of 123I-mIBG for detecting pheochromocytoma was 98%, but none of the seven articles about neuroblastoma met the eligibility criteria for the analysis of specificity.
Use of the random-effect model to account for the heterogeneity among pheochromocytoma studies yielded slightly lower sensitivity (94%) and specificity (92%).
"Because many of the published studies were retrospective and relatively small, there is the potential for bias in the data," Dr. Jacobson said. "We believe that the meta-analysis results represent the maximum performance characteristics for the imaging method, and in clinical practice, the results would probably be a few percent lower."
J Clin Endocrinol Metab 2010.
Patients with these tumors have been assessed with radiolabelled meta-iodobenzylguanidine (mIBG) for more than 20 years, lead author Dr. Arnold F. Jacobson told Reuters Health by e-mail. The 123I isotope was approved in Europe and Japan more than 10 years ago and in the US in 2008. The International Neuroblastoma Risk Group includes 123I-mIBG imaging in its recommendations for assessing children with neuroblastoma, Dr. Jacobson said.
He and his colleagues at GE Healthcare, Princeton, New Jersey, performed their meta-analysis "to provide companion and comparison data" to results of a randomized trial published last year. The results of the meta-analysis (and the prospective trial) are consistent with clinical experience, he said.
They included 22 studies (but not last year's randomized trial). Seven studies with 223 patients focused on the diagnostic performance of 123I-mIBG as an imaging agent for neuroblastoma, and 15 studies with 395 patients focused on pheochromocytoma.
Mean quality scores were 85% for the neuroblastoma articles and 76% for the pheochromocytoma articles.
The combined sensitivity of 123I-mIBG for detecting neuroblastoma was 97% and for detecting pheochromocytoma was 96%.
The combined specificity of 123I-mIBG for detecting pheochromocytoma was 98%, but none of the seven articles about neuroblastoma met the eligibility criteria for the analysis of specificity.
Use of the random-effect model to account for the heterogeneity among pheochromocytoma studies yielded slightly lower sensitivity (94%) and specificity (92%).
"Because many of the published studies were retrospective and relatively small, there is the potential for bias in the data," Dr. Jacobson said. "We believe that the meta-analysis results represent the maximum performance characteristics for the imaging method, and in clinical practice, the results would probably be a few percent lower."
J Clin Endocrinol Metab 2010.
VMP TREATMENT FOR MULTIPLE MYELOMA-VISTA TRIAL
J Clin Oncol. 2010 May 1;28(13):2259-66. Epub 2010 Apr 5.
Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.
Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Esseltine DL, Liu K, Cakana A, van de Velde H, San Miguel JF.
Hospital Universitario de Salamanca, Paseo San Vicente 58-182, 37007 Salamanca, Spain.
Abstract
PURPOSE: The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies. PATIENTS AND METHODS: Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338). RESULTS: With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months. CONCLUSION: VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent-based treatment until relapse.
Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.
Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Esseltine DL, Liu K, Cakana A, van de Velde H, San Miguel JF.
Hospital Universitario de Salamanca, Paseo San Vicente 58-182, 37007 Salamanca, Spain.
Abstract
PURPOSE: The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies. PATIENTS AND METHODS: Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338). RESULTS: With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months. CONCLUSION: VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent-based treatment until relapse.
TDM1 IS HERE
J Clin Oncol. 2010 Apr 26. [Epub ahead of print]
Phase I Study of Trastuzumab-DM1, a HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer.
Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, Girish S, Tibbitts J, Yi JH, Sliwkowski MX, Jacobson F, Lutzker SG, Burris HA.
Dana-Farber Cancer Institute, Boston, MA; Institute for Drug Development, San Antonio, TX; Memorial Sloan-Kettering Cancer Center, New York, NY; Sarah Cannon Research Institute, Nashville, TN; and Genentech, South San Francisco, CA.
Abstract
PURPOSE: Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer. PATIENTS AND METHODS: Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by standard solid-tumor phase I methods. RESULTS: Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-weeks schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the maximum-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels < 10 ng/mL. Clearance at doses < 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) included grade 1 nausea, vomiting, alopecia, or neuropathy events and no cardiac effects requiring dose modification were reported. The clinical benefit rate (objective response plus stable disease at 6 months) among 15 patients treated at the MTD was 73%, including five objective responses. The confirmed response rate in patients with measurable disease at the MTD (n = 9) was 44%. CONCLUSION: At the MTD of 3.6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way.
