Gerald Chodak, MD; December 11, 2014
The year 2014 has again provided important developments in the area of prostate cancer. New data and new treatments span the spectrum of prostate cancer management, from prevention and screening to optimal strategies for localized, locally advanced, and metastatic disease.
The SELECT trial[1] was a randomized controlled study designed to evaluate vitamin E, selenium, and the two in combination in the prevention of prostate cancer. Unfortunately, this study failed to show a benefit from either supplement. Many people were critical of the choice of vitamin E and selenium; these agents were chosen because they had been used in the studies that formed the basis for the SELECT trial.
Now, an update[2] of this study has shown that these agents actually harmed some men. Men with high levels of toenail selenium upon entering the study and who were randomly assigned to receive selenium (either with or without vitamin E) had a 91% increase in high-grade prostate cancer. In addition, men with low selenium levels who received vitamin E alone had a significantly increased risk for total, low-grade, and high-grade prostate cancer.
These findings have two important implications. First, the public needs to recognize that it is false to assume herbs, vitamins, and supplements cannot cause harm. Second, this study again illustrates the importance of properly testing supplements in randomized trials rather than making conclusions from epidemiologic or uncontrolled case studies.
Proponents of screening argue that screening has partly contributed to the significant decline in the death rate from prostate cancer and the lower incidence of metastatic disease at the time of diagnosis over the past 10 years, and therefore screening should continue to be offered. Proponents also contend that screening is not the problem; rather, it is the excess harm resulting from treating too many men with low-risk disease instead of placing them on active surveillance. Still others say that even if the benefit is negligible for the average man, screening should continue for high-risk individuals, such as African American men and those with a family history of prostate cancer. Unfortunately, that view is not based on any randomized data proving a benefit.
New data from Finland[5] challenge the belief that screening men with a family history is beneficial. Finland contributed the largest number of men to the European screening trial.[6] In a recent subanalysis of their results, investigators found that men with a family history of prostate cancer had an increased risk of being diagnosed with low-grade cancer but a decreased risk of being diagnosed with high-grade disease, compared with men with an average risk of developing the disease. Most important, after 12 years, screening these men did not improve overall survival or reduce prostate cancer mortality. These researchers concluded that men with a family history of prostate cancer are not more likely to benefit from screening.
The limitations of the study are that testing was conducted every 4 years, and the men underwent biopsy if the prostate-specific antigen (PSA) level was higher than 4 ng/mL or between 3 and 3.9 ng/mL and the free PSA level was less than 16%. Of course, longer follow-up may lead to different results. Unless other studies are conducted, the concerns about these results cannot be addressed. This study further demonstrates the importance of not making recommendations in the absence of supporting data.
Despite attempts to properly assess the impact of screening, limitations of all the studies have left us with inconclusive results, making counseling patients very challenging. For now, the best course of action is to explain the findings from the various studies so that men can decide what they want to do.
After 12 years of follow-up, the PIVOT trial showed a 2.6% nonsignificant improvement in survival in men whose prostate cancer was detected primarily by screening. However, a significant reduction in mortality was detected in men with PSAs greater than 10 ng/mL.
By contrast, the Scandinavian trial reported updated 18-year results showing that men who underwent radical prostatectomy had significantly better overall survival, better cancer-specific survival, and a lower risk for metastatic disease than those who did not undergo surgery. The surgery group had a 12.7% higher overall survival an 11% lower risk of dying from prostate cancer, and a 12.2% lower chance of developing metastatic disease at 18-year follow-up. The benefit was greatest in men younger than 65 years of age and those with intermediate-risk prostate cancer. The men older than 65 years, however, had no improvement in overall survival or cancer-specific survival.
Comparisons between the two studies are difficult because only a small proportion of cancers in the men in the Scandinavian trial were detected by screening and the mean PSA was 13 ng/mL, compared with a median PSA of 7.8 ng/mL in the PIVOT trial. In addition, the duration of follow-up was longer in the Scandinavian study, and the PIVOT trial was more likely to have found more non–life-threatening tumors.
Regardless, radical prostatectomy is clearly lowering mortality for some men; the challenge is to identify who they are. Genetic testing is improving and may offer a solution. We hope that other studies in progress will provide important information about the relative benefits of radical prostatectomy.
