Prostate Cancer

Background/Purpose: Dysregulation of osteoclast activity and uncontrolled bone resorption are hallmarks of multiple myeloma and metastatic prostate cancer, predisposing patients to net bone loss and pathologic fractures. Zoledronic acid, a bisphosphonate, induces osteoclast apoptosis and reduces bone resorption, reducing fracture risk, but the optimal dosing interval is the subject of current clinical debate. Historically, the standard dosing interval has been every 4 weeks, but recent research demonstrated no difference in the rate of skeletal-related events (SREs)—fracture, spinal compression, bone irradiation, or surgery—when zoledronic acid was dosed every 12 weeks. The primary objective of this study was to determine if extending the zoledronic acid dosing interval would increase the incidence of SREs in a Veteran population.

Methods: Retrospective observational analysis of multiple myeloma and prostate cancer patients who received zoledronic acid. Patients were stratified by zoledronic acid dosing interval (standard or extended). Baseline data, duration of treatment, type and incidence of SREs, and incidence of osteonecrosis of the jaw (ONJ) were determined for each group. Pearson’s chi-square test was used to determine statistical significance.

Results: One hundred twenty-three patients were eligible for inclusion based on prespecified criteria. No difference in the rate of SREs was found between the standard- and extended-interval dosing groups (30.6% vs 22.9%, P = 0.374). All instances of ONJ occurred in the standard-interval dosing group, but the difference in incidence between groups was not statistically significant (2.5% vs 0%, P = .347). Subgroup analysis did not reveal a difference between multiple myeloma and metastatic prostate cancer in the incidence of SREs (42.9% vs 14.3%, P = .172; and 28% vs 25%, P = .753, respectively) or ONJ (4.8% vs 0%, P = .451; and 2% vs 0%, P = .577, respectively).

Conclusions/Impliacations: Based on our results, extending the zoledronic acid dosing interval does not increase the incidence of SREs. Dosing zoledronic acid every three months offers a potential avenue to increase Veteran compliance and decrease the chance for adverse drug reactions without compromising therapeutic benefit.

Background/Purpose: Dysregulation of osteoclast activity and uncontrolled bone resorption are hallmarks of multiple myeloma and metastatic prostate cancer, predisposing patients to net bone loss and pathologic fractures. Zoledronic acid, a bisphosphonate, induces osteoclast apoptosis and reduces bone resorption, reducing fracture risk, but the optimal dosing interval is the subject of current clinical debate. Historically, the standard dosing interval has been every 4 weeks, but recent research demonstrated no difference in the rate of skeletal-related events (SREs)—fracture, spinal compression, bone irradiation, or surgery—when zoledronic acid was dosed every 12 weeks. The primary objective of this study was to determine if extending the zoledronic acid dosing interval would increase the incidence of SREs in a Veteran population.

Methods: Retrospective observational analysis of multiple myeloma and prostate cancer patients who received zoledronic acid. Patients were stratified by zoledronic acid dosing interval (standard or extended). Baseline data, duration of treatment, type and incidence of SREs, and incidence of osteonecrosis of the jaw (ONJ) were determined for each group. Pearson’s chi-square test was used to determine statistical significance.

Results: One hundred twenty-three patients were eligible for inclusion based on prespecified criteria. No difference in the rate of SREs was found between the standard- and extended-interval dosing groups (30.6% vs 22.9%, P = 0.374). All instances of ONJ occurred in the standard-interval dosing group, but the difference in incidence between groups was not statistically significant (2.5% vs 0%, P = .347). Subgroup analysis did not reveal a difference between multiple myeloma and metastatic prostate cancer in the incidence of SREs (42.9% vs 14.3%, P = .172; and 28% vs 25%, P = .753, respectively) or ONJ (4.8% vs 0%, P = .451; and 2% vs 0%, P = .577, respectively).

Conclusions/Impliacations: Based on our results, extending the zoledronic acid dosing interval does not increase the incidence of SREs. Dosing zoledronic acid every three months offers a potential avenue to increase Veteran compliance and decrease the chance for adverse drug reactions without compromising therapeutic benefit.

Background/Purpose: Dysregulation of osteoclast activity and uncontrolled bone resorption are hallmarks of multiple myeloma and metastatic prostate cancer, predisposing patients to net bone loss and pathologic fractures. Zoledronic acid, a bisphosphonate, induces osteoclast apoptosis and reduces bone resorption, reducing fracture risk, but the optimal dosing interval is the subject of current clinical debate. Historically, the standard dosing interval has been every 4 weeks, but recent research demonstrated no difference in the rate of skeletal-related events (SREs)—fracture, spinal compression, bone irradiation, or surgery—when zoledronic acid was dosed every 12 weeks. The primary objective of this study was to determine if extending the zoledronic acid dosing interval would increase the incidence of SREs in a Veteran population.

Methods: Retrospective observational analysis of multiple myeloma and prostate cancer patients who received zoledronic acid. Patients were stratified by zoledronic acid dosing interval (standard or extended). Baseline data, duration of treatment, type and incidence of SREs, and incidence of osteonecrosis of the jaw (ONJ) were determined for each group. Pearson’s chi-square test was used to determine statistical significance.

