Like HER2, they say in a press release, SPINK1 occurs in only a small subset of prostate cancers – about 10 percent. “But the gene is an ideal target for a monoclonal antibody, the same type of drug as Herceptin, which is aimed at HER2 and has dramatically improved treatment for this aggressive type of breast cancer.”

“Since SPINK1 can be made on the surface of cells, it attracted our attention as a therapeutic target. Here we show that a ‘blocking’ antibody to SPINK1 could slow the growth of prostate tumors in mice that were positive for the SPINK protein,” says study author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and a Howard Hughes Medical Institute Investigator. The study appears in the March 2 issue of Science Translational Medicine.

The researchers found that SPINK1 can bind to a receptor called EGFR (epidermal growth factor receptor). So they tested effects on SPINK1 positive tumors of a drug that blocks EGFR, cetuximab. This drug, trade name Erbitux, is a chimeric (mouse/human) monoclonal antibody, an epidermal growth factor receptor (EGFR) inhibitor, given by intravenous infusion. Erbitux is already approved by the U.S. Food and Drug Administration and in use in treatment of metastatic colorectal cancer and head and neck cancer.

The first clinical trials for Erbitux took place in the 1990s. Then known as IMC-C225, it was tested in a trial at MSKCC for men with advanced prostate cancer.

In mice, the targeted therapy shrank tumors positive for SPINK1 up to 74 percent

The University of Michigan researchers have found that cetuximab (Erbitux) reduces the cancerous effects of SPINK1. Using mice, they first tested a monoclonal antibody specifically designed to target SPINK1. They then tested cetuximab. Tumors treated with the SPINK1 antibody shrank 60 percent, while tumors treated with cetuximab shrank 40 percent. By combining the two drugs, tumors were 74 percent smaller.

The effect was seen only in tumors that expressed SPINK1 and was not seen in tumors that did not express SPINK1.

Previous clinical studies that looked at cetuximab for men with metastatic prostate cancer, including the first round mentioned above, have been disappointing, with only 8 percent of patients showing some benefit. The researchers suggest that the poor results may be because the treatment is appropriate only for patients with SPINK1-positive tumors.

“About 10 percent of prostate cancer patients are SPINK1-positive and strategies to block SPINK1 signaling may have utility in this subset of patients. These studies should stimulate the development of antibody-based therapies against SPINK1 or targeting of EGFR in SPINK1-positive cancer patients,” says study author Bushra Ateeq, a research fellow at the U-M Medical School.

SPINK1 is associated with a more aggressive form of prostate cancer. It can be detected in the urine of prostate cancer patients, making it an easy test for urologists to perform routinely.

“This non-invasive form of screening could be helpful in the molecular categorization of prostate cancer patients and administering therapies in a molecularly guided fashion,” says Chinnaiyan, S.P. Hicks Endowed Professor of Pathology at the U-M Medical School and an American Cancer Society Research Professor.

The study suggests that side effects were limited in mice. Future studies will need to determine whether targeting SPINK1 in humans would affect normal tissue. The researchers will also look to further understand why SPINK1 is elevated in a subset of prostate cancers. Clinical trials testing SPINK1 therapies are not available at this time.

News and links edited by J. Strax at psa-rising.com.

Last updated Thur March 3, 1109 pm EST

References: Therapeutic Targeting of SPINK1-Positive Prostate Cancer Science Translational Medicine, Vol. 3, No. 72, March 2, 2011

Additional authors on this study: Scott A. Tomlins, Bharathi Laxman, Irfan A. Asangani, Qi Cao, Xuhong Cao, Yong Li, Felix Y. Feng, Kenneth J. Pienta and Sooryanarayana Varambally

Funding: U.S. Department of Defense, Early Detection Research Network, Prostate SPORE, National Institutes of Health, Prostate Cancer Foundation

Disclosure: The University of Michigan has filed for patents on SPINK1, on which Chinnaiyan and Tomlins are named as inventors. The diagnostic field of use has been licensed to Gen-Probe Inc., who was not involved in the design or funding of these studies.

The study is published as: A Two-Step Toward Personalized Therapies for Prostate Cancer Sci Transl Med 2 March 2011

Related publication: A First-Generation Multiplex Biomarker Analysis of Urine for the Early Detection of Prostate Cancer (2008)

Resources:
U-M Cancer AnswerLine, 800-865-1125
U-M Comprehensive Cancer Center, www.mcancer.org
Clinical trials at U-M, www.UMClinicalStudies.org

According to the findings of the Phase 1-2 study, MDV3100 shrank patients’ tumors, lowered PSA (prostate-specific antigen) and stabilized disease that had spread to soft tissues and the bone. The drug also reduced the number of circulating tumor cells in the blood.