Phase I Study of Trastuzumab-DM1, a HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer.
Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, Girish S, Tibbitts J, Yi JH, Sliwkowski MX, Jacobson F, Lutzker SG, Burris HA.
Dana-Farber Cancer Institute, Boston, MA; Institute for Drug Development, San Antonio, TX; Memorial Sloan-Kettering Cancer Center, New York, NY; Sarah Cannon Research Institute, Nashville, TN; and Genentech, South San Francisco, CA.
Abstract
PURPOSE: Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer. PATIENTS AND METHODS: Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by standard solid-tumor phase I methods. RESULTS: Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-weeks schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the maximum-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels < 10 ng/mL. Clearance at doses < 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) included grade 1 nausea, vomiting, alopecia, or neuropathy events and no cardiac effects requiring dose modification were reported. The clinical benefit rate (objective response plus stable disease at 6 months) among 15 patients treated at the MTD was 73%, including five objective responses. The confirmed response rate in patients with measurable disease at the MTD (n = 9) was 44%. CONCLUSION: At the MTD of 3.6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way.
MONITOR TESTOSTERONE DURING ADT FOR PROSTATE CANCER
NEW YORK (Reuters Health) Apr 26 - Physicians should monitor serum testosterone levels during androgen-deprivation therapy (ADT) in men with prostate cancer, according to an April 16th online report in European Urology.
Although the androgen axis is involved throughout the natural history of prostate cancer, testosterone is not routinely measured in these patients. Dr. Claude C. Schulman, from the University of Brussels, Belgium, and associates convened an expert roundtable to review evidence for measuring testosterone in prostate cancer screening, diagnosis, and treatment.
Because multiple trials show no association between prostate cancer and testosterone, the experts do not recommend testosterone measurement to assess prostate cancer risk or for screening in the general population.
There's conflicting evidence on whether testosterone measurement improves the specificity of prostate specific antigen (PSA) tests. Until large prospective studies are conducted, the consensus panel does not advise assessment of serum testosterone-to-PSA ratio.
While several studies have linked low pretreatment serum testosterone with more aggressive tumors, recent trials have failed to confirm this link. At this time, the experts oppose using testosterone to assess tumor aggressiveness.
Current guidelines recommend PSA testing, along with digital rectal exam and symptom evaluation, to judge the efficacy of ADT. The authors say that serum testosterone is a more direct measure of treatment efficacy. Therefore, they recommend that serum testosterone be checked along with PSA levels (e.g., every three months) when first starting ADT.
If testosterone stays high and PSA is rising, the authors say treatment should be changed. "In this context, there is little evidence to guide the management decision, but options include surgical castration, change of luteinizing hormone-releasing hormone agonist, or the addition of bicalutamide," they write.
On the other hand, low testosterone and increasing PSA may indicate a transition to castration-resistant cancer, in which case testosterone measurement is mandatory for ruling out other causes, such as poor adherence, inappropriate dosing, failure to achieve intramuscular injection, or incorrect injection preparation.
Multiple trials support intermittent hormone therapy for prostate cancer as safe and feasible and a way to reduce side effects, lower health care costs, and improve quality of life. Dr. Schulman and colleagues suggest testosterone measurement as a criterion for reinitiating ADT and to standardize the length of androgen re-exposure.
Finally, they recommend that mass spectrometry-based assays be used in lieu of automatic immunoassays for measuring serum testosterone in men on ADT.
Eur Urol 2010.
Although the androgen axis is involved throughout the natural history of prostate cancer, testosterone is not routinely measured in these patients. Dr. Claude C. Schulman, from the University of Brussels, Belgium, and associates convened an expert roundtable to review evidence for measuring testosterone in prostate cancer screening, diagnosis, and treatment.
Because multiple trials show no association between prostate cancer and testosterone, the experts do not recommend testosterone measurement to assess prostate cancer risk or for screening in the general population.
There's conflicting evidence on whether testosterone measurement improves the specificity of prostate specific antigen (PSA) tests. Until large prospective studies are conducted, the consensus panel does not advise assessment of serum testosterone-to-PSA ratio.
While several studies have linked low pretreatment serum testosterone with more aggressive tumors, recent trials have failed to confirm this link. At this time, the experts oppose using testosterone to assess tumor aggressiveness.