Results: One hundred twenty-three patients were eligible for inclusion based on prespecified criteria. No difference in the rate of SREs was found between the standard- and extended-interval dosing groups (30.6% vs 22.9%, P = 0.374). All instances of ONJ occurred in the standard-interval dosing group, but the difference in incidence between groups was not statistically significant (2.5% vs 0%, P = .347). Subgroup analysis did not reveal a difference between multiple myeloma and metastatic prostate cancer in the incidence of SREs (42.9% vs 14.3%, P = .172; and 28% vs 25%, P = .753, respectively) or ONJ (4.8% vs 0%, P = .451; and 2% vs 0%, P = .577, respectively).

Conclusions/Impliacations: Based on our results, extending the zoledronic acid dosing interval does not increase the incidence of SREs. Dosing zoledronic acid every three months offers a potential avenue to increase Veteran compliance and decrease the chance for adverse drug reactions without compromising therapeutic benefit.

The main treatment for prostate cancer—the third leading cause of cancer death in American men—often is “watchful waiting.” But what happens before, during, and after that waiting period has changed tremendously in recent years. Innovative and improved methods and drugs allow for a more precise diagnosis, better risk stratification, targeted treatment options, and longer survival.

Innovations in diagnosis include a revised histologic grading system, which was incorporated into the 2016 World Health Organization classification of tumors. The new grading system ranks prostate cancer on a 1-to-5 scale, making it more discriminating, as validated in a study of more than 25,000 men.

The use of new prognostic biomarkers has advanced risk stratification. According to a recent review, biopsy guided by ultrasound misses between 21% and 28% of prostate cancers and undergrades between 14% and 17%.¹ But new serum-, tissue-, and image-based biomarkers may help identify potential false negatives. The prostate cancer antigen 3 test, for example, has an 88% negative predictive value for subsequent biopsy. Molecular biomarkers also can predict clinical progression, risk of adverse pathology, and metastatic risk.

Fortunately, biopsy guided by ultrasound is getting more precise. Advances in magnetic resonance imaging (MRI) now allow for “targeted biopsies.” The enhanced MRI has 89% sensitivity and 73% specificity for identifying prostate cancer. According to one study of 1,003 men, targeted prostate biopsy using MRI-ultrasound fusion identified 30% more cases of Gleason score ≥ 4 + 3 than did systematic prostate biopsy.¹ Updates in positron emission tomography are garnering interest for improved staging because this technology allows for better detection of local recurrence, regional lymph node metastases, and distant metastases.

Once a prostate cancer diagnosis has been confirmed, the decision of what to do next may be watchful waiting (treating symptoms palliatively), but recent research suggests that active surveillance that includes regular prostate-specific antigen testing, physical examinations, and prostate biopsies may be a better choice, particularly for men with less aggressive cancer. One study of 1,298 men with mostly very low-risk disease followed for up to 60 months found metastasis in only 5; only 2 died. The Prostate Testing for Cancer and Treatment (ProtecT) trial found that the number of deaths in the active monitoring group did not differ significantly from those in the surgery or radiation groups.

What should be the contemporary standard of care? Androgen deprivation therapy (ADT) is still the go-to treatment for men with metastatic prostate cancer. Although ADT has been associated with toxicity, a meta-analysis found continuous ADT was better than intermittent in terms of disease progression and survival.¹

Other research has focused on which types of prostate cancer respond best to specific therapies. Molecular subtyping (already available in bladder and breast cancer) is gaining popularity. Prostate cancer was thought to derive from glandular luminal cells, but recent evidence supports the idea that basal cells play a role as well. Researchers who analyzed nearly 4,000 samples suggest that luminal B tumors respond better to postoperative ADT than do nonluminal B cancers. These findings suggest that “personalized” ADT treatment may be possible.²

Several drugs have been shown to improve survival: Among them, docetaxel, abiraterone acetate, enzalutamide, and cabazitaxel. In the STAMPEDE trial, men with locally advanced or metastatic prostate cancer who received ADT plus abiraterone and prednisolone had significantly higher rates of overall and failure-free survival.³

Docetaxel, which can extend survival by 10 to 13 months compared with standard ADT, is taking on a bigger role for its ability to delay progression and recurrence while being well tolerated. Options for men whose cancer does not respond to ADT include abiraterone and enzalutamide. Both act on the androgen axis to slow progression and improve survival.

More than 30% of patients treated with radical prostatectomy will have recurrent cancer as will 50% of those treated with salvage radiation therapy. Bicalutamide has shown extremely promising action against recurrent cancer. In one study, the cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, compared with 23.0% in the placebo group.⁴

But while that study was going on, it was superseded by injectable gonadotropin-releasing hormone agonists as first-choice hormonal therapy with radiation. However, the researchers say that does not negate their findings on high-dose bicalutamide, which present “proof of principle” that adding hormone-based therapy to salvage radiation therapy is associated with significant and clinically important lower rates of metastases and death.

Multimodal therapy and precision medicine are becoming bywords in prostate cancer treatment. Drugs on the horizon likely will be tailored to tumor molecular biology, with genetic information used to specifically guide diagnosis and treatment. Prostate cancer may still be a slow killer, but immunotherapies (like sipuleucel-T, the first FDA-approved cancer vaccine), hormonal therapies, and bone-targeting agents enable men with prostate cancer to not only live longer but also with a better quality of life.

Click here to read the digital edition.

