A recent study by Swedish researchers found that rheumatoid arthritis (RA) patients did not experience an elevated cancer risk in the first 6 years after starting anti-tumor necrosis factor (TNF) therapy. The research team, led by Johan Askling, M.D., Ph.D., from Karolinska University Hospital in Stockholm, Sweden assessed the short-term and medium-term cancer risk for RA patients using anti-TNF therapies: infliximab, adalimumab, and etanercept. Details of the study appear in the November issue of Arthritis & Rheumatism, a journal of the American College of Rheumatology published by Wiley-Blackwell.

TNF is a cytokine (substance secreted by immune system cells) that regulates the body’s immune system and is involved in inflammation. TNF inhibitors (or TNF blockers) are a class of therapies used to reduce inflammation in chronic inflammation such as RA. The common immunosuppressant drugs and those included in the study are Enbrel®. As these therapies are used to treat chronic inflammatory illnesses, the long-term inhibition of TNF raises concerns for increased risk of infections and cancer.

This study, one of the largest and longest population-based assessments of cancer risks associated with immunosuppressive therapy, included data from several Swedish databases including the Biologics Register, the Cancer Register, and the Early RA Register. Researchers identified and analyzed data from 6,366 patients who started anti-TNF therapy between January 1999 and July 2006. Data from patients using TNF inhibitors was compared with other groups of RA patients - 61,160 not taking medication, 4015 using methotrexate (the gold standard in RA treatment) and 4,015 taking combinations of disease -modifying anti-rheumatic drugs (other than TNF inhibitors).

Results show there were 240 first primary cancers diagnosed during the 25,693 person-years of follow-up in the patients using anti-TNF therapy who had no history of cancer at the onset of immunosuppressant treatment. When compared to the larger national RA cohort who did not receive TNF inhibitors or have a history of cancer, the relative risk of anti-TNF therapy was 1.00 and remained unchanged for those taking immunosuppressant drugs for up to 6 years. “Our research indicates the overall cancer risk is the same for RA patients on immunosuppressant therapies and those not taking medications for the disease,” confirmed Dr. Askling, but adds that “given several remaining uncertainties, continued vigilance remains prudent.”

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by chronic inflammation in the joints, joint tissue, and other organs and is the most common form of inflammatory arthritis. A 2004 report from the World Health Organization (WHO) estimates 23.7 million people worldwide (1.3 million U.S. adults) are afflicted with RA, with 75% of those cases found in women.

Article: “Cancer Risk in Patients With Rheumatoid Arthritis Treated With Anti-Tumor Necrosis Factor a Therapies.” Johan Askling, Ronald F. van Vollenhoven, Fredrik Granath, Pauline Raaschou, C. Michael Fored, Eva Baecklund, Christina Dackhammar, Nils Feltelius, Lars Coster, Pierre Geborek, Lennart T. Jacobsson, Staffan Lindblad, Solbritt Rantapää-Dahlqvist, Tore Saxne, and Lars Klareskog. Arthritis & Rheumatism; Published Online: October 29, 2009 (DOI 10.1002/art.24941); Print Issue Date: November 2009

Source: Dawn Peters

Wiley-Blackwell

View drug information on Remicade.

Since the isolation and culture of Helicobacter pylori (H. pylori) in 1983, this bacterium has become accepted as an important human pathogen for the development of gastritis, peptic ulcer, and gastric cancer. Cyclooxgenase-2 (COX-2) is a prostaglandin-synthesizing enzyme. Elevated expression of COX-2 is observed in a wide variety of human malignancies, including gastric cancer. Long-term high dose COX-2 inhibitors can inhibit gastric carcinogenesis in animal models, but the possible life-threatening cardiovascular adverse events limit its popular application. Therefore, it is important to evaluate the optimal intervention point of COX-2 inhibitors for inhibiting H. pylori-associated gastric carcinogenesis.

A research article published in the World Journal of Gastroenterology addresses this problem. The research team led by Prof. Wu from the Department of Gastroenterology of Kaohsiung Medical University Hospital used the Mongolian gerbil model to evaluate the optimal intervention point of COX-2 inhibitor treatment for inhibiting H. pylori-associated gastric carcinogenesis. The article also investigates the possible mechanism of chemoprevention and possible side effects of COX-2 inhibitors.