Current guidelines recommend PSA testing, along with digital rectal exam and symptom evaluation, to judge the efficacy of ADT. The authors say that serum testosterone is a more direct measure of treatment efficacy. Therefore, they recommend that serum testosterone be checked along with PSA levels (e.g., every three months) when first starting ADT.
If testosterone stays high and PSA is rising, the authors say treatment should be changed. "In this context, there is little evidence to guide the management decision, but options include surgical castration, change of luteinizing hormone-releasing hormone agonist, or the addition of bicalutamide," they write.
On the other hand, low testosterone and increasing PSA may indicate a transition to castration-resistant cancer, in which case testosterone measurement is mandatory for ruling out other causes, such as poor adherence, inappropriate dosing, failure to achieve intramuscular injection, or incorrect injection preparation.
Multiple trials support intermittent hormone therapy for prostate cancer as safe and feasible and a way to reduce side effects, lower health care costs, and improve quality of life. Dr. Schulman and colleagues suggest testosterone measurement as a criterion for reinitiating ADT and to standardize the length of androgen re-exposure.
Finally, they recommend that mass spectrometry-based assays be used in lieu of automatic immunoassays for measuring serum testosterone in men on ADT.
Eur Urol 2010.
FIRST IMMUNOTHERAPY FOR METASTATIC PROSTATE CANCER APPROVED BY FDA AND COSTS ONLY 90000$
April 29, 2010 — In a widely anticipated announcement, the US Food and Drug Administration (FDA) has approved an immunotherapy, sipuleucel-T (Provenge, Dendreon), for the treatment of asymptomatic or minimally symptomatic metastatic, castration-resistant prostate cancer (mCRPC).
Often referred to as a vaccine, sipuleucel-T is an autologous active cellular immunotherapy, meaning that it is made from the patient's own white blood cells and stimulates a patient's immune system to respond against the cancer. The treatment needs to be manufactured individually for each patient.
"The availability of [sipuleucel-T] provides a new treatment option for men with advanced prostate cancer who currently have limited effective therapies available," said Karen Midthun, MD, acting director of the FDA's Center for Biologics Evaluation and Research, in a press statement.
Sipuleucel-T becomes the first product approved by the FDA in a new therapeutic class known as active cellular immunotherapies, according to Dendreon press materials.
To be approved by the FDA, investigators had to show that sipuleucel-T would extend survival in men with mCRPC.
In the pivotal phase 3 study, with a median follow-up of 36.5 months, men treated with sipuleucel-T (n = 341) had a median survival of 25.8 months, compared with men treated with placebo (n = 171), who had a median survival of 21.7 months
Thus, with the new therapy, there was a 4.1-month median survival advantage and a 24.1% reduction in the risk for death (hazard ratio, 0.759; P = .017), compared with placebo.
These latest data from the pivotal trial, known as IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment), were presented at the American Society of Clinical Oncology 2010 Genitourinary Cancers Symposium in March.
Last year, after a presentation of very similar survival data on sipuleucel-T at the 2009 American Urological Association (AUA) annual meeting, one of the study investigators hailed the survival benefit.
"This 4-month extension in survival is very, very significant," said David F. Penson, MD, MPH, at the AUA meeting. Dr. Penson is a professor of medicine at the University of Southern California Los Angeles.
"These patients have a life expectancy of about 2 years, so giving them 4 more months is pretty important. It gives them about 20% more life. And [sipuleucel-T] does it with minimal adverse events. So there is improved survival with good quality of life," he added.
According to the FDA press release, the most common adverse reactions reported with the new product are chills, fatigue, fever, back pain, nausea, joint ache, and headache. The majority of adverse reactions were mild or moderate. Serious adverse reactions, which were reported in approximately one quarter of the patients receiving sipuleucel-T, included some acute infusion reactions and stroke.
Cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5% of patients in the sipuleucel-T group, compared with 2.6% of patients in the placebo control group
The approval of sipuleucel-T has been a long time coming.
In 2007, the FDA deferred approval of sipuleucel-T until a statistically significant improvement in survival could be shown.
The study investigators revealed such an improvement at the 2009 AUA annual meeting.
At the time, AUA spokesman J. Brantley Thrasher, MD, chair of the Department of Urology at the University of Kansas Medical Center in Kansas City, said that "this will cause a big splash."
"We don't have anything for patients with hormone-refractory disease, which is very aggressive. . . . Improved survival with T cell immunotherapy is really very significant," he said.