A Scandinavian study[9] provided additional support for the value of including radiation with ADT. Men received 3 months of combined ADT using flutamide plus leuprolide, followed by daily flutamide. After the 3 months, these men were randomly assigned to receive radiation or no radiation. Prostate cancer mortality at 10 years was 39.4% for the ADT alone group vs. 29.6% for the men who also received radiation.
It is now clear that men with locally advanced disease need both ADT and radiation to maximize survival. The question of the optimal duration of ADT remains unanswered, however.
Other prechemotherapy treatments already approved include abiraterone plus prednisone, sipuleucel-T, and radium-223. Important studies are needed to identify which patients do or do not benefit from these therapies and what is the best way to sequence the drugs.
Another trial, the CHAARTED study,[11] compared ADT alone or in combination with docetaxel and found that chemotherapy improved median survival from 42.3 months to 52.7 months. In the men defined as having high-volume metastases (at least four bone or soft-tissue metastases), the improvement in survival was 17 months.
The study was well done, but because it began before the approval of the newer therapies, no standard approach was used to address progression in men in the control group. Therefore, we do not know whether using docetaxel along with ADT and delaying the use of these other options until the disease progresses would really be better than beginning with ADT, following with some sequence of these new treatments and then instituting docetaxel. The bottom line is that patients with metastases should be informed of the results from the CHAARTED study and the availability of the other therapies.
In summary, important studies were reported in 2014 that have significant implications for counseling men faced with detection or treatment of prostate cancer. We look forward to even more progress in the year ahead.
Prostate Cancer Prevention
Epidemiologic and case-control studies have suggested that several agents may lower the risk for prostate cancer; however, these types of studies are not sufficient to prove benefit. Randomized controlled trials have been conducted with 5-alpha reductase inhibitors, vitamin E, and selenium. For example, studies that were not designed specifically for prostate cancer suggested these agents were effective in preventing prostate cancer.The SELECT trial[1] was a randomized controlled study designed to evaluate vitamin E, selenium, and the two in combination in the prevention of prostate cancer. Unfortunately, this study failed to show a benefit from either supplement. Many people were critical of the choice of vitamin E and selenium; these agents were chosen because they had been used in the studies that formed the basis for the SELECT trial.
Now, an update[2] of this study has shown that these agents actually harmed some men. Men with high levels of toenail selenium upon entering the study and who were randomly assigned to receive selenium (either with or without vitamin E) had a 91% increase in high-grade prostate cancer. In addition, men with low selenium levels who received vitamin E alone had a significantly increased risk for total, low-grade, and high-grade prostate cancer.
These findings have two important implications. First, the public needs to recognize that it is false to assume herbs, vitamins, and supplements cannot cause harm. Second, this study again illustrates the importance of properly testing supplements in randomized trials rather than making conclusions from epidemiologic or uncontrolled case studies.
Screening and Early Detection
The debate about the risks and benefits of screening for prostate cancer seems unending, with a major disconnect between what science has shown us and what many clinicians believe is the right thing to do. This year, the US Preventive Services Task Force reiterated its recommendations against routine screening for prostate cancer.[3] A Canadian task force has made a similar recommendation.[4] Both groups concluded that the benefits of screening are small at best, and they are outweighed by the harms. Both also acknowledge, however, that the recommendation not to screen men 55-69 years of age is based on somewhat flawed data, which results in less than robust conclusions.Proponents of screening argue that screening has partly contributed to the significant decline in the death rate from prostate cancer and the lower incidence of metastatic disease at the time of diagnosis over the past 10 years, and therefore screening should continue to be offered. Proponents also contend that screening is not the problem; rather, it is the excess harm resulting from treating too many men with low-risk disease instead of placing them on active surveillance. Still others say that even if the benefit is negligible for the average man, screening should continue for high-risk individuals, such as African American men and those with a family history of prostate cancer. Unfortunately, that view is not based on any randomized data proving a benefit.
New data from Finland[5] challenge the belief that screening men with a family history is beneficial. Finland contributed the largest number of men to the European screening trial.[6] In a recent subanalysis of their results, investigators found that men with a family history of prostate cancer had an increased risk of being diagnosed with low-grade cancer but a decreased risk of being diagnosed with high-grade disease, compared with men with an average risk of developing the disease. Most important, after 12 years, screening these men did not improve overall survival or reduce prostate cancer mortality. These researchers concluded that men with a family history of prostate cancer are not more likely to benefit from screening.