Previous studies used relatively long-term periods of chemoprevention. However, COX-2 inhibitors were not a placebo and had toxic effects. COX-2 inhibitors should not be used too long for chemoprevention of gastric cancer. According to the findings of this study, Celecoxib may have effects including anti-oncogenic effect, inhibition of angiogenesis and metastasis, and it was shown that these effects were obtained by both late and short-term use of Celecobxib. The protective effect of Celecoxib could involve an early oncogenic phase not an early inflammation phase. The short-term use also resulted in less severe inflammation and inhibited the invasion degree of gastric cancer. According to these findings, Celecoxib could be used latterly and short-term for refractory H. pylori infection in a clinical situation; a point which was seldom discussed in previous reports. This is very important for decreasing the possible side effects of COX-2 inhibitors.

The research team suggests that COX-2 inhibitors should be used as chemoprevention for people older than about forty years old. This chemoprevention may play an important role for people who have extensive metaplastic gastritis with the highest risk for the development of gastric cancer, and it is also very important for those patients with refractory H. pylori infections at high risk of gastric cancer.

A gastroenterological expert said that this result provided some new information about personalized therapy for gastric cancer prevention and would prove beneficial for clinical application in the future.

Reference: Kuo CH, Hu HM, Tsai PY, Wu IC, Yang SF, Chang LL, Wang JY, Jan CM, Wang WM, Wu DC. Short-term Celecoxib intervention is a safe and effective chemopreventive for gastric carcinogenesis based on a Mongolian gerbil model. World J Gastroenterol 2009; 15(39): 4907-4914
http://www.wjgnet.com/1007-9327/15/4907.asp

Source: Jin-Lei Wang

World Journal of Gastroenterology

Like yoga for office drones, cells do have coping strategies for stress. Heat, lack of nutrients, oxygen radicals - all can wreak havoc on the delicate internal components of a cell, potentially damaging it beyond repair. Proteins called HSPs (heat shock proteins) allow cells to survive stress-induced damage. Scientists have long studied how HSPs work in order to harness their therapeutic potential.

Donna George, PhD, Associate Professor of Genetics, and Julie Leu, PhD, Assistant Professor of Genetics, both at the University of Pennsylvania School of Medicine, in collaboration with the lab of Maureen Murphy, PhD at Fox Chase Cancer Center, identified a small molecule that inhibits the heat shock protein HSP70. They also showed that the HSP inhibitor could stop tumor formation and significantly extend survival of mice. They describe their findings in this month’s issue of Molecular Cell.

HSP70 is an intracellular quality control officer, refolding misfolded proteins and preventing protein aggregation, which among other disorders, is associated with neurodegenerative diseases. HSP70 also ferries proteins to their proper intracellular locations. Tumor cells, which face an abundance of cellular stresses, typically overexpress HSP70, making it a potentially interesting anticancer target.

The cancer microenvironment exposes malignant cells to a variety of stressful conditions that promote protein misfolding. HSP70 helps cancer cells deal with this stress. Unlike normal cells, which typically express little, if any, of HSP70, cancer cells contain high levels of this protein all of the time. Indeed, HSP70 has been termed a cancer-critical survival factor, since cancer cells probably require the actions of this protein to survive the protein-altering adverse conditions. The inhibitor, called PES, interferes with the HSP70 activities that the cancer cell needs to survive, so by targeting HSP70, one can target the cancer cell.

The investigators showed that PES interacts with HSP70 by blocking its stress-relieving functions. It also induces HSP70-dependent cell death by disrupting the cell’s ability to remove damaged components. Paradoxically for a compound first identified for blocking the cell-death pathway of apoptosis, PES does kill cells, but by a different mechanism.

PES seems to be specifically targeting HSP70, a protein that is differentially expressed in normal versus cancerous cells, and “one that the cancer cell seems to require to survive” says George. “It’s still early days - we don’t know what it will do in a human. But, the exciting part is that this is a pathway and a protein target that clearly is important for cancer cells.”

Given the extreme heterogeneity of cancer cells, simultaneously disabling networks of signaling pathways may be important. Indeed, PES was more or less equally effective in every type of cancer cell tested, she says, “which is unusual and supports the idea that it is targeting a protein that is required for the functioning of multiple pathways.”

To figure out just what PES was doing Leu chemically tagged it to see what proteins it interacted with. They were surprised and excited to have pulled out HSP70.

Next, the team investigated the consequences of PES binding. Like many proteins, HSP70 doesn’t act alone; it functions through a cadre of interacting proteins, which augment its activity. So, the team systematically scanned these proteins, to see if PES blocked their interactions with HSP70. “We found several known HSP70-interacting proteins that were no longer interacting properly when the cells were exposed to the small molecule,” Leu notes.