Often referred to as a vaccine, sipuleucel-T is an autologous active cellular immunotherapy, meaning that it is made from the patient's own white blood cells and stimulates a patient's immune system to respond against the cancer. The treatment needs to be manufactured individually for each patient.
"The availability of [sipuleucel-T] provides a new treatment option for men with advanced prostate cancer who currently have limited effective therapies available," said Karen Midthun, MD, acting director of the FDA's Center for Biologics Evaluation and Research, in a press statement.
Sipuleucel-T becomes the first product approved by the FDA in a new therapeutic class known as active cellular immunotherapies, according to Dendreon press materials.
To be approved by the FDA, investigators had to show that sipuleucel-T would extend survival in men with mCRPC.
In the pivotal phase 3 study, with a median follow-up of 36.5 months, men treated with sipuleucel-T (n = 341) had a median survival of 25.8 months, compared with men treated with placebo (n = 171), who had a median survival of 21.7 months
Thus, with the new therapy, there was a 4.1-month median survival advantage and a 24.1% reduction in the risk for death (hazard ratio, 0.759; P = .017), compared with placebo.
These latest data from the pivotal trial, known as IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment), were presented at the American Society of Clinical Oncology 2010 Genitourinary Cancers Symposium in March.
Last year, after a presentation of very similar survival data on sipuleucel-T at the 2009 American Urological Association (AUA) annual meeting, one of the study investigators hailed the survival benefit.
"This 4-month extension in survival is very, very significant," said David F. Penson, MD, MPH, at the AUA meeting. Dr. Penson is a professor of medicine at the University of Southern California Los Angeles.
"These patients have a life expectancy of about 2 years, so giving them 4 more months is pretty important. It gives them about 20% more life. And [sipuleucel-T] does it with minimal adverse events. So there is improved survival with good quality of life," he added.
According to the FDA press release, the most common adverse reactions reported with the new product are chills, fatigue, fever, back pain, nausea, joint ache, and headache. The majority of adverse reactions were mild or moderate. Serious adverse reactions, which were reported in approximately one quarter of the patients receiving sipuleucel-T, included some acute infusion reactions and stroke.
Cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5% of patients in the sipuleucel-T group, compared with 2.6% of patients in the placebo control group
The approval of sipuleucel-T has been a long time coming.
In 2007, the FDA deferred approval of sipuleucel-T until a statistically significant improvement in survival could be shown.
The study investigators revealed such an improvement at the 2009 AUA annual meeting.
At the time, AUA spokesman J. Brantley Thrasher, MD, chair of the Department of Urology at the University of Kansas Medical Center in Kansas City, said that "this will cause a big splash."
"We don't have anything for patients with hormone-refractory disease, which is very aggressive. . . . Improved survival with T cell immunotherapy is really very significant," he said.
FIVE RISK FACTORS PREDICT PROGRESSION OF RENAL CELL CARCINOMA AFTER SURGERY
NEW YORK (Reuters Health) Apr 22 - Five factors can predict progression of localized renal cell carcinoma after surgery, according to new research.
These factors are stage pT2 tumors (7 cm or larger), male gender, symptomatic presentation, sarcomatoid de-differentiation, and macroscopic necrosis on pathology.
The findings are drawn from a cohort study of 925 patients followed for a median of 48.2 months. In an April 15th online paper in BJU International, the researchers report that of 618 patients who had one or two risk factors, 20 (3.2%) progressed to metastatic disease at a median of 37.1 months. Of 130 patients with three or more risk factors, 33 (25.4%) progressed at a median of 25.2 months. Meanwhile, there was no progression in any of the 177 patients with none of the risk factors.
"This risk stratification can be used to follow up patients," senior author Dr. Christopher Wood of the University of Texas M. D. Anderson Cancer Center in Houston told Reuters Health by e-mail.
He continued, "In theory, if a patient has no risk factors, they would not need any followup after definitive surgery. Furthermore, those with three or more risk factors need to be followed very closely for evidence of recurrence. (These are) very timely data in light of the issues surrounding radiation exposure from imaging studies and risk of secondary malignancy."
Dr. Wood and his colleagues identified their subjects through a review of their hospital's records from 1994-2007. The patients had undergone partial or radical nephrectomy for renal cell carcinoma. The researchers excluded patients with multi-focal tumors, bilateral disease, inadequate follow-up, or local disease recurrence after surgery.