“We were encouraged to see antitumor activity in men whose disease had spread to other parts of the body after either becoming resistant to previous hormone treatments or progressing following chemotherapy,” said the study’s lead author Howard Scher, MD, Chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering. “These findings strengthen the drug’s potential to change the outlook for a group of patients who currently have limited effective treatment options from which to choose.”

According to the research, MDV3100 slows tumor growth and induces tumor cells to die in men with CRPC. Although this advanced stage of prostate cancer is defined by resistance to standard therapies used to lower or block those hormones, the cancer cells actually may still depend on male hormones to grow.  MDV3100 works by blocking testosterone from binding to the androgen (male hormone) receptor, stopping the movement of the androgen receptor to the nucleus of prostate cancer cells, preventing the receptor from binding to DNA, and inducing cancer cell death, even when the expression of the androgen receptor is elevated.

“This study validates what our preclinical studies have suggested: that sustained androgen receptor signaling drives CRPC and that a substantial number of CRPC tumors that progress despite multiple hormone and chemotherapy treatments remain dependent on androgen receptor signaling for growth,” said study co-author, Charles Sawyers, MD, Chair of Memorial Sloan-Kettering’s Human Oncology and Pathogenesis Program and a Howard Hughes Medical Institute investigator.

The drug was co-invented by Dr. Sawyers and Michael Jung, PhD, Professor of Chemistry at the University of California, Los Angeles. Their research originally demonstrated that CRPC cells have increased expression of the androgen receptor and that elevated expression of this receptor may contribute to disease progression due to a developed resistance to hormone treatment. Their collaboration led to the discovery of a number of nonsteroidal, small molecule antiandrogen compounds, including MDV3100.

In the current study, 140 patients were treated with doses of MDV3100 ranging from 30 to 600 mg daily. PET imaging, bones scans, and blood tests were used to assess the antitumor effects of the drug, which were observed at all dosages. Investigators reported declines in PSA of at least 50 percent in more than half of the patients and tumor regressions in 22 percent of the patients. Overall, two-thirds of patients had partial remissions or stable disease in tumors that had spread to soft tissue or bone.

The findings also showed that the number of circulating tumor cells fell in 49 percent of patients, and 91 percent of patients who initiated therapy with favorable counts retained favorable counts during treatment. This is important because previous research shows that changes in circulating tumor cell counts after treatment were more predictive of survival than were changes in PSA, with favorable post-treatment counts associated with a 21-month median survival.

The drug was generally well tolerated, with nausea, constipation, diarrhea, and anorexia being the most common mild side effects reported. The most frequently reported Grade 3 side effect at higher doses was fatigue. The researchers determined that the maximum tolerated dose for sustained treatment was 240 mg daily.

More details in the source article in The Lancet:

Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1—2 study

Based on the positive results of the current study, a multinational randomized Phase 3 clinical trial has begun to examine MDV3100 versus a placebo for the treatment of men with advanced prostate cancer who were previously treated with chemotherapy. Information about patient eligibility and enrollment can be obtained by visiting www.affirmtrial.com or by calling the AFFIRM study’s toll free hotline at 888-782-3256 and by visiting our blog page:

http://www.psa-rising.com/blog/2010/04/mdv3100-trial-phase3/

The research was supported by Medivation; the Prostate Cancer Foundation, the National Cancer Institute, the Howard Hughes Medical Institute, and the Department of Defense Prostate Cancer Research Program Clinical Consortium (which includes Memorial Sloan-Kettering, the Oregon Health and Science University Knight Cancer Institute, The University of Washington, the Dana-Farber Cancer Institute, and M. D. Anderson Cancer Center).

Posted by J. Strax.

“This finding addresses one of the most important clinical questions of prostate cancer – the ability at an early stage to distinguish between aggressive and slow-growing disease,” said Jianfeng Xu, M.D., Dr. P.H., professor of epidemiology and cancer biology.

“Although the genetic marker currently has limited clinical utility, we believe it has the potential to one day be used in combination with other clinical variables and genetic markers to predict which men have aggressive prostate cancer at a stage when the disease is still curable.”

The research will be reported online this week,  Jan. 11-15, in the Proceedings of the National Academy of Sciences. Previously, Canadian researchers in  discovered a higher risk of death from prostate cancer in patients carrying a faulty variant of the BRCA gene.