Among those were proteins that help HSP70 refold misfolded proteins and proteins that abet its protein trafficking functions.

When they then studied the effect that loss of those functions had on the cell, the team discovered that PES blocks the cell’s ability to get rid of the proteins damaged by cellular stress in a process called autophagy, a process in which cells were basically eating themselves to death. In mice, Murphy and her students Julia Pimkina and Amanda Frank found that PES could inhibit tumor formation and significantly extend survival.

“That was one of the highlights from our perspective, because PES has potential to be developed as a therapeutic,” says Murphy.

PES should also be a boon to researchers trying to untangle the biology of HSP70, say the researchers. Other HSP70 inhibitors exist but they are neither generally available, nor sufficiently specific. It also provides a novel platform for anticancer therapeutics, either directly as a treatment, or as a starting point for further development.

The research was funded by the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

Source: Karen Kreeger

University of Pennsylvania School of Medicine

A new, innovative form of radiation based on verified scientific facts will be available to patients all over Europe within the next few decades. The official kick-off meeting of the Community project ULICE (Union of LIght Ions Centres in Europe), which the European Union supported with nearly 10 million euros, was held in the fall of 2009 in the Department of Radiooncology and Radiation Therapy of the Heidelberg University Hospital. This consortium consists of a total of 21 European research and treatment facilities in the field of ion therapy who have joined forces in an interdisciplinary network in order to advance basic research in the fields of physics, biology and medicine, and to effectively use the existing ion therapy facilities in Europe in a joint effort to further develop this technique.

Transnational clinical studies

The project as a whole is divided into three programs:

• Patients will be treated in the context of joint transnational clinical therapy studies in ion therapy facilities. This project is to be coordinated and directed from Heidelberg, where patient assignment and indications will be structured and established, and transnational and transinstitution databases for clinical and preclinical parameters will be established.

• The second program will consist of the research and further development of ion therapy in the various clinical and preclinical sub-areas in focus; these joint research activities will be centrally coordinated from Vienna.
• The third program will focus on communication and interaction as well as interdisciplinary discussion and consensus building, and will be centrally directed by the European Organization for Nuclear Research (CERN) in Geneva.

Four primary project directors will be responsible for the project: Prof. Dr. Roberto Orrechia, Medical Director of Radiooncology and the National Center for Hadron Therapy (Centro Nazionale di Adroterapia Oncologica, CNAO) in Milan, Prof. Dr. Richard Potter, Medical Director of the Department of Radiooncology and Radiation Therapy at the General Hospital (AKH) of Vienna, Prof. Dr. Manjit Djosanjh of the European Organization for Nuclear Research (CERN) in Geneva, and Prof. Dr. Dr. Jürgen Debus, Medical Director of the Department of Radiooncology and Radiation Therapy at the Heidelberg University Hospital.

A total of 22 centers of excellence in Europe involved

In addition to the four centers of excellence (Heidelberg, Milan, Geneva and Vienna), a total of 18 other European centers will be included in the joint project. Essential preliminary work has already been completed, especially in Berkeley, California, USA and at the GSI Helmholtz Center for Heavy Ion Research in Darmstadt, Germany. So far, more than 70,000 patients all over the world have been treated with ion radiation, most of them with protons and heavy ions. Heavy ions (carbon ions) differ from conventional photon radiation therapy and proton therapy by an increased relative biological effectiveness (RBE), which has shown critical therapeutic advantages, especially for slow-growing and radiation-resistant tumors.

Since 1997 far more than 400 patients have been treated by the Heidelberg radiooncologists with carbon ions in cooperation with the GSI Helmholtz Center for Heavy Ion Research in Darmstadt and the Department of Medical Physics at the German Cancer Research Center (DKFZ) in Heidelberg, as well as the Rossendorf Research Center in Dresden. Therapeutic results have been significantly improved, especially for tumors at the base of the skull.

Heidelberg Ion Radiation Therapy Center is opened

Based on this preliminary work, the Heidelberg Ion Radiation Therapy Center (HIT) has been set up at the Heidelberg University Hospital and will soon begin clinical operation. There, it will be possible to treat over 1,300 patients per year with ion radiation. In particular, tumors of the base of the skull such as chordomas, chondrosarcomas and meningiomas as well as tumors of the salivary glands and prostate carcinomas will be treated. Brain tumors such as glioblastomas and low-grade astrocytomas will also be treated in the context of clinical studies at the HIT.