There was progression to metastatic disease in 53 patients, representing 5.7% of the group. Progression occurred in 20 (2.6%) of 774 patients with pT1 cancer and 33 (21.9%) of 151 with pT2.
The researchers identified 11 risk factors and whittled them down to five through multivariable stepwise logistic regression analysis and construction of a receiver operating characteristic curve.
"Male gender and macroscopic necrosis were two that hadn't been reported before and therefore were a bit surprising," Dr. Wood said. "Microscopic histologic necrosis has been reported by Mayo, but not macroscopic in this population."
BJU Int 2010.
These factors are stage pT2 tumors (7 cm or larger), male gender, symptomatic presentation, sarcomatoid de-differentiation, and macroscopic necrosis on pathology.
The findings are drawn from a cohort study of 925 patients followed for a median of 48.2 months. In an April 15th online paper in BJU International, the researchers report that of 618 patients who had one or two risk factors, 20 (3.2%) progressed to metastatic disease at a median of 37.1 months. Of 130 patients with three or more risk factors, 33 (25.4%) progressed at a median of 25.2 months. Meanwhile, there was no progression in any of the 177 patients with none of the risk factors.
"This risk stratification can be used to follow up patients," senior author Dr. Christopher Wood of the University of Texas M. D. Anderson Cancer Center in Houston told Reuters Health by e-mail.
He continued, "In theory, if a patient has no risk factors, they would not need any followup after definitive surgery. Furthermore, those with three or more risk factors need to be followed very closely for evidence of recurrence. (These are) very timely data in light of the issues surrounding radiation exposure from imaging studies and risk of secondary malignancy."
Dr. Wood and his colleagues identified their subjects through a review of their hospital's records from 1994-2007. The patients had undergone partial or radical nephrectomy for renal cell carcinoma. The researchers excluded patients with multi-focal tumors, bilateral disease, inadequate follow-up, or local disease recurrence after surgery.
There was progression to metastatic disease in 53 patients, representing 5.7% of the group. Progression occurred in 20 (2.6%) of 774 patients with pT1 cancer and 33 (21.9%) of 151 with pT2.
The researchers identified 11 risk factors and whittled them down to five through multivariable stepwise logistic regression analysis and construction of a receiver operating characteristic curve.
"Male gender and macroscopic necrosis were two that hadn't been reported before and therefore were a bit surprising," Dr. Wood said. "Microscopic histologic necrosis has been reported by Mayo, but not macroscopic in this population."
BJU Int 2010.
BRCA DEFICIENT OVARIAN CANCER OFTEN SPREADS TO VISCERA
NEW YORK (Reuters Health) Apr 22 - Women with sporadic ovarian cancer and BRCA1/2 germline mutations have a higher risk for visceral metastases, researchers from Scotland suggested in the Journal of Clinical Oncology. Their report appeared online April 19.
The authors say that to their knowledge, "no association between BRCA1/2 mutation status and frequency of visceral relapse has been reported previously in ovarian cancer."
The clinical implications of these findings are twofold, according to lead author Dr. Charlie Gourley from University of Edinburgh and colleagues. First, the researchers advise clinicians to consider BRCA1/2 mutations in women with ovarian cancer who develop visceral metastases. This might inform genetic counseling for both the patient and her family, and it might also identify women who are eligible for trials of the poly ADP-ribose polymerase (PARP) inhibitor olaparib, they say.
"Second, our data extend the BRCAness phenotype in ovarian cancer. It suggests that BRCA1/2-associated ovarian cancer is a discrete clinical entity, the behavior of which is different from most sporadic ovarian cancers," the investigators said.
Dr. Gourley and his associates compared the rates of visceral relapse in women with BRCA1/2-deficient epithelial ovarian cancer/primary peritoneal cancer (EOC/PPC) to those in women with nonhereditary EOC/PPC.
They identified all 79 patients with EOC/PPC and BRCA1/2 germline mutations diagnosed in Scotland before May 2008. Fifteen of the women had inadequate clinical data, 2 had carcinosarcoma, 27 had previous breast cancer, and 16 were in remission; all were excluded.
Of the remaining 19 patients with BRCA1/2 mutations, 14 (74%) developed visceral metastases, compared to 6 (16%) of 38 matched control patients.
The rates of liver, lung and splenic metastases in the BRCA1/2 mutation carriers were 53%, 32%, and 32%, respectively, compared to 5%, 3%, and 5%, respectively, in controls.