The main treatment for prostate cancer—the third leading cause of cancer death in American men—often is “watchful waiting.” But what happens before, during, and after that waiting period has changed tremendously in recent years. Innovative and improved methods and drugs allow for a more precise diagnosis, better risk stratification, targeted treatment options, and longer survival.

Innovations in diagnosis include a revised histologic grading system, which was incorporated into the 2016 World Health Organization classification of tumors. The new grading system ranks prostate cancer on a 1-to-5 scale, making it more discriminating, as validated in a study of more than 25,000 men.

The use of new prognostic biomarkers has advanced risk stratification. According to a recent review, biopsy guided by ultrasound misses between 21% and 28% of prostate cancers and undergrades between 14% and 17%.¹ But new serum-, tissue-, and image-based biomarkers may help identify potential false negatives. The prostate cancer antigen 3 test, for example, has an 88% negative predictive value for subsequent biopsy. Molecular biomarkers also can predict clinical progression, risk of adverse pathology, and metastatic risk.

Fortunately, biopsy guided by ultrasound is getting more precise. Advances in magnetic resonance imaging (MRI) now allow for “targeted biopsies.” The enhanced MRI has 89% sensitivity and 73% specificity for identifying prostate cancer. According to one study of 1,003 men, targeted prostate biopsy using MRI-ultrasound fusion identified 30% more cases of Gleason score ≥ 4 + 3 than did systematic prostate biopsy.¹ Updates in positron emission tomography are garnering interest for improved staging because this technology allows for better detection of local recurrence, regional lymph node metastases, and distant metastases.

Once a prostate cancer diagnosis has been confirmed, the decision of what to do next may be watchful waiting (treating symptoms palliatively), but recent research suggests that active surveillance that includes regular prostate-specific antigen testing, physical examinations, and prostate biopsies may be a better choice, particularly for men with less aggressive cancer. One study of 1,298 men with mostly very low-risk disease followed for up to 60 months found metastasis in only 5; only 2 died. The Prostate Testing for Cancer and Treatment (ProtecT) trial found that the number of deaths in the active monitoring group did not differ significantly from those in the surgery or radiation groups.

What should be the contemporary standard of care? Androgen deprivation therapy (ADT) is still the go-to treatment for men with metastatic prostate cancer. Although ADT has been associated with toxicity, a meta-analysis found continuous ADT was better than intermittent in terms of disease progression and survival.¹

Other research has focused on which types of prostate cancer respond best to specific therapies. Molecular subtyping (already available in bladder and breast cancer) is gaining popularity. Prostate cancer was thought to derive from glandular luminal cells, but recent evidence supports the idea that basal cells play a role as well. Researchers who analyzed nearly 4,000 samples suggest that luminal B tumors respond better to postoperative ADT than do nonluminal B cancers. These findings suggest that “personalized” ADT treatment may be possible.²

Several drugs have been shown to improve survival: Among them, docetaxel, abiraterone acetate, enzalutamide, and cabazitaxel. In the STAMPEDE trial, men with locally advanced or metastatic prostate cancer who received ADT plus abiraterone and prednisolone had significantly higher rates of overall and failure-free survival.³

Docetaxel, which can extend survival by 10 to 13 months compared with standard ADT, is taking on a bigger role for its ability to delay progression and recurrence while being well tolerated. Options for men whose cancer does not respond to ADT include abiraterone and enzalutamide. Both act on the androgen axis to slow progression and improve survival.

More than 30% of patients treated with radical prostatectomy will have recurrent cancer as will 50% of those treated with salvage radiation therapy. Bicalutamide has shown extremely promising action against recurrent cancer. In one study, the cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, compared with 23.0% in the placebo group.⁴

But while that study was going on, it was superseded by injectable gonadotropin-releasing hormone agonists as first-choice hormonal therapy with radiation. However, the researchers say that does not negate their findings on high-dose bicalutamide, which present “proof of principle” that adding hormone-based therapy to salvage radiation therapy is associated with significant and clinically important lower rates of metastases and death.

Multimodal therapy and precision medicine are becoming bywords in prostate cancer treatment. Drugs on the horizon likely will be tailored to tumor molecular biology, with genetic information used to specifically guide diagnosis and treatment. Prostate cancer may still be a slow killer, but immunotherapies (like sipuleucel-T, the first FDA-approved cancer vaccine), hormonal therapies, and bone-targeting agents enable men with prostate cancer to not only live longer but also with a better quality of life.

Click here to read the digital edition.

The main treatment for prostate cancer—the third leading cause of cancer death in American men—often is “watchful waiting.” But what happens before, during, and after that waiting period has changed tremendously in recent years. Innovative and improved methods and drugs allow for a more precise diagnosis, better risk stratification, targeted treatment options, and longer survival.

Innovations in diagnosis include a revised histologic grading system, which was incorporated into the 2016 World Health Organization classification of tumors. The new grading system ranks prostate cancer on a 1-to-5 scale, making it more discriminating, as validated in a study of more than 25,000 men.

The use of new prognostic biomarkers has advanced risk stratification. According to a recent review, biopsy guided by ultrasound misses between 21% and 28% of prostate cancers and undergrades between 14% and 17%.¹ But new serum-, tissue-, and image-based biomarkers may help identify potential false negatives. The prostate cancer antigen 3 test, for example, has an 88% negative predictive value for subsequent biopsy. Molecular biomarkers also can predict clinical progression, risk of adverse pathology, and metastatic risk.