Source: Dr. Juergen Debus

University Hospital Heidelberg

UroToday.com - In the online edition of the Journal of Clinical Oncology, a multi-institutional study reports on prostate cancer (CaP)-specific mortality after radical prostatectomy (RP) treated since the introduction of PSA.

The study sought to establish a predictive nomogram and modeled the nomogram on 6,398 patients treated with RP at Baylor and MSKCC between 1987 and 2005. External validation of the nomogram was performed on 4,103 patients treated at the Cleveland Clinic and 2,176 patients treated at the University of Michigan. Patients were observed for disease recurrence and death was attributed to CaP using death certificates.

In the modeling cohort, 117 patients died from CaP and 343 died from competing causes over a median follow-up of 48 months. The 15-year prostate cancer specific mortality was 12% and the all-cause mortality was 38%. Results were similar in the validation cohort. Patients lost to follow-up at 5, 10, and 15 years were 17%, 24%, and 16%, respectively. The 5-year PSA progression-free probability (PFP) derived from a nomogram was significantly associated with PCSM. In the most favorable quartile, the 15-year PCSM was 5% compared with 38% in the lowest quartile. When analyzed by previously validated risk groups for PSA recurrence, the 15-year PCSM was 2%, 10% and 19% for patients classified as good risk, intermediate risk, and high risk. Multivariable analysis showed that primary and secondary biopsy Gleason grade 4 and 5 and increasing PSA were associated with PCSM. Patients undergoing RP in more recent times had an improved prognosis. PSA velocity was not associated with PCSM. A nomogram predicting PCSM at 10 and 15 years was constructed and adjusted for the year of surgery.

The externally validated concordance index was 0.82 and predictions closely approximated the actual outcome. The model assumes that patients are treated in the year 2005. Considering all 11,649 patients in both cohorts with complete data, only 1,980 (17%) had a predicted 15-year PCSM greater than 5% and 467(4%) had a probability greater than 30%. Considering the 7,403 patients treated since 1998, 296 (4%) had a probability of PCSM >5% and 37 (0.5%) had a predicted risk greater than 30%.

Stephenson AJ, Kattan MW, Eastham JA, Bianco FJ Jr, Yossepowitch O, Vickers AJ, Klein EA, Wood DP, Scardino PT
J Clin Oncol. 2009 Jul 27. Epub ahead of print.
doi:10.1200/JCO.2008.18.2501

Written by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

UroToday - the only urology website with original content written by global urology key opinion leaders actively engaged in clinical practice. To access the latest urology news releases from UroToday, go to:
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Copyright © 2009 - UroToday

Results of two phase 1 studies demonstrate that the novel, investigational prostate cancer and other solid malignancies, setting the stage for phase 2 studies. The data are being presented at the International Society for Biological Therapy of Cancer 2009 Annual Meeting.

MKC1106-MT is an active immunotherapeutic product consisting of three components, a DNA plasmid and two synthetic peptides, each of which is administered separately by the unique route of intranodal injection and together are designed to target two tumor-specific antigens that are commonly expressed by melanoma tumor cells. MKC1106-PP is a similar agent that is designed to target two specific tumor antigens commonly expressed by various solid tumor cells.

“MKC1106-MT and MKC1106-PP met the primary end-points of both trials and, in addition, showed early evidence of clinical benefit, which marks an important step forward for MannKind’s oncology portfolio,” said Peter Richardson, MRCP, Corporate Vice President and Chief Scientific Officer, MannKind Corporation. “These encouraging results set the stage to move into phase 2 trials with these innovative, targeted therapies, which represent the cornerstone of our cancer immunotherapy program.”

MKC-1106 MT Study Design and Key Findings

In an ongoing, open-label, multicenter trial, 18 patients with advanced melanoma were treated with MKC1106-MT and were evaluated after each therapeutic cycle of six weeks. Patients demonstrating a clinical response or no evidence of disease progression remained in the clinical trial and received up to eight cycles of treatment over one year. In all patients, repeat administration of the treatment was well tolerated with limited adverse events.