Prostate cancer accounts for one-fourth of all cancer diagnoses in the United States. Autopsy studies suggest that most aging men will develop prostate lesions that, if detected clinically, would be diagnosed as cancer.

Although most men have a slow-growing form of the disease, aggressive prostate cancers are currently the second-leading cause of cancer death in the U.S., accounting for 27,000 deaths annually.

“The current inability to accurately distinguish risk for life-threatening, aggressive prostate cancer from the overwhelming majority of slow-growing cases creates a treatment dilemma,” said Xu.

While researchers, including Xu’s team, have identified multiple genetic variants associated with the risk of developing prostate cancer in the first place, until now there have been no genetic factors associated with disease aggressiveness.

Based on existing evidence that some men are genetically predisposed to developing aggressive prostate cancer, the researchers hypothesized that inherited genetic variants exist that could be used as markers to identify these men at an early, curable stage of disease.

“Identifying factors that are associated with a risk of having or developing aggressive disease is urgently needed to reduce over-diagnosis and over-treatment of this common cancer,” said Karim Kader, M.D., Ph.D., a Wake Forest Baptist urologist specializing in prostate cancer and a co-author on the paper.

The study involved the analysis of genetic information from 4,849 men with aggressive disease and 12,205 with slow-growing disease to determine if the men with aggressive disease had genetic variants in common. The analysis included participants in the Genetic Markers of Susceptibility study performed by the National Cancer Institute (NCI) as well as additional study populations in the U.S. and Sweden.

The researchers identified a genetic variant (rs4054823) that was associated with a 25 percent higher risk of developing aggressive disease.

“A single variant with a moderate effect such as this is unlikely to be sufficient on its own at predicting risk,” said Xu. “But its identification is significant because it indicates that variants predisposing men to aggressive disease exist in the genome.”

He said that as more variants associated with aggressive disease are identified, it is possible that doctors could test men to determine their risk of aggressive disease not only at the time of diagnosis, but early enough in their lives to target them for increased screening.

“We speculate that a panel of variants could be an important part of developing a screening strategy that could reduce the number of men requiring screening, thereby reducing over-diagnosis, while also identifying men at risk for developing aggressive disease at a stage when the disease is potentially curable.”

Edited by J. Strax

The research was primarily funded by NCI.
Co-researchers were: S. Lilly Zheng, M.D., Jielin Sun, Ph.D., Ge Li, M.D., Lina D. Purcell, B.S., Seong-Tae Kim, Ph.D., and Fang-Chi Hsu, Ph.D., all with Wake Forest University School of Medicine; Sarah D. Isaacs, M.S., Kathleen E. Wiley, M.S., Patrick C. Walsh, M.D. and William B. Isaacs, Ph.D., all from Johns Hopkins Medical Institutions; Fredrik Wiklund, Ph.D., Jan Adolfsson, M.D., Ph.D., and Henrik Grönberg, M.D., Ph.D. all from the Karolinska Institutet in Stockholm, Sweden; Pär Stattin, M.D., Ph.D. from Umeå University Hospital in Umeå, Sweden; Jeffrey M. Trent, Ph.D., David Duggan, Ph.D., and John Carpten, Ph.D., from Translational Genomics Research Institute in Phoenix, Ariz.; and Jonas Hugosson, M.D., from Sahlgrenska University Hospital, Goteborg, Sweden.

Wake Forest University Baptist Medical Center (www.wfubmc.edu) is an academic health system comprised of North Carolina Baptist Hospital, Brenner Children’s Hospital, Wake Forest University Physicians, and Wake Forest University Health Sciences, which operates the university’s School of Medicine and Piedmont Triad Research Park. The system comprises 1,056 acute care and rehabilitation beds and has been ranked as one of “America’s Best Hospitals” by U.S. News & World Report since 1993. Wake Forest Baptist also holds the Gold Seal of Approval™ from the Joint Commission, the nation’s esteemed standards-setting and accrediting body for health care quality. Wake Forest Baptist is ranked 32nd in the nation by America’s Top Doctors for the number of its doctors considered best by their peers. The institution ranks in the top third in funding by the National Institutes of Health and fourth in the Southeast in revenues from its licensed intellectual property.

Cancer may lower good, HDL cholesterol and low total cholesterol may be a sign of undiagnosed cancer, a long-running study following nearly thirty thousand men for almost 20 years has discovered.   A related study suggests that lowering total cholesterol may help men reduce risk of high-grade prostate cancer.

