Purpose
Hormonal therapy (HT) is the current mainstay of systemic treatment for prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical prostatectomy by early versus delayed use of HT and by a risk stratified approach.
Materials and Methods
Of 5,382 men in the database who underwent primary radical prostatectomy (RP), 4,967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1,352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metastasis and a late HT group for patients (997) who received no HT before clinical metastasis or by current followup. The primary end point was the development of clinical metastases. Of the 1,352 patients with PSAR clinical metastases developed in 103 (7.6%). Patients were also stratified by surgical Gleason sum, PSA doubling time and timing of recurrence. Univariate and multivariate Cox proportional hazard models were used to evaluate the effect of early and late HT on clinical outcome.
Results
Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less (Hazards ratio = 2.12, p = 0.01). However, in the overall cohort early HT did not impact clinical metastases. Race, age at RP and PSA at diagnosis had no effect on metastasis-free survival (p >0.05).
Conclusions
The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue
Judd W. Moula, d, Hongyu Wua, Leon Suna, David G. McLeodd, Christopher Amlinge, Timothy Donahueb, Leo Kusudaf, Wade Sextong, Keith O’Reilly, Javier Hernandezh, , Andrew Chungc, and Douglas Soderdahl
Prostate Cancer Vaccine Effective In Mice, Study Shows
Researchers at the University of Southern California have developed a prostate cancer vaccine that prevented the development of cancer in 90 percent of young mice genetically predestined to develop the disease. In the February 1 issue of Cancer Research, they suggest the same strategy might work for men with rising levels of PSA (prostate specific antigen) , a potential diagnostic indicator of prostate cancer.
By early vaccination, we have basically given these mice life-long protection against a disease they were destined to have," said the study's lead investigator, W. Martin Kast, Ph.D., a professor of Molecular Microbiology & Immunology and Obstetrics & Gynecology at the Norris Comprehensive Cancer Center. "This has never been done before and, with further research, could represent a paradigm shift in the management of human prostate cancer."
Now, men with rising prostate specific antigen PSA levels but no other signs of cancer are advised "watchful waiting" -- no treatment until signs of the cancer appear, Kast says. "But what if instead of a watchful wait, we vaccinate" That could change the course of the disease."
The study findings also represent a new way to think about the use of therapeutic prostate cancer vaccines, Kast says. Vaccines now in testing are designed to treat men whose cancers are advanced and unresponsive to therapy, and results have offered limited clinical benefit, he says. This novel approach targets the precancerous state with the aim of preventing cancer from developing, he says.
The Kast team's preventive vaccine is designed to mount an immune response against prostate stem cell antigen (PSCA), the protein target of some therapeutic vaccines under development. PSCA, a membrane protein, is over-expressed in about one-third of early-stage prostate cancers, but expression ramps up in all prostate tumors as they grow and advance. PSCA is also expressed at low-levels in normal prostate gland tissue as well as in the bladder, colon, kidney and stomach.
The researchers created a prime-boost vaccination scheme using two kinds of vaccines and tested it in 8-week-old mice that were genetically altered to develop prostate cancer later in life. The first vaccine simply delivered a fragment of DNA that coded for PSCA, thus producing an influx of PSCA protein to alert the immune system. The booster shot, given two weeks later, used a modified horse virus to deliver the PSCA gene.
"Confronting the immune system in two different ways forces it to mount a strong response," Kast said.
In the experimental group, two of 20 mice developed prostate cancer at the end of one year, and by contrast, all control mice had died of the disease. Researchers found that mice in the experimental group had all developed very small tumors that did not progress. "There were tiny nodules of prostate cancer in the mice that were surrounded by an army of immune system cells," Kast said. "The vaccination turned the cancer into a chronic, manageable disease."
The vaccination strategy also works with other antigens, Kast says. The researchers recently tried another prostate cancer membrane target and found that after 1.5 years, 65 percent of experimental mice were still alive, and of those that died, the suspected cause was old age.
Crucially, investigators further found that treated mice did not develop autoimmune disease, a side effect that could develop if the vaccine had also targeted PSCA expression in normal cells. "Theoretically, the vaccine could produce a response in any tissue that expresses the antigen, but the fact that PSCA is expressed in such low levels in normal tissue may prevent that complication," he said.