Findings reveal an immune response rate of greater than 40 percent, defined as the percentage of patients who showed elevated numbers of antigen specific T cells in the blood upon immunization, and preliminary evidence of clinical benefit. Of the 18 patients treated, 14 had visceral metastases and the remaining four had metastases confined to the lymphatic system. All four patients with lymphatic metastatic disease achieved durable objective responses (partial response based on tumor imaging [RECIST criteria]), an unexpected outcome for a phase 1 study in this type of setting. A subset analysis identified the presence of melanoma-specific T cells at baseline in the patients with lymphatic metastatic disease. Overall, these results identified patients that could benefit most from this type of therapy and will be used to design the phase 2 trial of MKC1106-MT in advanced melanoma.

“Cancer vaccines have been explored in the past with very limited success to curb the disease progression of malignant melanoma,” said Antoni Ribas, MD, Associate Professor, Division of Hematology-Oncology, David Geffen School of Medicine at UCLA. “The promising preliminary results of this ongoing study warrant further evaluation of MKC1106-MT in advanced disease and as an adjuvant therapy.”

MKC1106-PP Study Design and Key Findings

In the second study, 26 patients with advanced cancer who had diverse tumor types, metastatic disease and/or progressive, refractory disease were treated with MKC1106-PP. Patients were evaluated after two therapeutic cycles (12 weeks) and again at 24 weeks, as applicable. Patients demonstrating a clinical response or no evidence of disease progression remained in the clinical trial and received up to six cycles of treatment over nine months. In all patients, repeat administration of the treatment was well tolerated with limited adverse events.

As with the MKC1106-MT trial, an immune response rate and encouraging preliminary evidence of clinical benefit were achieved. In this study, an immune response rate of 60 percent was observed. Of the 26 patients treated, seven patients achieved clinical responses defined as partial response (RECIST), change in PSA doubling time or stable disease for at least six months. Patients attaining an immune response against both antigens, persisting throughout the first two cycles of therapy, were more likely to show clinical benefit, setting the stage for further evaluation in phase 2 studies.

“These findings lay the foundation for additional trials evaluating the clinical benefit of MKC1106-PP in select indications,” said Nicholas J. Vogelzang MD, Chair and Medical Director, Developmental Therapeutics and Co-Chair, GU Committee, US Oncology Research, Comprehensive Cancer Centers of Nevada. “Further study of this investigational agent’s mechanism of action will also be important in assessing its promise in biomarker-defined patient populations.”

Source
MannKind Corporation

Below is a statement for attribution to ASCO CEO Allen S. Lichter, MD:

“Today, CMS issued its physician fee schedule for 2010. The schedule included a one percent cut to oncology services in 2010, part of an overall six percent reduction in reimbursement for cancer care over the next four years. We are deeply concerned that these cuts will continue to erode access to cancer care in the United States.

“The cumulative effect of previous cuts has already caused oncologists to close practices, consolidate locations, and turn away Medicare patients. Further reductions will jeopardize access to care for more people with cancer across the country. Oncology cannot sustain additional cuts at a time when the number of people with cancer is increasing, practice expenses continue to rise, and the oncology workforce is dwindling.”

ASCO’s fee schedule fact sheet summarizes how cuts in Medicare coverage to date have already affected patient care, forcing physicians to close practices, consolidate locations, and turn away Medicare patients.

Source
American Society of Clinical Oncology

SAN FRANCISCO, April 27 — Lapatinib (Tykerb) may offer an option for inflammatory breast cancer when other treatments have failed, researchers said.

• Explain to interested patients that inflammatory breast cancer is a relatively uncommon but aggressive tumor type with few treatment options once patients have failed chemotherapy and trastuzumab.
• Caution patients that lapatinib monotherapy is not FDA approved for treating refractory or relapsed inflammatory breast cancer.

Lapatinib yielded tumor responses in 39% of women with HER2+ inflammatory breast cancer heavily pretreated with chemotherapy, including trastuzumab (Herceptin), Bella Kaufman, M.D., of the Chaim Sheba Medical Center in Tel Hashomer, Israel, and colleagues found.

In the phase II study, lapatinib responses lasted 20.9 weeks on average, a clinically meaningful effect, the researchers reported online in The Lancet Oncology.

Inflammatory breast cancer is an aggressive type with a higher frequency of HER2 overexpression than other breast cancers (40%).

Treatment is typically multimodal involving neoadjuvant combination chemotherapy followed by surgery, adjuvant chemotherapy, or radiotherapy.

For patients with tumors overexpressing HER2 who are refractory to or fail these treatments, there are currently no other options, Dr. Kaufman’s group noted.

Since lapatinib is a tyrosine kinase inhibitor selective for HER2, the researchers tested its efficacy in a phase II study of 126 patients with relapsed or refractory HER2+ inflammatory breast cancer.