A National Cancer Institute scientist says that one of a pair of studies in Cancer Epidemiology, Biomarkers & Prevention, lays to rest the decades-long concern that lower total cholesterol may lead to cancer.

Demetrius Albanes, M.D., a senior investigator at NCI, said early studies suggested that low cholesterol could increase the risk of certain types of cancer.

“Our study affirms that lower total cholesterol may be caused by undiagnosed cancer. In terms of public health message, we found that higher levels of ‘good cholesterol’ (HDL) seem to be protective for all cancers, which is in line with recommendations for cardiovascular health,” said Albanes.

The researchers observed 29,093 men from the Alpha-Tocopheral, Beta-Carotene Cancer Prevention Study cohort for 18 years, making it the largest and longest study of its kind. In that follow-up period, they noted 7,545 cancer cases. Low total cholesterol blood levels were associated with an 18 percent higher risk of cancer overall, similar to the increases seen in previous studies, but this risk disappeared when the researchers excluded cases that occurred in the early years after the original blood draw.

This finding suggests that the low total cholesterol levels did not cause cancer, but rather were the result of underlying cancer, said Albanes. Higher levels of HDL cholesterol were associated with a 14 percent decreased risk of cancer even after excluding nine years of early cases.

In an accompanying study that looked specifically at risk for high-grade prostate cancer, Elizabeth Platz, Sc.D., M.P.H., associate professor in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health and co-director of the Cancer Prevention and Control Program at the Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University, found a link between low cholesterol and decreased risk of high-grade prostate cancer among 5,586 men older than 55 years.

Specifically, if men had total cholesterol of less than 200 mg/dL they had a 59 percent reduced risk of high-grade prostate cancer, defined as a Gleason score eight to 10. No association was seen for prostate cancer overall or for prostate cancer with a lower Gleason score. Platz said that the study supports another benefit of keeping cholesterol low among men in this age group.

Subscribe to the AACR News RSS Feed: http://feeds.feedburner.com/aacr

Subscribe to the Cancer Epidemiology, Biomarkers & Prevention RSS Feed: http://cebp.aacrjournals.org/rss/recent.xml

Edited by J. Strax from information provided by AACR.

Men with lower cholesterol are less likely than those with higher levels to develop high-grade prostate cancer — an aggressive form of the disease with a poorer prognosis, according to results of a Johns Hopkins collaborative study.

In a prospective study of more than 5,000 U.S. men, epidemiologists say they now have evidence that having lower levels of heart-clogging fat may cut a man’s risk of this form of cancer by nearly 60 percent.

“For many reasons, we know that it’s good to have a cholesterol level within the normal range,” says Elizabeth Platz, Sc.D., M.P.H., associate professor at the Johns Hopkins Bloomberg School of Public Health and co-director of the cancer prevention and control program at the Johns Hopkins Kimmel Cancer Center. “Now, we have more evidence that among the benefits of low cholesterol may be a lower risk for potentially deadly prostate cancers.

Normal range is defined as less than 200 mg/dL (milligrams per deciliter of blood) of total cholesterol.

Platz and her colleagues found similar results in a study first published in 2008, and in 2006, she linked use of cholesterol-lowering statin drugs to lower risk of advanced prostate cancer.

For the current study, Platz, members of the Southwest Oncology Group, and other collaborators analyzed data from 5,586 men aged 55 and older enrolled in the Prostate Cancer Prevention Trial from 1993 to 1996. Some 1,251 men were diagnosed with prostate cancer during the study period.

Men with cholesterol levels lower than 200 mg/dL had a 59 percent lower risk of developing high-grade prostate cancers, which tend to grow and spread rapidly. High-grade cancers are identified by a pathological ranking called the Gleason score. Scores at the highest end of the scale, between eight and 10, indicate cancers considered the most worrisome to pathologists who examine samples of the diseased prostate under the microscope.

In Platz’s study, cholesterol levels had no significant effect on the entire spectrum of prostate cancer incidence, only those that were high-grade, she says.

Platz cautions that, while the group took into account factors that could bias the results, such as smoking history, weight, family history of prostate cancer, and dietary cholesterol, other things could have affected their results. One example is whether men in the study were taking cholesterol-lowering drugs at the time of the blood collections, a data point the researchers expect to analyze soon.

Results of the current study are expected to be published online Nov. 3 in the journal Cancer Epidemiology, Biomarkers & Prevention. Also in the journal is an accompanying paper from the National Cancer Institute showing that lower cholesterol in men conferred a 15 percent decrease in overall cancer cases.

