Recent evidence suggests that androgen suppression therapy increases the risk of cardiovascular events in men of advanced age, lead author Dr. Anthony V. D’Amico of Brigham and Women’s Hospital in Boston and his associates note.

To examine the interaction between comorbidity and treatment outcome, they obtained long-term follow-up data from a trial in which men with prostate cancer had been randomly assigned to receive radiation therapy alone or radiation therapy and androgen suppression therapy combined.

The study included 206 patients, median age 72.5 years, with localized prostate cancer and at least one of four unfavorable prognostic factors – PSA > 10 ng/mL, a biopsy Gleason score of 7-10, extracapsular extension, or seminal vesicle invasion. At baseline between 1995 and 2001, subjects were randomized to external beam radiation therapy alone or in combination with 6 months of androgen suppression therapy.

The authors determined comorbidity scores based on the severity of several clinically relevant ailments present at baseline.

Seventy-four men died during median follow-up of 7.6 years. For the group as a whole, the risk of all-cause mortality was significantly increased in the radiation therapy group (44 vs 30 deaths, hazard ratio 1.8, p = .01).

“However, the increased risk in all-cause mortality appeared to apply only to men randomized to radiation therapy with no or minimal comorbidity” (31 vs 11 deaths; HR 4.2, p < .001), Dr. D’Amico’s team reports.

For those with moderate or severe comorbidity, mortality rates did not differ significantly between treatment groups (13 vs 19 deaths, HR 0.54, p = .08).

“The clinical significance of this finding is that preexisting comorbid illness may increase the negative effects of specific anticancer treatments such as androgen suppression therapy,” Dr. D’Amico and his associates suggest.

As their study was a hypothesis-generating, post-randomization subgroup analysis, they recommend the findings be verified in a clinical trial specifically designed to assess the interaction of comorbidity with androgen suppression therapy treatment.

Furthermore, they add, studies should be designed to identify the impact of specific comorbid illnesses on life expectancy and health-related quality of life.

“To offer the patient a better evaluation of his prostate gland, the physician should perform the DRE as well as the PSA test,” Dr. William J. Catalona from Northwestern University Feinberg School of Medicine, Chicago, said.

Dr. Catalona and colleagues compared clinical variables and survival outcomes between patients diagnosed with prostate cancer by DRE alone versus those diagnosed by PSA level, regardless of DRE findings.

Of 2233 men who were diagnosed with prostate cancer and underwent radical prostatectomy, 303 (14%) were diagnosed on the basis of DRE alone, 1426 (64%) on the basis of PSA alone, and 504 (22%) based on abnormalities of both tests, the authors report.

Eighteen percent of men who underwent a prostate biopsy because of abnormal DRE findings alone were diagnosed with prostate cancer.

Twenty percent of cancers detected by DRE alone were nonorgan-confined, 20% had a Gleason score of 7 or higher, 16% had positive surgical margins, 3% had seminal vesicle invasion, and 1.3% had lymph node metastases.

Adverse pathology was significantly more likely in men with abnormalities in both DRE and PSA than in those detected by either test alone, the researchers say.

Ten-year progression-free survival was similar for cancers detected by DRE only (83%) or PSA only (82%), but significantly lower for cancers detected by abnormalities in both DRE and PSA (63%), the investigators note. Similar results were seen for overall survival and cancer-specific survival.

“Eliminating DRE from screening protocols would miss a significant proportion of patients with a clinically important and potentially curable prostate cancer,” the authors conclude.

However, “it may be reasonable to avoid DRE in men with a PSA level less than 1 ng/mL,” they add.

“PSA testing and DRE must be continued on a regular (annual) basis to be most effective, and persistent changes over time are as important as the absolute findings at any one point in time,” Dr. Catalona said.

The update of the TAX 327 study, which compared D3P to a weekly docetaxel treatment with prednisone (D1P) and with mitoxantrone plus prednisone (MP), was published in the January 10 issue of the Journal of Clinical Oncology.