Prior treatment included more than four chemotherapy regimens for 61% of patients, trastuzumab for 75%, and more than three trastuzumab regimens for 9%.

All patients got lapatinib 1,500 mg once a day in a nonrandomized, open-label fashion.

None of the patients had a complete response, defined as disappearance of all measurable disease on combined clinically evaluable skin-disease criteria and RECIST criteria, although one had response as measured by skin disease only.

After a median 12.1 weeks of lapatinib, 39% of the women (95% confidence interval 30% to 48%) met the primary endpoint of an objective response with at least a 50% decrease in the extent of skin disease from baseline.

Looking only at the clinically evaluable skin-disease criteria, the objective response rate was 40% (95% CI 31% to 50%), but the rate by RECIST criteria that included only patients with measurable sites of locally advanced or metastatic disease at baseline was just 15% (95% CI 9% to 24%).

Response rates were lower in patients previously treated with trastuzumab (35% versus 48%). But among those who responded, median overall survival after the first lapatinib dose was not significantly different for those who had prior trastuzumab treatment (18.4 versus 14.0 months).

In fact, patients with prior trastuzumab exposure who responded to lapatinib had the longest survival of any group, followed by those who responded without prior trastuzumab treatment.

“This finding confirms the clinical benefit of targeted therapy in these patients,” Dr. Kaufman’s group said.

Adverse event rates and severity were similar to that seen in prior lapatinib monotherapy studies.

Although 32% of patients had at least one serious adverse event, most were judged to be not treatment related. The most common of these were dyspnea (6%) and pleural effusion (4%).

Five patients (4%) died from adverse events considered to be possibly treatment related: one case of acute hepatitis and abdominal sepsis; one case of dyspnea, cyanosis, and pyrexia; one of pulmonary edema; one of superior mesenteric artery syndrome; and one case of jaundice.

However, the researchers noted, these fatal serious adverse events were also possibly related to underlying disease. “The cause of these events is difficult to discern because of the poor clinical outcome inherent in this heavily pretreated population of patients with inflammatory breast cancer.”

The study was funded by GlaxoSmithKline . Five of the researchers reported being employees or former employees of GlaxoSmithKline and holding stock in the company. One reported serving as a consultant to GlaxoSmithKline for the development of a skin scale of measurement for another trial, receiving travel grants from the company, and having given expert testimony at FDA and Health Canada presentations. Another reported having received honoraria from GlaxoSmithKline .

Primary source: The Lancet Oncology

Source reference:

Kaufman B, et al “Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study” Lancet Oncol 2009; DOI:10.1016/S1470-2045(09)70087-7.

CHICAGO, April 27 — A man’s PSA value at age 60 reliably predicted the risk of fatal prostate cancer over the next 25 years, according to data from a Swedish study.

• Explain to patients that this study showed that a man’s PSA value at age 60 predicted the risk of dying of prostate cancer to age 85.
• The findings require validation in other patient populations.
• Note that this study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Men who had PSA values below the median of ?1 ng/mL had less than a 1% risk of dying of prostate cancer by age 85, Hans Lilja, M.D., of Memorial Sloan-Kettering Cancer Center in New York, reported at the American Urological Association meeting.

At the other end, the risk of fatal prostate cancer soared into double digits in men who had a PSA value of 3 to 4 ng/mL or higher at age 60.

“Sixty-year-old men with PSA at or below the population median can be advised that although they may harbor cancer, it is unlikely to become life threatening,” said Dr. Lilja. “Those with PSA elevated above thresholds such as 3 or 4 ng/mL are at greatly increased risk of clinically diagnosed prostate cancer and prostate cancer-specific death.”

Men with PSA values below those that trigger prostate biopsies have a substantial risk of developing prostate cancer. However, the clinical focus should be on men who have an increased risk of developing symptomatic or fatal prostate cancer, not prostate cancer per se, said Dr. Lilja.

“Screening and chemoprevention in men age 60 and above should focus on subgroups of men with PSA levels strongly associated with symptoms or death,” he asserted.

To investigate the relationship, researchers analyzed data from the Malmo Prevention Project, a study of cardiovascular disease conducted from 1974 to 1986 in Malmo, Sweden. PSA testing was uncommon at that time, but frozen plasma samples from study participants permitted PSA assessment more than two decades later.