Fortunately, biopsy guided by ultrasound is getting more precise. Advances in magnetic resonance imaging (MRI) now allow for “targeted biopsies.” The enhanced MRI has 89% sensitivity and 73% specificity for identifying prostate cancer. According to one study of 1,003 men, targeted prostate biopsy using MRI-ultrasound fusion identified 30% more cases of Gleason score ≥ 4 + 3 than did systematic prostate biopsy.¹ Updates in positron emission tomography are garnering interest for improved staging because this technology allows for better detection of local recurrence, regional lymph node metastases, and distant metastases.

Once a prostate cancer diagnosis has been confirmed, the decision of what to do next may be watchful waiting (treating symptoms palliatively), but recent research suggests that active surveillance that includes regular prostate-specific antigen testing, physical examinations, and prostate biopsies may be a better choice, particularly for men with less aggressive cancer. One study of 1,298 men with mostly very low-risk disease followed for up to 60 months found metastasis in only 5; only 2 died. The Prostate Testing for Cancer and Treatment (ProtecT) trial found that the number of deaths in the active monitoring group did not differ significantly from those in the surgery or radiation groups.

What should be the contemporary standard of care? Androgen deprivation therapy (ADT) is still the go-to treatment for men with metastatic prostate cancer. Although ADT has been associated with toxicity, a meta-analysis found continuous ADT was better than intermittent in terms of disease progression and survival.¹

Other research has focused on which types of prostate cancer respond best to specific therapies. Molecular subtyping (already available in bladder and breast cancer) is gaining popularity. Prostate cancer was thought to derive from glandular luminal cells, but recent evidence supports the idea that basal cells play a role as well. Researchers who analyzed nearly 4,000 samples suggest that luminal B tumors respond better to postoperative ADT than do nonluminal B cancers. These findings suggest that “personalized” ADT treatment may be possible.²

Several drugs have been shown to improve survival: Among them, docetaxel, abiraterone acetate, enzalutamide, and cabazitaxel. In the STAMPEDE trial, men with locally advanced or metastatic prostate cancer who received ADT plus abiraterone and prednisolone had significantly higher rates of overall and failure-free survival.³

Docetaxel, which can extend survival by 10 to 13 months compared with standard ADT, is taking on a bigger role for its ability to delay progression and recurrence while being well tolerated. Options for men whose cancer does not respond to ADT include abiraterone and enzalutamide. Both act on the androgen axis to slow progression and improve survival.

More than 30% of patients treated with radical prostatectomy will have recurrent cancer as will 50% of those treated with salvage radiation therapy. Bicalutamide has shown extremely promising action against recurrent cancer. In one study, the cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, compared with 23.0% in the placebo group.⁴

But while that study was going on, it was superseded by injectable gonadotropin-releasing hormone agonists as first-choice hormonal therapy with radiation. However, the researchers say that does not negate their findings on high-dose bicalutamide, which present “proof of principle” that adding hormone-based therapy to salvage radiation therapy is associated with significant and clinically important lower rates of metastases and death.

Multimodal therapy and precision medicine are becoming bywords in prostate cancer treatment. Drugs on the horizon likely will be tailored to tumor molecular biology, with genetic information used to specifically guide diagnosis and treatment. Prostate cancer may still be a slow killer, but immunotherapies (like sipuleucel-T, the first FDA-approved cancer vaccine), hormonal therapies, and bone-targeting agents enable men with prostate cancer to not only live longer but also with a better quality of life.

Click here to read the digital edition.

PSA Screening

William J. Aronson, MD. I’m very encouraged that the U.S. Preventive Services Task Force (USPSTF) has recently drafted revised guidelines for screening men for prostate cancer in which they now are proposing a C grade for prostate specific antigen (PSA) screening in men aged < 70 years. In this age group they now propose an informed discussion with the patient regarding the pros and cons of screening (shared decision making). The USPSTF recommended against PSA screening in men aged ≥ 75 years in 2008 (D grade), and they recommended against PSA screening in all men in 2012 (D grade). Previously the USPSTF put a great deal of emphasis on the PLCO (Prostate, Lung, Colorectal, and Ovarian Screening Trial). In that trial, there was no difference in prostate cancer mortality between the study groups, but, it appears that up to 90% of men in the control group received PSA screening, therefore, invalidating the studies findings.

I still have serious concerns about giving a D grade for men aged > 70 years. Dr. Jim Hu from Cornell University recently published a study in JAMA Oncology and reported that men aged > 74 years now have twice the rate (12%) of presenting with metastatic disease at the time of diagnosis compared with men aged > 74 years prior to the 2008 USPSTF recommendations. In my view, otherwise healthy men with a good life expectancy, even if they’re aged > 70 years, should still have an informed discussion with their physician about getting PSA screening.

Julie N. Graff, MD. I completely agree with Dr. Aronson, and I would add that our veterans are a special group of patients who have risk factors that aren’t seen in the general population. For example, Agent Orange exposure, and I think the VA has not necessarily embraced those recommendations. I’d also add that people are living longer, and most of the men who die of prostate cancer are over the age of 80 years. We need to consider each patient individually and his life expectancy. It’s okay to diagnose someone with prostate cancer, and it’s important to have a conversation about how likely that cancer is to shorten his life and not just turn a blind eye to it.