TAX 327 enrolled 1,006 patients from 24 countries between March 2000 and June 2002. When the original analysis was done in August 2003, 557 deaths had occurred. The D3P arm was found have a median survival time of 18.9 months, versus 17.4 months for the D1P arm and 16.5 months for the MP arm (P = 0.009 for D3P versus MP).

Updated median survival times were 19.2 months for the D3P arm, 17.8 months for the D1P arm and 16.3 months for the MP arm. The p value for D3P versus MP, 0.004, was slightly stronger than in the earlier analysis. Similar trends were seen in subgroup analysis between patients older and younger than the median age of 68.

“The docetaxel every 3 weeks regimen was very well tolerated in this elderly patient population,” Dr. Ronald de Wit, of the Erasmus University Medical Center, Rotterdam, The Netherlands, said. “The most uncomfortable side effects are hair loss and fatigue.”

The incidence of serious toxicity in all courses of treatment was less than 5%, with the exception of neutropenia, Dr. de Wit said.

The researchers concluded that “docetaxel administered every 3 weeks with prednisone remains the preferred treatment option for most patients with metastatic hormone-resistant prostate cancer. The consistency of results among subgroups indicates rigorous data.”

As clear as these results are, they are likely somewhat understated, Dr. de Wit said. “Since docetaxel was commercially available (for other indications, such as breast cancer), up to 30% of patients crossed over to docetaxel after they had disease progression on mitoxantrone, and even despite the confounding effect by this frequent cross-over to the superior treatment, a significant benefit in the docetaxel q3 weekly arm was obtained.”

“The detection of short circulating DNA fragments in patients’ serum allows distinguishing of prostate cancer patients and patients with benign prostate hyperplasia — including healthy controls — sensitively and specifically,” lead investigator Dr. Jorg Ellinger said.

Dr. Ellinger, of University Clinic Bonn, and colleagues studied 168 patients with prostate cancer, 5 with incidental prostate cancer, 42 patients with benign prostatic hyperplasia (BPH) and 11 healthy controls.

Distinctively more elevated median concentrations of cell-free PTS2 fragments were seen in the cancer patients (70.2 ng/mL) than in the BPH group (10.5 ng/mL) or controls (7.1 ng/mL). The apoptosis index (AI) was also significantly increased in the cancer patients.

The concentration of PTGS2 fragments allowed discrimination of prostate cancer from BPH with a sensitivity of 88% and a specificity of 64%. Corresponding proportions using the AI were 70% and 82%.

Thus, continued Dr. Ellinger, “the diagnostic information of cell-free DNA fragments was well above the diagnostic information of prostate specific antigen testing in our patient cohort.”

“Furthermore, patients with increased levels of cell-free DNA had a shorter period of PSA-recurrence free survival following radical prostatectomy.”

“These data indicate that cell-free DNA may be a valuable diagnostic and prognostic marker, but further validation in prospective studies is necessary,” he concluded.

The risk of prostate cancer in older age ranged from 1.0% to 7.5% if the mid-life tPSA was 0.5 ng/mL or lower, the investigators report in the February 1st issue of the Journal of Clinical Oncology.

Men with a tPSA of 0.51 to 1.0 ng/ml had a 2.5-fold increase in prostate cancer risk compared with men with tPSA levels of 0.5 ng/ml and lower.

Men with tPSA levels of 2.0 to 3.0, which are often considered within the normal range, had a more than 19-fold increase in prostate cancer risk compared with men with tPSA levels of 0.5 ng/ml and lower.

Free PSA and hK2 levels at baseline were also significant predictors of prostate cancer.

“The current data suggest that early biochemical changes (ie, slightly increased release of PSA and hK2 into blood) indicate a predisposition to prostate cancer that may be detectable two decades before the disease is diagnosed clinically,” Dr. Lilja and colleagues conclude.

They caution that “recommendations to undergo biopsy on the basis of our findings would be premature, given that biopsies performed 15 to 25 years before the cancer would otherwise be diagnosed may not be informative.”

“Our data strongly suggest that we should encourage all men to get a PSA test at age 45 to 50, not to try to detect cancer, but to work out their long-term cancer risk,” Dr. Lilja said.

