Prostate Cancer Prevention
Some epidemiological and cohort-controlled studies have shown that several drugs can reduce the risk of prostate cancer, however, these types of studies are not sufficient to prove that patients can benefit from them. For example, the current randomized controlled studies of 5α-reductase inhibitors, vitamins, and selenium, which were not specific to prostate cancer per se, have found these drugs to be effective in preventing prostate cancer.
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a randomized controlled study that evaluated the role of vitamin E, selenium, and the combination of the two in prostate cancer prevention. Unfortunately, this study did not show that patients could benefit from either drug. Many people disagree with the study of vitamin E and selenium, but they were the basis for the SELECT trial.
Now, recent evidence confirms that these drugs have a harmful effect on some men. This study included men with high toenail selenium levels who were randomized to receive selenium (with or without vitamin E) who had a 91% increase in the incidence of high-grade prostate cancer. In addition, men with low selenium levels who were treated with vitamin E alone were at higher risk for total, low-grade and high-grade prostate cancer occurrence.
These findings have two important implications: First, the general public needs to be aware that some herbs, vitamins and supplements can be harmful. Second, these studies suggest that randomized controlled studies should be used to demonstrate the effects of these drugs, rather than drawing conclusions only from epidemiological and uncontrolled cohort studies.
Screening and Early Detection
The seemingly never-ending debate about the risks and benefits of prostate cancer screening is problematic because there are significant differences between the results of scientific studies and what physicians believe to be the correct approach. This year, the U.S. Preventive Services Task Force reiterated that routine screening for prostate cancer is not recommended for men 55-69.
A Canadian task force made a similar recommendation. Both task forces believe the benefits of screening are minimal and can be outweighed by the resulting harm. However both also acknowledge that this recommendation is based on flawed data and therefore the conclusions are not very adequate.
Proponents of screening argue that screening has largely reduced prostate cancer deaths and metastases over the past decade. Therefore, screening should be continued. Proponents also claim that the screening process itself is not problematic, but rather that it is overtreatment for low risk, rather than active surveillance, that is harmful.
Others say that even though the benefits of screening are small for most people, it is still necessary for people at high risk, such as African Americans and those with a family history of prostate cancer. Unfortunately, this view is not supported by data from any randomized clinical trials.
A study from Finland refutes the idea that screening is beneficial for men with a family history of prostate cancer. Researchers found that men with a family history of prostate cancer had a higher risk of being diagnosed with a low-grade tumor and a lower risk of being diagnosed with a high-grade tumor compared to the average risk of developing prostate cancer. Most importantly, screening after 12 years did not improve overall survival or reduce prostate cancer mortality in these men. The researchers therefore concluded that men with a family history of prostate cancer did not appear to benefit from screening.
The limitation of the study is that screening was performed every 4 years, with biopsies performed when prostate-specific antigen (PSA) levels were above 4 ng/mL or between 3 and 3.9 ng/mL and free PSA levels were below 16%. Of course longer follow-up may lead to different results. Unless additional studies are performed, there is no certainty about these results.
Despite attempts to properly assess the impact of screening, the limitations of all studies do not allow us to draw definitive conclusions, which makes patient counseling more challenging. For now, the best practice is to explain the different findings to patients and let them make their own choices.
Treatment of localized early-stage disease
Another ongoing debate is about the choice of treatment for localized early-stage prostate cancer. There are only two relevant randomized studies: the Scandinavian trial and the PIVOT trial, but the results of these two trials are contradictory. Both studies compared two treatment options for localized early-stage prostate cancer (watchful waiting vs. radical resection).
After 12 years of follow-up, the PIVOT trial showed no significant improvement in survival in patients with prostate cancer detected primarily by screening, but a significant reduction in mortality in patients with PSAs levels greater than 10 ng/mL. In contrast, the Scandinavian trial showed that patients who underwent radical prostate cancer surgery had higher overall survival, tumor-specific survival, and a lower risk of metastasis compared to those who did not undergo surgery.
The 18-year follow-up found a 12.7% improvement in overall survival, an 11% reduction in the risk of death, and a 12.2% reduction in the incidence of metastases in the surgical group. Patients younger than 65 years of age and those with intermediate-risk prostate cancer benefited the most, while overall survival and tumor-specific survival did not improve significantly in men older than 65 years.
Comparing the two studies is difficult because only a small percentage of patients with tumors in the Scandinavian trial were screened, with a mean PSA of 13 ng/mL, compared with a mean PSA of 7.8 ng/mL in the PIVOT trial. in addition, the Scandinavian trial had a longer follow-up period, and the PIVOT trial was more likely to find tumors that were not life-threatening.
In any case, radical resection of prostate cancer can significantly reduce mortality for some people, and the question is how to identify the right people for the procedure. Genetic testing may provide a solution. We hope that other studies will provide more information to identify patients who are better able to benefit from surgery.
Treatment of Locally Progressive Disease
The treatment of locally progressive disease has been intensively studied in the past few years. The combination of androgen deprivation therapy (ADT) and radiation therapy has been reported to improve overall survival compared to radiation therapy alone. Ongoing research is focused on determining the optimal duration of ADT to improve survival and reduce morbidity. Other experts question the need for radiation therapy.
A Scandinavian study affirmed the value of combining radiotherapy and ADT. Subjects received 3 months of combined ADT (with flutamide plus leuprolide) followed by daily flutamide. 3 months later, subjects were randomly assigned to the radiotherapy and non-radiotherapy groups. The 10-year mortality rate for prostate cancer was 39.4% in the non-radiotherapy group compared to 29.6% in the radiotherapy group.
The need for combined ADT and radiotherapy in patients with locally advanced disease is now well established. However, the optimal duration of ADT remains unanswered.
Metastatic lesion treatment
The treatment of metastatic prostate cancer has improved significantly over the past few years thanks to the availability of several effective new drugs, but new challenges have also been presented. So far this year, the U.S. Food and Drug Administration has approved the use of enzalutamide before chemotherapy based on the results of the PREVAIL trial. The new study showed that the drug improved overall survival by 29% and progression-free survival on imaging by 81% compared to placebo.
Other approved pre-chemotherapy agents are abiraterone plus prednisone, prostate cancer vaccine (sipuleucel-T) and radium 223. Further studies are needed to determine which patients will benefit from these therapies and to find the optimal sequence of drug use.
Another trial (the CHAARTED study) compared the efficacy of ADT alone with that of combined docetaxel and found that the mean survival time increased from 42.3 months to 52.7 months after combined chemotherapy. In patients defined as having multiple metastases (at least four in bone or soft tissue), survival time rose by 17 months.
This study was well done, but because it was conducted before the new therapy was approved, it did not use standard methods to assess progression in the control group. So we don’t know if combining docetaxel and ADH after disease progression is better than using ADH and docetaxel at the beginning. But the bottom line is that we should inform patients with metastases of the results of the CHAARTED study as well as other effective approaches.