“Cholesterol may affect cancer cells at a level where it influences key signaling pathways controlling cell survival,” Platz says. “Cancer cells use these survival pathways to evade the normal cycle of cell life and death.”

Targeting cholesterol metabolism may be one route to treating and preventing the disease, she says, adding that this remains to be tested.

Funding for the study was provided by the National Cancer Institute.

Authors of the study include Cathee Till, Phyllis J. Goodman, Marian L. Neuhouser and Alan R. Kristal from the Fred Hutchinson Cancer Research Center; Howard L. Parnes, William D. Figg, and Demetrius Albanes from the National Cancer Institute; Eric A. Klein from the Cleveland Clinic; and Ian M. Thompson Jr., from the University of Texas Health Sciences Center.

Related News:

• Anti-Cholesterol Statins May Yield Triple Benefits for Men’s …

  Apr 26, 2009 … Statins , drugs widely prescribed to lower cholesterol, may have protective effects on prostate health and on male erectile function.

• Anti-cholestoral drugs called statins effective against bone loss

  Common anti-cholesterol drugs called statins are surprisingly effective against bone loss or osteoporosis, a common side-effect of hromonal therapy in men …

• Statins Protect Against Prostate Cancer . . .

  The use of statins , rather than other cholesterol-lowering agents, significantly reduced the incidence of prostate cancer in the population-based Finnish …

• Statins May Lower PSA, Do They Cut Cancer Risk?

Oct 28, 2008 … Popular cholesterol-busting drugs — statins — appear to lower men’s PSA values along with their cholesterol levels, according to …

• More Evidence Suggests Statins Help Cut Risk for Advanced Prostate . . .

  In a 10-year study of more than 30000 health professionals, researchers at Johns Hopkins and Harvard found that the longer men take cholesterol-lowering …

Dr. Elizabeth Platz is on the faculty of Johns Hopkins Bloomberg School of Public Health. She studies genetic and environmental factors in prostate and colon cancer and investigates methods of cancer prevention.

Cancer Epidemiology, Biomarkers & Prevention:
http://cebp.aacrjournals.org/

This page posted by JAcqueline Strax, November 4, 2004

Hypofractionated radiation treatment, a newer type of radiation treatment that delivers higher doses of radiation in fewer treatments than conventional radiation therapy, is significantly more effective than the older method in stopping cancer growth in high risk patients and causes no increase in negative side effects, an Italian clinical trial shows.

“The study not only shows that hypofractionated radiation improves the control of prostate cancer, but it also cuts the number of treatment visits in half for patients. This is an important benefit for these high-risk patients, who are typically an older, less mobile population,” Giorgio Arcangeli, M.D., lead author of the study and a radiation oncologist at the Regina Elena National Cancer Institute in Rome, Italy said. “It’s also especially helpful for those living at long distance from radiation treatment centers.”

Dr. Arcangeli presented the trial findings November 4, 2009 in Chicago at the 51st Annual Meeting of the American Society for Radiation Oncology (ASTRO).

All men in the study were treated with three-dimensional conformal radiation therapy, or 3D-CRT. It is a type of external beam radiation therapy that uses computers and special imaging techniques to show the size, shape and location of the tumor as well as surrounding organs to precisely tailor the radiation beams to the size and shape of the tumor. Because the radiation beams are very precisely directed, nearby normal tissue receives less radiation and is able to heal more quickly.

During external beam radiation therapy, a beam of radiation is directed through the skin to the cancer and the immediate surrounding area in order to destroy the main tumor and any nearby cancer cells.

From January 2003 to December 2007, a total of 168 high risk prostate cancer patients were randomized to receive either hypofractionated or conventional schedules of 3D-CRT to the prostate and surrounding area. Patients who received hypofractionated radiation had only 20 sessions of radiation (four weeks of daily radiation therapy treatments), instead of the 40 to 45 (eight to nine weeks of daily treatments) sessions typically required during standard radiation treatment.

Study findings show that the patients treated with hypofractionated radiation had a better chance (87 percent vs. 79 percent) that their cancer would stop growing, compared to patients treated with standard radiation therapy.

There was also no difference in the late side effects of genito-urinary and gastro-intestinal function between the two groups of patients, Dr. Arcangelli says.

Effect of hyperfractionated radiation on the rectal wall was investigated earlier in a Phase 2 trial (see links below). For 6 months that study followed 114 patients radiated for localized prostate cancer and concluded that “The similar rate of late toxicity in the two arms seems to indicate the feasibility of hypofractionated regimes in prostate cancer.” There was a difference of under 3% in the number of cases of rectal wall side effects reported by these patients and confirmed by the physicians.