“We should now focus our subsequent screening efforts on the men at highest risk, spending our time and energy making sure that these men come in for regular screening (e.g. yearly) and making sure that they get the very best tests available. Men at lower risk of cancer may not require such intensive screening.”

Dr. Hans Lilja, from Memorial Sloan-Kettering Cancer Center in New York, and colleagues analyzed the long-term predictive power of total PSA, free PSA, and human kallikrein 2 levels measured between the ages of 44 and 50 years in 21,277 men enrolled in the Malmo (Sweden) Preventive Project between 1974 and 1986. The analysis focused on the 498 patients who developed prostate cancer during follow-up through 1999, and on 1222 matched control patients who did not.

Cancer risk was 1.0% to 7.5% for men with a total PSA of 0.5 ng/mL or lower, the investigators report in the February 1st issue of the Journal of Clinical Oncology.

At follow-up, up to 25 years later, men with a total PSA of 0.51 to 1.0 ng/mL had a 2.51-fold increase in prostate cancer risk compared with men with levels of 0.5 ng/mL or lower.

Men with total PSA levels of 2.01 to 3.00 ng/mL, which are often considered within the normal range, had a 19.1-fold increase in prostate cancer risk compared with men who had levels of 0.5 ng/mL or lower.

Free PSA and human kallikrein 2 levels in middle age were also significant predictors of prostate cancer later on, the report indicates. However, in predicting the long-term risk of prostate cancer, these measures did not provide useful information beyond that obtained with total PSA testing alone.

“The current data suggest that early biochemical changes (ie, slightly increased release of PSA and human kallikrein 2 into blood) indicate a predisposition to prostate cancer that may be detectable two decades before the disease is diagnosed clinically,” Dr. Lilja and colleagues conclude.

They caution that “recommendations to undergo biopsy on the basis of our findings would be premature, given that biopsies performed 15 to 25 years before the cancer would otherwise be diagnosed may not be informative.”

“Our data strongly suggest that we should encourage all men to get a PSA test at age 45 – 50, not to try to detect cancer, but to work out their long-term cancer risk,” Dr. Lilja said.

“We should now focus our subsequent screening efforts on the men at highest risk, spending our time and energy making sure that these men come in for regular screening (e.g. yearly) and making sure that they get the very best tests available. Men at lower risk of cancer may not require such intensive screening.”

In the journal Clinical Cancer Research, they report that low doses of the COX-2 inhibitor celecoxib (sold as Celebrex), given along with a green tea polyphenol slowed the growth of prostate cancer in cell cultures and in a mouse model of the disease.

“Celecoxib and green tea have a synergistic effect, each triggering cellular pathways, that, combined, are more powerful than either agent alone,” Dr. Hasan Mukhtar from the University of Wisconsin, Madison, said in a statement.

Prior studies have linked the COX-2 enzyme to many cancer types, including prostate cancer. Mukhtar and colleagues previously found that COX-2 inhibitors like Celebrex suppress prostate cancer in animals. COX-2 inhibitors also have been shown to have adverse effects on the heart when taken at high doses for long periods of time.

Mukhtar’s team also previously found that the green tea polyphenol called EGCG has cancer-fighting abilities of its own; EGCG, they found, modulates key chemical pathways that fuel the death of human prostate cancer cells.

In their current studies, treatment of cultured human prostate cancer cells with either a COX-2 inhibitor or green tea extract significantly inhibited prostate cancer cell growth, but the combination was most effective, increasing cancer inhibition 15 percent to 28 percent more than the additive effects of the two therapies alone.

Similar results were obtained in a mouse model of human prostate cancer, with the Celebrex plus green tea combination inhibiting the growth of prostate tumors by 81 percent, compared with 42 percent with green tea extract alone and 57 percent with Celebrex alone.

This is the first time a synergism between these agents against prostate cancer cells has been demonstrated, the authors say.

“Prostate cancer typically arises from more than one defect in the cellular mechanics, which means that a single therapeutic might not work fighting a particular cancer long-term,” Mukhtar said. “If tests in human trials replicate these results, we could see a powerful combination therapy that is both simple to administer and relatively cost effective.”