Still, studies in humans are needed to ensure autoimmunity does not develop, Kast says.
"We feel this is a very promising approach," he said. "With just two shots, the vaccine will prime immune cells to be on the lookout for any cell that over-expresses PSCA."
The study was funded by a pre-doctoral training grant from the National Institutes of Health and a grant from the Margaret E. Early Medical Research Trust. Co-authors include researchers from the University of Southern California as well as from AlphaVax, inc., of Research Triangle Park, North Carolina.
Adapted from materials provided by American Association for Cancer Research.
By early vaccination, we have basically given these mice life-long protection against a disease they were destined to have," said the study's lead investigator, W. Martin Kast, Ph.D., a professor of Molecular Microbiology & Immunology and Obstetrics & Gynecology at the Norris Comprehensive Cancer Center. "This has never been done before and, with further research, could represent a paradigm shift in the management of human prostate cancer."
Now, men with rising prostate specific antigen PSA levels but no other signs of cancer are advised "watchful waiting" -- no treatment until signs of the cancer appear, Kast says. "But what if instead of a watchful wait, we vaccinate" That could change the course of the disease."
The study findings also represent a new way to think about the use of therapeutic prostate cancer vaccines, Kast says. Vaccines now in testing are designed to treat men whose cancers are advanced and unresponsive to therapy, and results have offered limited clinical benefit, he says. This novel approach targets the precancerous state with the aim of preventing cancer from developing, he says.
The Kast team's preventive vaccine is designed to mount an immune response against prostate stem cell antigen (PSCA), the protein target of some therapeutic vaccines under development. PSCA, a membrane protein, is over-expressed in about one-third of early-stage prostate cancers, but expression ramps up in all prostate tumors as they grow and advance. PSCA is also expressed at low-levels in normal prostate gland tissue as well as in the bladder, colon, kidney and stomach.
The researchers created a prime-boost vaccination scheme using two kinds of vaccines and tested it in 8-week-old mice that were genetically altered to develop prostate cancer later in life. The first vaccine simply delivered a fragment of DNA that coded for PSCA, thus producing an influx of PSCA protein to alert the immune system. The booster shot, given two weeks later, used a modified horse virus to deliver the PSCA gene.
"Confronting the immune system in two different ways forces it to mount a strong response," Kast said.
In the experimental group, two of 20 mice developed prostate cancer at the end of one year, and by contrast, all control mice had died of the disease. Researchers found that mice in the experimental group had all developed very small tumors that did not progress. "There were tiny nodules of prostate cancer in the mice that were surrounded by an army of immune system cells," Kast said. "The vaccination turned the cancer into a chronic, manageable disease."
The vaccination strategy also works with other antigens, Kast says. The researchers recently tried another prostate cancer membrane target and found that after 1.5 years, 65 percent of experimental mice were still alive, and of those that died, the suspected cause was old age.
Crucially, investigators further found that treated mice did not develop autoimmune disease, a side effect that could develop if the vaccine had also targeted PSCA expression in normal cells. "Theoretically, the vaccine could produce a response in any tissue that expresses the antigen, but the fact that PSCA is expressed in such low levels in normal tissue may prevent that complication," he said.
Still, studies in humans are needed to ensure autoimmunity does not develop, Kast says.
"We feel this is a very promising approach," he said. "With just two shots, the vaccine will prime immune cells to be on the lookout for any cell that over-expresses PSCA."
The study was funded by a pre-doctoral training grant from the National Institutes of Health and a grant from the Margaret E. Early Medical Research Trust. Co-authors include researchers from the University of Southern California as well as from AlphaVax, inc., of Research Triangle Park, North Carolina.
Adapted from materials provided by American Association for Cancer Research.
Prostate-Specific Antigen (PSA)
A prostate-specific antigen (PSA) test measures the amount of prostate-specific antigen in the blood. PSA is released into a man's blood by his prostate gland . Healthy men have low amounts of PSA in the blood. The amount of PSA in the blood normally increases as a man's prostate enlarges with age. PSA may increase as a result of an injury, a digital rectal exam , sexual activity ( ejaculation ), inflammation of the prostate gland ( prostatitis ), or prostate cancer .