“Studies are in progress to test the benefits of even shorter treatment schedules,” Dr. Arcangeli said.

Sources & Links to Related Material

A summary of the trial, “A Phase III Randomized Study Of High Dose Conventional Vs Hypofractionated Radiotherapy In Patients With High Risk Prostate Cancer,” was presented on Wednesday, November 4, 2009.

For more information on radiation therapy for prostate cancer, visit www.rtanswers.org.

EBRT is a mailing list offering discussion and support for patients interested in external beam radiotherapy. The list has extensive archives available for members to browse. Visit our page for patient-centered prostate cancer related mailing lists.

Dr. Giorgio Arcangeli and colleagues recently published results from a Phase 2 trial comparing rectal side effects from hyperfracationated and standard EBR. This report is available in full free text online:

ASTRO – A shorter, 5-week course of radiation treatment that delivers higher doses of radiation in fewer sessions, known as hypofractionation, appears just as effective and as safe for moderate and higher risk prostate cancer as standard radiation therapy, yet is delivered in two-and-a-half weeks less time.

These interim results from an ongoing randomized study were presented November 4, 2009, at the 51st Annual Meeting of the American Society for Radiation Oncology (ASTRO).

“The study shows that hypofractionated radiation could potentially be used in place of standard radiation therapy for intermediate and high risk prostate cancer patients, but the results are still preliminary,” Alan Pollack, M.D., lead author of the study and a radiation oncologist at the University of Miami Miller School of Medicine in Miami, Fla., said.

“We are excited about this research because the shorter course of treatment is more convenient, would reduce health care costs and appears just as effective.”

Patients in this study received the type of external beam radiation called intensity modulated radiation therapy, or IMRT. This method of delivering radiation to the body allows the beam to be more exactly shaped to fit the prostate.

Using IMRT, the amount of radiation received by healthy tissues near the tumor are reduced. This allows for higher doses per day without increasing toxicity significantly.

The study involved 303 men with intermediate and high risk prostate cancer who were randomized to receive hypofractionated IMRT for 26 treatments (five weeks of daily radiation therapy) or standard IMRT for 38 treatments (seven-and-a-half weeks of daily treatments) to the prostate and surrounding area. High-risk patients also received treatment to the pelvic lymph nodes.

In addition to radiation treatment, 34 of the 200 intermediate risk patients received short-term hormone therapy for a median of four months, while 102 of 103 high risk patients in the hypofractionated group received long-term hormone therapy for 25 months.

The study found that 39 months after treatment, there is no significant difference in cancer recurrence between patients who underwent hypofractionated IMRT (14 percent) and standard IMRT (19 percent). There is also no difference in genitourinary and gastrointestinal side effects between the two groups.

“Although these are significant findings, longer follow-up is needed and a final analysis is planned for 2011,” Dr. Pollack said. “Other clinical trials are exploring hypofractionation and I encourage men with prostate cancer interested in shorter treatments to talk to their radiation oncologist about joining a study.”

SOURCE

The summary “Hypofractionation For Prostate Cancer: Interim Results of a Randomized Trial,” were presented at a scientific session at at the 51st Annual Meeting of the American Society for Radiation Oncology (ASTRO)on Wednesday, November 4, 2009.

This page complied by Jacqueline Strax, last modified November 4 2009.

New research indicates that the use of minimally invasive procedures (including the use of robotic assistance) for radical prostatectomy, which have increased significantly in recent years, may shorten hospital stays and decrease respiratory and surgical complications, but may also result in an increased rate of certain complications, including incontinence and erectile dysfunction, according to a study in the October 14 issue of JAMA

Jim C. Hu, M.D., M.P.H., of Brigham and Women’s Hospital, Boston, presented the findings of the study at a JAMA media briefing in Chicago.

Minimally invasive radical prostatectomy (MIRP), in particular with the use of robotic assistance, has increased from 1 percent to 40 percent of all radical prostatectomies from 2001 to 2006, according to background information in the article. But this rapid increase has occurred despite limited data on outcomes and greater costs compared with open retropubic radical prostatectomy (RRP; surgery in which an incision is made in the lower abdomen to remove the prostate, which is located in the pelvis behind the pubic bone).