Nicholas G. Nickols, MD, PhD. I don’t think there’s really anything clinically meaningful about PSA screening that can be gleaned from the PLCO trial. However, there was another trial that looked at PSA screening, the ERSPC (European Randomized Study of Screening for Prostate Cancer) trial, and had less contamination in the nonscreened arm and actually did ultimately show a 27% reduction in prostate cancer mortality in the screened men. We also know that local treatment in men with high-risk prostate cancer actually improves survival. By not screening, men with high-risk disease are going to miss out on potentially curative therapy.

Dr. Aronson. I think other endpoints are crucial to consider beyond just survival. Once patients have metastatic disease that can markedly impact their quality of life. Also, patients who are starting androgen deprivation therapy (ADT) have very significant issues with quality of life as well. I believe these other endpoints should also be considered by the USPSTF.

Jenna M. Houranieh, PharmD, BCOP. The American Cancer Society, ASCO (American Society of Clinical Oncology), NCCN (National Comprehensive Cancer Network), and the American Urological Association all had a different view on screening compared with the USPSTF that I think go more in line with some of the ways that we practice, because they take into consideration life expectancy, patients’ risks, and the age of screening as well.

Active Surveillance

Dr. Aronson. Active surveillance is now a wellestablished, reasonable approach to managing patients with low-risk prostate cancer. When we talk about the various treatment options, we always include a discussion of active surveillance and watchful waiting. Certainly, patients who have a Gleason score of 3+3, a low PSA (< 10) and low volume disease are ideal candidates for active surveillance. There is no established protocol for active surveillance, though there are a number of large series that report specific ways to go about doing it. The key issue for patients is to deemphasize the importance of the PSA, which is a very poor tool for monitoring progression of prostate cancer in men on active surveillance, and to focus on periodically obtaining prostate biopsies.

For patients with prostate cancer who have multiple medical problems and limited life expectancy, there is no reason to do biopsies on a regular basis. Watchful waiting would be more appropriate for these patients. One key issue, which is challenging right now, is that probably the best way to do active surveillance is with the more sophisticated biopsy technology that is now available. That includes both fusing magnetic resonance imaging (MRI) of the prostate into the ultrasound unit we are using to perform transrectal prostate biopsies. The more advanced biopsy units also provide the ability to perform same-site biopsies. There are specific coordinates at each site where a biopsy is performed so that we can go back to that same site on subsequent biopsies. Due to cost issues, these advanced biopsy units are not yet being used at a high frequency.

Dr. Nickols. The large ProtecT trial in the UK randomized men diagnosed with prostate cancer out of a PSA screening cohort to an active surveillance arm, a radical prostatectomy arm, and a radical radiation arm, and has a median of 10 years’ followup. Importantly, the endpoints of overall survival and prostate cancer specific survival were actually the same for all 3 arms, and were quite high. A little more than half of the patients who were on surveillance ended up getting delayed radical therapy of some kind within 10 years.

There was, however, a difference in metastasis-free survival and clinical progression, which were both higher in the active surveillance arm as compared to the treatment arms. Progression to metastatic disease was more than twice as high in the active surveillance arm than the other 2. Most of the patients who had progressed on the active surveillance arm were Gleason 7, and probably were not ideal candidates for active surveillance by today’s standards and would not normally be recommended active surveillance.

Androgen Deprivation Therapies

Dr. Houranieh. Androgen deprivation therapy plays a large role in prostate cancer management and is used in several areas of prostate cancer care. Androgen deprivation therapy can given be before, during or after radiation or alone in the metastatic setting. It's also continued along with chemotherapy in the more advanced stages. It's use is generally guided by our urologists and the duration of therapy is determined by the risk and stage of the cancer. It can be used for as little as a few months for lower risk, early stage disease or for a few years for higher risk disease. It can also be continued indefinitely for metastatic disease. Androgen deprivation therapy is a combination of 2 types of therapies, injectable LHRH (luteinizing hormone-releasing hormone) agonists and oral antiandrogens.

A number of products are available. The most commonly used LHRH agonist, at least at the Lexington VAMC in Kentucky, is leuprolide, which comes either in an intramuscular or subcutaneous formulation and can be given at different frequencies either monthly, every 3 months, or every 6 months.

There are also a number of antiandrogens available on the market. The most commonly used one is bicalutamide. It is generally the best tolerated and given once daily, as opposed to the other 2, which are either given twice or 3 times daily.

Dr. Nickols. We typically add ADT to radiation for patients with high-risk prostate cancer, defined as any of the following: A PSA ≥ 20, clinical T3 or higher disease, or Gleason score of ≥ 8. The addition of ADT to radiation in high-risk patients improves overall survival, prostate cancer survival, and biochemical recurrence-free survival. The backbone of this hormone therapy is usually a GnRH analogue like leuprolide.

The data are extensive, including many large phase 3 randomized trials of patients with highrisk prostate cancer treated with radiation plus or minus androgen suppression. Many of these trials were led by the big cooperative trial groups: the Radiation Therapy Oncology Group (RTOG), the European Organisation for Research and Treatment of Cancer (EORTC), and others. Looking
at all of the data, the answer to the general question of whether hormone therapy is beneficial is yes. The unknown question is what is the optimal duration for this concurrent and adjuvant hormone therapy. The optimal duration is probably somewhere between 1 and 3 years. That’s a large range, and clearly preferences of the patient and the comorbidities play a role in the decision of duration. The radiation doses were considerably lower than what is considered standard of care at this time in the trials that have established the use of concurrent and adjuvant hormone therapy with radiation, which needs to be taken in context.