Prostate cancer often grows very slowly, without causing major problems. Detecting prostate cancer early and treating it may prevent some health problems and reduce the risk of dying from the cancer. However, some treatments for prostate cancer can cause other problems, such as controlling urination (incontinence) or erection problems (erectile dysfunction). Some men may choose not to have a PSA test or treat prostate cancer if it is detected. For example, a man older than age 75 who has no bothersome symptoms of prostate cancer may choose not to treat the cancer if it is found, so he would not need a PSA test.
Prostate cancer often grows very slowly, without causing major problems. Detecting prostate cancer early and treating it may prevent some health problems and reduce the risk of dying from the cancer. However, some treatments for prostate cancer can cause other problems, such as controlling urination (incontinence) or erection problems (erectile dysfunction). Some men may choose not to have a PSA test or treat prostate cancer if it is detected. For example, a man older than age 75 who has no bothersome symptoms of prostate cancer may choose not to treat the cancer if it is found, so he would not need a PSA test.
Biology of Prostate-Specific Antigen
Prostate-specific antigen (PSA) is an androgen-regulated serine protease produced by both prostate epithelial cells and prostate cancer (PCa) and is the most commonly used serum marker for cancer. Prostate specific antigen (PSA) is a protein produced by the cells of the prostate gland. Prostate-specific antigen is present in small quantities in the serum of normal men, and is often elevated in the presence of prostate cancer and in other prostate disorders.
PSA is a major protein in semen , where its function is to cleave semenogelins in the seminal coagulum. PSA is secreted into prostatic ducts as an inactive 244–amino acid proenzyme (proPSA) that is activated by cleavage of seven N-terminal amino acids. PSA that enters the circulation intact is rapidly bound by protease inhibitors, primarily alpha1-antichymotrypsin, although a fraction is inactivated in the lumen by proteolysis and circulates as free PSA
A PSA blood test is the most effective test currently available for the early detection of prostate cancer. Higher than normal levels of PSA are associated with both localized and metastatic prostate cancer (CaP).
Prostate-specific antigen (PSA), also known as kallikrein III, seminin, semenogelase, γ-seminoprotein and P-30 antigen is a 34 kD glycoprotein manufactured almost exclusively by the prostate gland; PSA is produced for the ejaculate where it liquifies the semen and allows sperm to swim freely. It is also believed to be instrumental in dissolving the cervical mucous cap, allowing the entry of sperm.
In addition to measuring human Prostate Specific Antigen in blood, tissue samples can be stained for the presence of PSA in order to determine the origin of maligant cells that have metastasized.
PSA is a major protein in semen , where its function is to cleave semenogelins in the seminal coagulum. PSA is secreted into prostatic ducts as an inactive 244–amino acid proenzyme (proPSA) that is activated by cleavage of seven N-terminal amino acids. PSA that enters the circulation intact is rapidly bound by protease inhibitors, primarily alpha1-antichymotrypsin, although a fraction is inactivated in the lumen by proteolysis and circulates as free PSA
A PSA blood test is the most effective test currently available for the early detection of prostate cancer. Higher than normal levels of PSA are associated with both localized and metastatic prostate cancer (CaP).
Prostate-specific antigen (PSA), also known as kallikrein III, seminin, semenogelase, γ-seminoprotein and P-30 antigen is a 34 kD glycoprotein manufactured almost exclusively by the prostate gland; PSA is produced for the ejaculate where it liquifies the semen and allows sperm to swim freely. It is also believed to be instrumental in dissolving the cervical mucous cap, allowing the entry of sperm.
In addition to measuring human Prostate Specific Antigen in blood, tissue samples can be stained for the presence of PSA in order to determine the origin of maligant cells that have metastasized.
Prostate-Specific Antigen Levels as a Predictor of Lethal Prostate Cancer
Prostate-Specific Antigen Levels as a Predictor of Lethal Prostate Cancer . Rates of long-term survival among patients with untreated localized prostate cancer are high. To avoid unnecessary treatment, tools are needed to identify the small proportion of patients who are destined to develop lethal prostate cancer. Conclusions: Although baseline PSA value and rate of PSA change are prognostic factors for lethal prostate cancer, they are poor predictors of lethal prostate cancer among patients with localized prostate cancer who are managed by watchful waiting. Source: Journal of the National Cancer Institute 2007 99(7):526-532; doi:10.1093/jnci/djk110
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