The limitations of the study are that testing was conducted every 4 years, and the men underwent biopsy if the prostate-specific antigen (PSA) level was higher than 4 ng/mL or between 3 and 3.9 ng/mL and the free PSA level was less than 16%. Of course, longer follow-up may lead to different results. Unless other studies are conducted, the concerns about these results cannot be addressed. This study further demonstrates the importance of not making recommendations in the absence of supporting data.
Despite attempts to properly assess the impact of screening, limitations of all the studies have left us with inconclusive results, making counseling patients very challenging. For now, the best course of action is to explain the findings from the various studies so that men can decide what they want to do.
Treatment of Localized Disease
Another ongoing controversy involves the impact of treating men with localized prostate cancer. The only two randomized studies reporting results are the Scandinavian trial[7] and the PIVOT trial,[8] with conflicting findings. Both studies compared watchful waiting with radical prostatectomy for localized prostate cancer.After 12 years of follow-up, the PIVOT trial showed a 2.6% nonsignificant improvement in survival in men whose prostate cancer was detected primarily by screening. However, a significant reduction in mortality was detected in men with PSAs greater than 10 ng/mL.
By contrast, the Scandinavian trial reported updated 18-year results showing that men who underwent radical prostatectomy had significantly better overall survival, better cancer-specific survival, and a lower risk for metastatic disease than those who did not undergo surgery. The surgery group had a 12.7% higher overall survival an 11% lower risk of dying from prostate cancer, and a 12.2% lower chance of developing metastatic disease at 18-year follow-up. The benefit was greatest in men younger than 65 years of age and those with intermediate-risk prostate cancer. The men older than 65 years, however, had no improvement in overall survival or cancer-specific survival.
Comparisons between the two studies are difficult because only a small proportion of cancers in the men in the Scandinavian trial were detected by screening and the mean PSA was 13 ng/mL, compared with a median PSA of 7.8 ng/mL in the PIVOT trial. In addition, the duration of follow-up was longer in the Scandinavian study, and the PIVOT trial was more likely to have found more non–life-threatening tumors.
Regardless, radical prostatectomy is clearly lowering mortality for some men; the challenge is to identify who they are. Genetic testing is improving and may offer a solution. We hope that other studies in progress will provide important information about the relative benefits of radical prostatectomy.
Treatment of Locally Advanced Disease
The management of locally advanced disease has been well studied in previous years, with reports demonstrating that combining androgen deprivation therapy (ADT) with radiation results in improved overall survival compared with radiation alone. Ongoing work has been directed at determining the optimal duration of ADT, to improve survival while minimizing morbidity. Some experts have questioned whether the radiation is really necessary.A Scandinavian study[9] provided additional support for the value of including radiation with ADT. Men received 3 months of combined ADT using flutamide plus leuprolide, followed by daily flutamide. After the 3 months, these men were randomly assigned to receive radiation or no radiation. Prostate cancer mortality at 10 years was 39.4% for the ADT alone group vs. 29.6% for the men who also received radiation.
It is now clear that men with locally advanced disease need both ADT and radiation to maximize survival. The question of the optimal duration of ADT remains unanswered, however.
Treatment of Metastatic Disease
The management of men with metastatic prostate cancer has improved substantially during the past few years because of the availability of new drugs, but this has also presented new challenges. This year, the US Food and Drug Administration approved the use of enzalutamide before chemotherapy. Approval was based on results of the PREVAIL trial. Updated results[10] demonstrate that the drug improved overall survival by 29% and radiographic progression-free survival by 81% compared with placebo.Other prechemotherapy treatments already approved include abiraterone plus prednisone, sipuleucel-T, and radium-223. Important studies are needed to identify which patients do or do not benefit from these therapies and what is the best way to sequence the drugs.
Another trial, the CHAARTED study,[11] compared ADT alone or in combination with docetaxel and found that chemotherapy improved median survival from 42.3 months to 52.7 months. In the men defined as having high-volume metastases (at least four bone or soft-tissue metastases), the improvement in survival was 17 months.
The study was well done, but because it began before the approval of the newer therapies, no standard approach was used to address progression in men in the control group. Therefore, we do not know whether using docetaxel along with ADT and delaying the use of these other options until the disease progresses would really be better than beginning with ADT, following with some sequence of these new treatments and then instituting docetaxel. The bottom line is that patients with metastases should be informed of the results from the CHAARTED study and the availability of the other therapies.
In summary, important studies were reported in 2014 that have significant implications for counseling men faced with detection or treatment of prostate cancer. We look forward to even more progress in the year ahead.