The analysis included 1,167 men who were born in 1921 and whose blood samples were obtained during 1981 and 1982. Researchers followed the men until death or age 85, whichever came first.

Dr. Lilja said 133 men (11.4%) developed prostate cancer during follow-up, and 31 men (2.7%) died of prostate cancer.

The median PSA value for the entire study group was 1.06 ng/mL. Men who had PSA values at or below the median at age 60 had a 0.3% risk of prostate cancer death by age 85.

The risk of dying of prostate cancer by age 85 increased to 1.5% in men whose PSA value was 1.5 ng/mL at age 60 (67th percentile). Prostate cancer mortality increased to 3.7% in men who had a PSA level of 2.1 ng/mL at age 60 (80th percentile).

From 2.1 to 3.4 ng/mL (90th percentile), the risk of fatal prostate cancer increased to 8.9%. The risk almost doubled to 15% with a PSA value of 5.2 ng/mL at age 60 (95th percentile) and doubled again to 31% with a PSA value of 15 ng/mL (99th percentile).

Two thirds of prostate cancer deaths involved men who had PSA values ≥3.4 ng/mL. A PSA value of 1.5 ng/mL at age 60 identified 90% of the men who would subsequently die of prostate cancer. The median value for the study population (1.06 ng/mL) comprised 93% of all prostate cancer deaths.

Dr. Lilja said the findings must be reproduced in other populations before they can be applied to clinical practice.

Dr. Lilja and colleagues reported no competing interests.

Primary source: American Urological Association

Source reference:
Vickers AJ, et al “Prostate-specific antigen level at age 60 and death from prostate cancer” AUA 2009; Abstract 162.

CHICAGO, April 28 — Men who were taking statins at the time of radical prostatectomy had a 30% reduction in prostate cancer recurrence, data reported here showed.

Statin users also had lower PSA values and were more likely to have T1 disease than nonusers, Robert J. Hamilton, M.D., of the University of Toronto, said at the American Urological Association meeting.

“Our findings suggest that statins may slow prostate cancer progression after radical prostatectomy,” said Dr. Hamilton. However, he emphasized, “at this point we cannot say with confidence that statins reduce the risk of prostate cancer recurrence after radical prostatectomy.”

He said the findings require confirmation in other studies, such as a randomized controlled trial placing men on statins who are about to undergo surgery.

• Explain to patients that use of statin drugs has been associated with benefits related to several urologic conditions.
• All of the data came from retrospective studies of databases and therefore do not prove that statins are beneficial for the conditions.
• Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Dr. Hamilton’s study was one of a half-dozen statin-related abstracts featured at an AUA press briefing. Collectively, the studies suggested that statins have favorable effects on prostate cancer risk, lower urinary tract symptoms (LUTS), benign prostatic hyperplasia (BPH), and erectile dysfunction.

Dr. Hamilton reported findings from a study of 1,325 men who underwent radical prostatectomy for prostate cancer. Information collected before surgery included current statin use — 237 (18%) men were taking one of the drugs at the time of surgery. The principal outcomes were pathologic features of the cancer and biochemical recurrence.

There were no differences between those taking statins and those not taking the drugs with respect to the frequency of positive surgical margins, seminal vesicle invasion, extracapsular extension, or lymph node metastases. However, significantly more statin users had a Gleason score of 7 (60% versus 49%, P=0.003).

Statin users presented a mixed bag of risk characteristics. They had a lower mean PSA value (6.2 ng/mL versus 6.9 ng/mL, P=0.04), and 67% of statin users had stage T1c disease compared with 58% of nonusers (P=0.009).

On the negative side, statin users were 2 years older and had a higher rate of obesity, as well as the higher proportion of Gleason 7 disease.

In a multivariate analysis, statin users had an odds ratio for recurrence of 0.70 compared with nonusers (95% CI 0.50 to 0.97, P=0.03).

Adding to statins’ association with prostate cancer, Lionel Banez, M.D., of Duke University in Durham, N.C., reported findings from an analysis of obesity, statin use, and tumor inflammation.

Mounting evidence suggests inflammation may play a role in prostate cancer evolution and progression. Obesity has been associated with inflammation and more aggressive cancer, Dr. Banez said. Statins, on the other hand, have well-documented anti-inflammatory activity and have been associated with reduced cancer risk.

Dr. Banez and colleagues reviewed data on 254 men who underwent radical prostatectomy. About half of the patients reported statin use.

One pathologist graded all of the surgical specimens with respect to inflammatory infiltrates.