“Moreover, the widespread direct-to-consumer advertising and marketed benefits of robotic-assisted MIRP in the United States may promote publication bias against studies that detail challenges and suboptimal outcomes early in the MIRP learning curve. Until comparative effectiveness of robotic-assisted MIRP can be demonstrated, open RRP, with a 20-year lead time for dissemination of surgical technique relative to MIRP, remains the gold standard surgical therapy for localized prostate cancer,” the authors write.

Dr. Hu and colleagues assessed the outcomes for men with prostate cancer who underwent MIRP (n = 1,938) vs. RRP (n = 6,899), using U.S. Surveillance, Epidemiology, and End Results Medicare linked data. During the study period, the use of MIRP increased almost 5-fold, from 9.2 percent in 2003 to 43.2 percent in 2006-2007

After analyses, the researchers found that men undergoing MIRP vs. RRP experienced shorter hospital length of stay (median [midpoint], 2.0 vs. 3.0 days), were less likely to receive transfusions (2.7 percent vs. 20.8 percent), and were at lower risk of postoperative respiratory complications (4.3 percent vs. 6.6 percent) and miscellaneous surgical complications (4.3 percent vs. 5.6 percent)

“However, men undergoing MIRP vs. RRP experienced more genitourinary complications [involving the genital and urinary organs or their functions; 4.7 percent vs. 2.1 percent) and were more often diagnosed as having incontinence and erectile dysfunction. The need for additional cancer therapies was similar by surgical approach,” the authors write.

The researchers also found that greater receipt of MIRP vs. RRP was associated with living in areas of higher socioeconomic status based on education and income, and that this may be the result of a “highly successful robotic-assisted MIRP marketing campaign disseminated via the Internet, radio, and print media channels likely to be frequented by men of higher socioeconomic status.”

“In light of the mixed outcomes associated with MIRP, our finding that men of higher socioeconomic status opted for a high-technology alternative despite insufficient data demonstrating superiority over an established gold standard may be a reflection of a society and health care system enamored with new technology that increased direct and indirect health care costs but had yet to uniformly realize marketed or potential benefits during early adoption,” the authors conclude.

Jim C. Hu; Xiangmei Gu; Stuart R. Lipsitz; Michael J. Barry; Anthony V. D’Amico; Aaron C. Weinberg; Nancy L. Keating. Comparative Effectiveness of Minimally Invasive vs Open Radical Prostatectomy. JAMA, 2009; 302 (14): 1557-1564.

The answer, they say, is hidden tumors located on the top of the prostate that evade traditional diagnostic procedures, including ultrasound-guided needle biopsy. The PMH research, published online today in the British Journal of Urology International (BJU 8938), demonstrates that magnetic resonance imaging (MRI) is the best tool to reveal such tumours.

“Our findings identify a specific high-risk group whose tumors are difficult to diagnose because of location. These men benefit from MRI, which guides the biopsy procedure with a high degree of accuracy,” says author Dr. Nathan Lawrentschuk, Urologic Oncology Fellow, PMH Cancer Program, University Health Network. “The research team calls the clinical presentation of elevated PSA and repeated negative biopsy results in ‘prostate evasive anterior tumor syndrome’ (PEATS).”

This use of MRI is not foolproof but it is a significant advance. A team of urologists, surgeons, radiologists and pathologists studied 31 PMH patients who had positive biopsy results and tumors on top of their prostate as shown on MRI. They found that MRI was able to help diagnose hidden prostate tumors 87% of the time.

Dr. Lawrentschuk says clinicians need to be aware of PEATS because these hidden tumors can be aggressive.

Edited by J. Strax 10/08/09

LINKS

Princess Margaret Hospital, Toronto, Canada is a member of University Health Network, which also includes Toronto General Hospital and Toronto Western Hospital. All three are research hospitals affiliated with the University of Toronto. Their research arm is Ontario Cancer Institute.

ABSTRACT of the publication

The role of magnetic resonance imaging in targeting prostate cancer in patients with previous negative biopsies and elevated prostate-specific antigen levels.