For patients with localized intermediate-risk prostate cancer, a shorter course of hormone therapy is reasonable. The RTOG 9408 and DFCI 95096 trials showed that a 4- to 6-month course of ADT with RT in mostly intermediate-risk patients was better than RT alone. However, studies looking at the different comorbidities present in these patients showed that patients with less comorbidity actually benefit more from the addition of hormone therapy, which needs to be taken into account.

The benefit to the intermediate-risk patients is probably driven by the patients with unfavorable intermediate-risk disease, for example, with the primary Gleason 4 patterns, such as Gleason 4+3 patients rather than Gleason 3+4, patients with higher volume of prostate cancer, patients with multiple intermediate-risk features, etc. For the truly favorable intermediate-risk patients, low-volume disease, low PSA, and Gleason 3+4 pattern, the added value of concurrent ADT may be small.

The mechanism of why ADT may contribute to radiation efficacy may be explained by direct radio-sensitization: the transcription factor androgen receptor activates expression of many genes involved in DNA repair. Interfere with that, and you sensitize to radiation.

Dr. Graff. Of note, we don’t use ADT as the primary treatment for localized prostate cancer. This is for use in combination with radiation, in people with positive lymph nodes after surgery and in people with incurable prostate cancer.

Dr. Nickols. The question of whether or not to treat patients with localized high-risk prostate cancer with hormone therapy alone has been answered: The SPCG-7 and NCIC CTG PR3/MRC PR07 trials proved that adding radiation to long-term ADT improved survival in these patients.

The DFCI 95096 trial also showed that patients with a high level of comorbidities benefitted the least from concurrent hormone therapy; cardiovascular risks from the hormone therapy can offset the anticancer effect in these patients.

Analyses of the large randomized trials of radiation with or without hormones looking at the question of whether or not there was increased cardiovascular mortality in the patients that had hormone therapy did not show more cardiovascular mortality. Importantly, those trials were not enriched for patients with comorbidities that would set them up for this risk. One needs to weigh the benefits of adding hormones to radiation against the risks on a patient-to-patient basis.

Dr. Aronson. Another scenario where we used ADT is for patients whose cancer progressed after primary therapy; for example, when radical prostatectomy and RT are not successful for a patient. We see patients on a regular basis with a rising PSA after primary therapy. Our main goal is to avoid giving ADT to these patients as long as possible and only use it when it is clearly indicated.

The best measure that we typically use is the PSA doubling time. If the PSA doubling time, for example, is > 1 year, than we feel more confident in holding off on starting ADT and instead just monitoring the PSA. Adverse effects (AEs) of ADT are dramatic. We know that patients can get significant fatigue, gain weight, lose muscle mass, have an increased risk of diabetes mellitus, get hot flashes, and develop impotence and loss of libido. And now there are emerging data on an increased risk of Alzheimer disease. We use ADT but only when clearly indicated.

When I start patients on ADT, in addition to explaining the AEs, I also strongly suggest that, if their health allows, they walk at a brisk rate for at least 30 minutes daily and get on a regular weight training or a resistance training program to try to maintain muscle mass. They need to watch their diet more carefully because they are at increased risk for weight gain. And if they also can do balancing exercises, that would also be ideal. Typically, we also start patients on calcium and vitamin D as there is a risk for bone loss and osteoporosis, and we monitor their bone density.

Dr. Nickols. There’s another role for ADT. In patients who have a PSA recurrence after surgery, RT directed to the prostate bed and/or pelvic nodes is a potential curative therapy. There’s now some emerging evidence that analogous to the definitive radiation setting, the addition of hormone therapy to salvage radiation may be of value.

There were 2 recent trials published. The RTOG-9601 trial showed a benefit to the addition of bicalutamide for patients who had rising PSA after a surgery and were randomized to radiation that was directed to the prostate bed plus or minus 2 years of bicalutamide. The second trial, GETUG-AFU 16, was similar except that in this case the hormone therapy used was 6 months of the GnRH analogue leuprolide. The RTOG-9601 trial had positive outcomes in multiple endpoints, including survival. The GETUG trial is not as mature but had a biochemical improvement.

I don’t think the interpretation of this should be to use hormones with salvage radiation all the time. Importantly, in the RTOG 9601 trial, the patients that had the greatest benefit to the addition of concurrent hormone therapy were those that had a PSA of higher than 0.5 or 0.7. Most patients who get salvage radiation now get it at a much lower PSA, so we probably don’t want to overinterpret that data. And, of course, we have to wait for the GETUG-AFU data to mature more to see if there’s any hard clinical endpoints met
there. Notably, the incidence of gynecomastia in the bicalutamide arm of RTOG 9601 was near 70%. I discuss the addition of hormones with my patients who are getting salvage radiation and usually recommend it to the ones who have the high-risk features, those who would have gotten the concurrent hormones in the definitive setting, those with a PSA greater than 0.5 at the time of salvage, and those with a rapid PSA doubling time.