Significantly more statin users were overweight (48%) and obese (31%, P<0.001). However, increasing body mass index had only a marginal association with inflammation (OR 2.16, P=0.07).

In a multivariate analysis, statin use was associated with a 72% reduction in the risk of tumor inflammation (OR 0.28, P=0.01).

Stacy Loeb, M.D., of Johns Hopkins, summarized findings from a study that examined statin use and tumor characteristics associated with aggressive disease. The study involved 1,282 men who underwent radical prostatectomy from 2003 to 2008 and included 418 patients who reported statin use at the time of surgery.

Statin users had a significantly lower tumor volume, percentage of cancer in the prostatectomy specimen, prevalence of positive surgical margins, and Gleason score of 7 to 10.

Collectively, the findings suggested statin use was associated with more favorable tumor features at prostatectomy.

The remaining studies came from the Mayo Clinic in Rochester, Minn. Rodney Breau, M.D., presented findings from an analysis of 2,427 men who participated in an observational study of prostate cancer. The cohort included 618 statin users.

During a median follow-up of 14.1 years, 75 (12.2%) statin users had a prostate biopsy and 30 (4.9%) had a prostate cancer diagnosis. Compared with nonusers, patients who used statins had more than a 60% reduction in the odds ratio for prostate biopsy and prostate cancer diagnosis.

Among patients who had biennial PSA measurements, statin users were 65% less likely to have PSA values that exceeded age-specific thresholds.

Dr. Breau offered two possible interpretations of the results: The effect of statins on PSA values might account for the lower rates of biopsy and prostate cancer diagnosis. Alternatively, statin use may lower the risk of developing prostate cancer.

Jennifer L. St. Sauver, M.D., reviewed data from a study examining the impact of statins and nonsteroidal anti-inflammatory drugs (NSAIDs) on benign urinary conditions, specifically LUTS and BPH. Records for 2,447 men showed 729 were using statins.

Statin users had a 63% reduction in the odds ratio for moderate or severe LUTS (as defined by AUA symptoms score), a 52% reduction in the frequency of reduced urinary flow, and a 57% reduction in the odds ratio for prostatic enlargement. The magnitude of the reductions increased with duration of statin use, said Dr. St. Sauver. Men who reported taking statins and NSAIDs had even greater reductions in the outcomes assessed.

Ajay Nehra, M.D., presented data from an analysis of statin use and erectile dysfunction (ED) in the same 2,447 men, including 2,075 who had complete data on erectile function and use of phosphodiesterase type 5 (PDE-5) inhibitors.

Dr. Nehra and his colleagues excluded men with ED or PDE-5 inhibitor use at baseline, those who had no regular sexual partner, and those who had a history of prostate cancer, leaving 1,480 for the analysis. Of those, 417 were statin users.

The statin users had a significantly higher prevalence of comorbid conditions that could adversely affect sexual function, including diabetes, hypertension, and coronary disease. Additionally, statin users were significantly more likely to be taking NSAIDs, antidepressants, and drugs to treat LUTS or BPH.

After adjustment age, comorbidities, and medication use, men taking statins had a 37% reduction in the hazard ratio for ED (HR 0.63, 95% CI 0.51 to 0.77).

Moreover, the risk of ED was lowest in men who had taken statins for the longest period of time.

Collectively, the presentations reflected the growing body of literature suggesting that statins influence PSA levels and certain aspects of prostate cancer risk, said J. Brantley Thrasher, M.D., of the University of Kansas in Kansas City, who moderated the press briefing.

However, he said, the studies reported to date have not provided enough information to warrant prescribing statins for prostate cancer or other urologic conditions.

Dr. Banez disclosed relationships with AstraZeneca and Veridex. Dr. Nehra disclosed relationships with GlaxoSmithKline , Pfizer, and sanofi-aventis. Dr. Thrasher disclosed a relationship with sanofi-aventis.

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Primary source: American Urological Association

Source reference:
Hamilton RJ et al “Statin medication use and the risk of biochemical recurrence following radical prostatectomy: results from the SEARCH database” AUA 2009; Abstract 1598.

Additional source: American Urological Association

Source reference:
Banez LL et al. “Association between statins, obesity, and prostate tumor inflammatory infiltrate in men undergoing radical prostatectomy” AUA 2009; Abstract 575.

Additional source: American Urological Association

Source reference:
Loeb S et al. “Is statin use associated with prostate cancer aggressiveness?” AUA 2009; Abstract 576.

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