It’s worth noting that the dose of Celebrex used in the studies translates into about 200 milligrams per day, which is much lower than the typical colon cancer prevention trials where doses of up to 800 milligrams per day were used.

Because of this, lead investigator Dr. David A. Katz said, “the psychological consequences of screening are non-trivial and should be accounted for in evaluating the risks and benefits of screening in the general population.”

Using data collected in a telephone survey, Dr. Katz, of the VA Iowa City Health Care System, and colleagues, further evaluated 109 men who had had abnormal prostate cancer screening tests, but negative biopsy findings, and 101 men with normal screening results, who served as controls.

The false-positive patients rated their concern about having prostate cancer as 4.5 on a 5-point scale. This was significantly higher than the 3.9 rating given by controls. These patients also perceived their risk of prostate cancer as being significantly greater than did controls.

In addition, 19% of the patients reported that sexual function was a “moderate to big” problem, compared with 10% of controls, researchers report in the February issue of Urology.

Summing up, Dr. Katz noted that “although it is often difficult to integrate counseling about screening into busy primary care practices, men need to understand the pros and cons of prostate cancer screening, and in particular, the limitations of the PSA test.”

“To reduce patient anxiety,” he concluded, “men with abnormal test results should receive prompt work-up and should be offered counseling if they have persistent worry despite having a negative prostate biopsy.”

“Patients with the most aggressive non-metastatic prostate cancers — Gleason scores 8-10 — if treated with prostatectomy or radiation, can expect to live more than 14 years,” lead investigator Dr. Ashutosh Tewari said. “Those treated conservatively will live, on average, less than 7 years.”

Dr. Tewari and associates at New York Presbyterian Hospital, Weill Medical College of Cornell University conducted a retrospective study of 453 prostate cancer patients with a Gleason score of 8 or higher. The findings are reported in the March issue of the Journal of Urology.

Of this group, 197 (44%) were treated conservatively, 137 (30%) received radiation therapy and 119 (26%) underwent radical prostatectomy. Corresponding median overall survival times were 5.2, 6.7 and 9.7 years.

Median cancer-specific survival was 7.8 years for conservative therapy and more than 14 years for radiation therapy and radical prostatectomy. “The risk of cancer-specific death following radical prostatectomy was 68% lower than for conservative treatment and 49% lower than for radiation therapy,” Dr. Tewari’s group found.

The researchers conclude that “even high-grade cancers are potentially curable. Retrospectively, there is a significant difference in long-term outcome among patients undergoing conservative treatment, radiation therapy and radical prostatectomy.”

“Men who have undergone potentially curative treatment for prostate cancer but also suffer from severe effects of hypogonadism may benefit from a trial of testosterone replacement, with close monitoring of the PSA,” Dr. Michael F. Sarosdy from South Texas Urology and Urologic Oncology, San Antonio, said. “In our experience, most have done well.”

Dr. Sarosdy investigated the long-term effects of TRT in 31 men after treatment for prostate cancer using brachytherapy. The findings are published in the February 1st issue of Cancer.

TRT was begun a median 2.0 years after brachytherapy, the report indicates. Treatment with testosterone ranged from 0.5 years to 8.5 years (median, 4.5 years).

Only one patient showed any rises in PSA after TRT, and all rises were followed by declines. Three quarters of patients had PSA values below 0.1 ng/mL at last follow-up, and all 31 patients had PSA values below 1.0 ng/mL.

None of the patients had to stop using TRT because of possible or confirmed recurrence or progression of prostate cancer.

“TRT in these patients should be driven by presence of symptoms of low testosterone, not simply a low testosterone blood test,” Dr. Sarosdy said.

“Until more confirmatory data are available, those with low testosterone but no major hypogonadal symptoms should probably be followed rather than treated, as we’ve done in such patients.”

“A randomized trial might be scientifically desirable, but given the lack of substantial numbers of events or failures in this report, such a study would likely have to include a thousand or more patients to reach valid endpoints,” Dr. Sarosdy added.