Dr. Houranieh. Androgen deprivation therapy includes use of LHRH agonists, like leuprolide and antiandrogens like bicalutamide. Some of the short-term AEs from androgen deprivation that we counsel patients on are things like tumor flare, hot flashes, erectile dysfunction, and injection site reactions. Some of the more long-term complications that we touch upon are osteoporosis, obesity, insulin resistance, increased risk of diabetes mellitus and cardiovascular events. We counsel patients on these adverse reactions and do our best with monitoring and prevention.

Dr. Nickols. The ProtecT trial also had some valuable patient-reported outcomes that were very carefully tracked. It confirmed what we already believe. The patients that had primary RT had the greatest negative impact on bowel function and on urinary irritative and obstructive symptoms. The patients who had surgery had the greatest negative impact on sexual function and on urinary incontinence. Obviously, active surveillance had the benefit of avoiding or postponing AEs of local therapy.

You can break up RT for localized disease, into 2 general approaches. The first is external beam radiation. This can be delivered as intensity-modulated radiotherapy (IMRT), which is the most common approach right now, typically stretched over more than 2 months of daily treatments. In addition, there is a newer technique called stereotactic body radiation therapy (SBRT), which has been applied to localized prostate cancer now for more than a decade. It’s efficacy was demonstrated first in low-risk patients as normally is the case. It has the advantage of convenience; it is just 5 treatment days total, which can be accomplished in a couple of weeks. And its convenient for patients who are commuting some distance. That’s really important for veterans, as radiotherapy is not available at all VAs.

At the West LA VAMC, we offer SBRT as a standard treatment for men with low and favorable intermediate risk prostate cancer. In addition, we offer it in the context of a clinical trial for patients with unfavorable intermediate- and high-risk prostate cancer.

The other type of radiation therapy is brachytherapy in which the radiation is temporarily or permanently inserted into the target, the prostate. It is a good stand-alone option for men with low- or intermediate-risk prostate cancer. It has the advantage of being relatively fast in that it is done in a day, although it is more invasive than IMRT or SBRT, and certain anatomic features of the prostate and the patient’s baseline urinary function can limit its appropriateness in some patients.

There are some recent data of interest for the combination of brachytherapy and externalbeam radiation therapy (EBRT). The recently reported ASCENDE-RT trial randomized mostly high-risk patients to either EBRT with 1 year of androgen suppression or EBRT with a boost of brachytherapy to the prostate and 1 year of ADT.

The arm that got the brachytherapy boost actually had half the biochemical recurrence of the EBRT alone but had double the rate of grade 2 acute genitourinary toxicity and triple the rate of grade 3. Metastasis-free survival and other hard clinical endpoints will need longer follow-up, but the biochemical control was quite high: It was about 80% at 10 years out.

Dr. Aronson. For surgical approaches, many VAs now have the da Vinci robot system (Sunnyvale, CA). When we look at the key results, which examine cancer care and AEs, such as incontinence and impotence, there actually is no clear advantage over the open procedure that we previously used. That being said, with the robotic surgery, because we do it laparoscopically, there’s significantly less blood loss. The magnification is such that it is much easier to do the surgery. It’s also much easier on the surgeon’s body, given that you’re in an anatomically, ergonomically good position, and patients go home much sooner, typically on postoperative day 1 or postoperative day 2 with less morbidity following the procedure and a much quicker recovery.

Precision Medicine

Dr. Graff. Prostate cancer may not be cured, even after the best attempts at surgery or radiation. The medical oncologist is probably most utilized with people with incurable prostate cancer. Once it’s incurable, it develops tumors in the bones and lymph nodes most commonly, and we call it metastatic prostate cancer.

Right now we use mostly a once-size-fits-all approach. Everyone initially gets some form of castration therapy, usually medical castration with LHRH agonists. However, prostate cancer invariably becomes resistant to those maneuvers. We call that castration-resistant prostate cancer. That opens the door to 6 other treatments that can prolong survival in prostate cancer. Two of the treatments are hormonal (enzalutamide and abiraterone), 2 are chemotherapy (docetaxel and cabazitaxel), 1 is IV radiation with radium-223, and 1 is an immunotherapy (sipuleucel-T).

At this point, there’s not a lot of guidance about what to use when except that each of these therapies has unique AEs, so we may not use one of the therapies because it causes a lot of fatigue or it could cause seizures, for example, in a patient at risk for those. Sometimes the therapies are inappropriate. For example, with radium, you wouldn’t give it to a patient with a tumor in the liver.

We don’t have readily available companion diagnostics to help us narrow the selection. In 2015, there was an article in Cell that looked at men with metastatic castration-resistant prostate cancer. The tumors were biopsied and analyzed, and we found some surprising things, including certain mutations called DNA repair defects that could make them susceptible to a drug already approved in ovarian cancer, such as olaparib and rucaparib.

A subsequent study in the New England Journal of Medicine looked at patients with advanced prostate cancer whose cancers have these DNA repair defects. Those cancers were susceptible to the PARP (poly ADP ribose polymerase) inhibitor olaparib. That’s an example of where looking and sequencing a tumor could lead to a treatment selection. The PARP inhibitors are not yet approved in prostate cancer, but the Prostate Cancer Foundation is interested in supporting research that could help deliver appropriate therapies to veterans in particular whose cancers have certain markers.