Compared with controls with no personal or family history of BRCA1/2-associated malignancies, study subjects with no breast cancer history who relapsed from EOC/PPC had a 21-fold higher rate of visceral metastases.
"This relationship is particularly strong for BRCA1 mutation carriers, 92% of whom developed visceral metastases compared with only 16% in our control group," the research team reported.
The overall median follow-up for patients who remained alive without visceral metastases was 30 months (range, 8 to 104). After excluding events that occurred outside of the matched follow-up period, the frequency of all visceral, hepatic, pulmonary, and splenic metastases in BRCA1/2 mutation carriers was 58%, 42%, 16%, and 32%, respectively. All of these were significantly greater than in matched controls (range, 0% to 5%).
The researchers repeated the analysis using an independent validation set of 24 patients with BRCA1/2-deficient ovarian cancer treated in a phase I study of olaparib plus two matched controls for each patient. In this analysis, the frequency of visceral, hepatic, pulmonary and splenic metastases was similar to that in the initial data set (63%, 46%, 13%, and 17%, respectively). Again, the rates were higher than in matched controls (11%, 4%, 2% and 2%, respectively), although only the differences in total visceral and hepatic metastases reached statistical significance, the authors say.
As theirs was a retrospective study, Dr. Gourley and colleagues point out that additional studies will be required to confirm their findings.
J Clin Oncol 2010.
The authors say that to their knowledge, "no association between BRCA1/2 mutation status and frequency of visceral relapse has been reported previously in ovarian cancer."
The clinical implications of these findings are twofold, according to lead author Dr. Charlie Gourley from University of Edinburgh and colleagues. First, the researchers advise clinicians to consider BRCA1/2 mutations in women with ovarian cancer who develop visceral metastases. This might inform genetic counseling for both the patient and her family, and it might also identify women who are eligible for trials of the poly ADP-ribose polymerase (PARP) inhibitor olaparib, they say.
"Second, our data extend the BRCAness phenotype in ovarian cancer. It suggests that BRCA1/2-associated ovarian cancer is a discrete clinical entity, the behavior of which is different from most sporadic ovarian cancers," the investigators said.
Dr. Gourley and his associates compared the rates of visceral relapse in women with BRCA1/2-deficient epithelial ovarian cancer/primary peritoneal cancer (EOC/PPC) to those in women with nonhereditary EOC/PPC.
They identified all 79 patients with EOC/PPC and BRCA1/2 germline mutations diagnosed in Scotland before May 2008. Fifteen of the women had inadequate clinical data, 2 had carcinosarcoma, 27 had previous breast cancer, and 16 were in remission; all were excluded.
Of the remaining 19 patients with BRCA1/2 mutations, 14 (74%) developed visceral metastases, compared to 6 (16%) of 38 matched control patients.
The rates of liver, lung and splenic metastases in the BRCA1/2 mutation carriers were 53%, 32%, and 32%, respectively, compared to 5%, 3%, and 5%, respectively, in controls.
Compared with controls with no personal or family history of BRCA1/2-associated malignancies, study subjects with no breast cancer history who relapsed from EOC/PPC had a 21-fold higher rate of visceral metastases.
"This relationship is particularly strong for BRCA1 mutation carriers, 92% of whom developed visceral metastases compared with only 16% in our control group," the research team reported.
The overall median follow-up for patients who remained alive without visceral metastases was 30 months (range, 8 to 104). After excluding events that occurred outside of the matched follow-up period, the frequency of all visceral, hepatic, pulmonary, and splenic metastases in BRCA1/2 mutation carriers was 58%, 42%, 16%, and 32%, respectively. All of these were significantly greater than in matched controls (range, 0% to 5%).
The researchers repeated the analysis using an independent validation set of 24 patients with BRCA1/2-deficient ovarian cancer treated in a phase I study of olaparib plus two matched controls for each patient. In this analysis, the frequency of visceral, hepatic, pulmonary and splenic metastases was similar to that in the initial data set (63%, 46%, 13%, and 17%, respectively). Again, the rates were higher than in matched controls (11%, 4%, 2% and 2%, respectively), although only the differences in total visceral and hepatic metastases reached statistical significance, the authors say.
As theirs was a retrospective study, Dr. Gourley and colleagues point out that additional studies will be required to confirm their findings.
J Clin Oncol 2010.
Εγγραφή σε:
Αναρτήσεις (Atom)