In the past 20 years, magnetic resonance imaging (MRI) has developed rapidly, along with the management of localized prostate cancer. We summarize current data on the efficacy of MRI for targeting cancer, compared with biopsies, in patients with previous negative prostate biopsies and persistently elevated prostate-specific antigen (PSA) levels. The key clinical question is how many men benefit by having had prostate cancer detected purely because of the MRI-targeted, as opposed to standard scheme, biopsies. We reviewed all available databases for prospective studies in patients having MRI and prostate biopsy with previous negative biopsies and persistently elevated PSA levels. Six studies fulfilled the selection criteria, with 215 patients in all; in these studies, the cancer-detection rate at repeat biopsy was 21-40%. For MRI or combined MRI/MR spectroscopy, the overall sensitivity for predicting positive biopsies was 57-100%, the specificity 44-96% and the accuracy 67-85%. In five studies, specific MRI-targeted biopsies and standard cores were taken, with a significant proportion (34/63, 54%) having cancer detected purely because of the MRI-targeted cores. The value of endorectal MRI and MR spectroscopy in patients with elevated PSA levels and previous negative biopsies to target peripheral zone tumours appears to be significant. Although more data obtained with current technologies are needed, published results to data are encouraging. A comparison study and cost-benefit analysis of MRI-targeted vs saturation biopsy in this group of patients would also be ideal, to delineate any advantages.

British Journal of Urology International website

RELATED

Using MRI to Detect Bone Metastases in High-Risk Prostate Cancer Patients

MRI is more accurate than bone scans or plain radiographs for detecting bone metastases, but is better detection always the best course? JournalWatch.org, August 2007

To see whether Celebrex (celecoxib) can reduce prostate cancer size and spread, a team from several leading US cancer centers led by Dr. Alan Partin and Dr. Michael Carducci conducted a randomized, double-blind trial enrolling high-risk men before primary treatment with surgery or radiation. They measured the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy on these men.

The trial was conducted because Celebrex, a non-steroidal anti-inflammatory drug (NSAID) used primarily in treatment of conditions like arthritis, is designed to work by targeting and inhibiting Cyclooxygenase-2 (COX-2). COX-2 is of interest, the team explains, as “a potential pharmacologic target for the prevention of various malignancies, including prostate cancer.”

As measurements of whether Celebrex controlled the prostate tumors, the investigators decided to focus on markers of prostate cancer progression in biopsy tissue removed from these higher-risk patients after half of the group took relatively high-dose Casodex for several weeks before undergoing surgery.

Patients with localized prostate cancer and Gleason sum of 7 or above, prostate-specific antigen (PSA) at 15 ng/mL or above, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy.

The primary measure of interest was difference in prostatic prostaglandin levels between the men who either took or did not receive Casodex. Prostaglandins are arachidonic acid metabolites of COX-2 and are used as biomarkers of tumor invasiveness.

Secondary end points to be measured were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. In addition, the trial aimed to assess drug safety and compliance (ability of the patients to stay on the drug).

RESULTS

Seventy-three patients consented to enroll in the trial. Of these, 64 men were randomly assigned either to take Celebrex or to take a dummy drug and all their results were counted in the final analaysis.

Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities.

But no treatment differences in any of the primary or secondary outcomes were seen. Statistical analysis revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67. Ki-67 is a molecule that can be easily detected in growing cells in order to gain an understanding of the rate at which the cells within a tumor are growing and giving rise to more cancer cells.

The authors conclude: “Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.”

Psa-rising.com news story reported by Jacquie Strax.

Source and Links

The study was published in Journal of Clinical Oncology, online August 31, 2009.

Abstract

Phase II, Randomized, Placebo-Controlled Trial of Neoadjuvant Celecoxib in Men With Clinically Localized Prostate Cancer: Evaluation of Drug-Specific Biomarkers. Partin AW, Carducci MA, and colleagues.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Brady Urological Institute at Johns Hopkins, Baltimore; National Cancer Institute, Bethesda, MD; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA; and Weill Cornell Medical College, New York, NY.

PURPOSE: Cyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy. PATIENTS AND METHODS: Patients with localized prostate cancer and Gleason sum >/= 7, prostate-specific antigen (PSA) >/= 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance. RESULTS: Seventy-three patients consented, and 64 were randomly assigned and included in the intention-to-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P < .0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities. CONCLUSION: Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.

Related

Requirement of cyclooxygenase-2 expression and prostaglandins for human prostate cancer cell invasion, William B. Campell et al. Clinical and Experimental Metastasis, 2004)

FATTY ACID EFFECTS ON COX-2 DEPENDENT PROSTATE CANCER, M Failla et al. COLLEGE OF HUMAN ECOLOGY, OHIO STATE UNIVERSITY

The resistance to the tumor suppressive effects of COX inhibitors and COX-2 gene disruption in TRAMP mice is associated with the loss of COX expression in prostate tissue. Xingya Wang, Jennifer K.L. Colby, Peiying Yang, Susan M. Fischer, Robert A. Newman and Russell D. Klein., Carcinogensis, October 2007.