So, we are biopsying patients’ tumors, looking at the mutations in their germline DNA, and matching patients to treatments and vice versa. The DNA repair defects is the one that’s probably under most active evaluation right now. Another example of a biomarker is the AR-V7, which is a mutation in the androgen receptor that renders the cancer resistant to enzalutamide and abiraterone.

Also, I have a study of pembrolizumab which is a PD-1 inhibitor, and I’ve seen some very good responses to that therapy. And we’re not yet sure how to identify prospectively those patients who are likely to respond.

Use of Imaging

Dr. Nickols. The sensitivity of technetium-99m bone scans and CT (computed tomography) scans is not good enough. Many patients that we classify as M0, but with clear evidence of disease with a rising PSA, will be more accurately classified as M1 when the imaging allows this to be the case.

I think prostate-specific membrane antigen positron emission tomography (PET), which is not approved at this time, is going to be of value. A lot of data are coming out of Europe and in the recurrence setting show that PET imaging can detect metastatic sites at PSA values as low as 0.2 with the per lesion sensitivity around 80% and a specificity upward of 97%. This is clearly far and away much better than anything we have now.

There’s going to be a whole cohort of patients that we literally can’t see now, patients with essentially minimally metastatic disease, and they will be revealed when the imaging gets there. And the question is what to do for these patients. Treating patients with a heavy metastatic disease burden is much different from treating patients who may have just one or a few areas of disease outside of their prostate. And we need new strategies for these patients. We are now looking at new treatment regimens for patients with limited metastatic disease burden. I think this is going to be important going forward.

It’s also worth asking: What is the role of local therapy in patients with advanced prostate cancer, patients with metastatic disease? If you look at the patients who were in a lot of the old trials, for example, the NCIC trial, that was adding radiation to hormone therapy for high-risk patients, about 25% of patients in that trial had a PSA > 50. That’s a lot. Many of those patients probably had occult metastases. And there are trials now looking at the role of local therapy in metastatic patients.

Another area of interest is precision oncology, which Dr. Graff touched on, is starting to play a big role in the metastatic setting, but what about the local setting? There are now genomic classifiers available to help with risk assessments, but we don’t yet have much in the way of predictive tools that help guide specific therapies in the localized setting. We know that patients, for example, who have germline BRCA1 or 2 mutations have a worse outcome, period, after local therapy; and right now it may play some into treatment decisions, but we don’t have tailored therapy yet in the localized setting at the molecular level. And I think this is something that we need to start looking at.

Dr. Aronson. The VA is a very rich environment for performing clinical research as well as translational research (bench to bedside). And for example, at the West Los Angeles VAMC, I think one of the key steps that we have taken, moving forward is now our urology, radiation oncology, and hematology-oncology research groups have now merged together. This allows us to not only combine our administrative resources but to really improve the ability for us to perform highquality research in our veterans. And so that’s a model which I think other VAs might consider pursuing, depending upon their circumstances.

Author Disclosures
Dr. Graff has received research support from Sanofi, Astellas, Merck, Janssen, and Bristol Myers Squibb; an honorarium from Astellas; travel support from Clovis and Sanofi; and has consulted for Bayer and Dendreon. No other authors report actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

PSA Screening

William J. Aronson, MD. I’m very encouraged that the U.S. Preventive Services Task Force (USPSTF) has recently drafted revised guidelines for screening men for prostate cancer in which they now are proposing a C grade for prostate specific antigen (PSA) screening in men aged < 70 years. In this age group they now propose an informed discussion with the patient regarding the pros and cons of screening (shared decision making). The USPSTF recommended against PSA screening in men aged ≥ 75 years in 2008 (D grade), and they recommended against PSA screening in all men in 2012 (D grade). Previously the USPSTF put a great deal of emphasis on the PLCO (Prostate, Lung, Colorectal, and Ovarian Screening Trial). In that trial, there was no difference in prostate cancer mortality between the study groups, but, it appears that up to 90% of men in the control group received PSA screening, therefore, invalidating the studies findings.

I still have serious concerns about giving a D grade for men aged > 70 years. Dr. Jim Hu from Cornell University recently published a study in JAMA Oncology and reported that men aged > 74 years now have twice the rate (12%) of presenting with metastatic disease at the time of diagnosis compared with men aged > 74 years prior to the 2008 USPSTF recommendations. In my view, otherwise healthy men with a good life expectancy, even if they’re aged > 70 years, should still have an informed discussion with their physician about getting PSA screening.

Julie N. Graff, MD. I completely agree with Dr. Aronson, and I would add that our veterans are a special group of patients who have risk factors that aren’t seen in the general population. For example, Agent Orange exposure, and I think the VA has not necessarily embraced those recommendations. I’d also add that people are living longer, and most of the men who die of prostate cancer are over the age of 80 years. We need to consider each patient individually and his life expectancy. It’s okay to diagnose someone with prostate cancer, and it’s important to have a conversation about how likely that cancer is to shorten his life and not just turn a blind eye to it.

Nicholas G. Nickols, MD, PhD. I don’t think there’s really anything clinically meaningful about PSA screening that can be gleaned from the PLCO trial. However, there was another trial that looked at PSA screening, the ERSPC (European Randomized Study of Screening for Prostate Cancer) trial, and had less contamination in the nonscreened arm and actually did ultimately show a 27% reduction in prostate cancer mortality in the screened men. We also know that local treatment in men with high-risk prostate cancer actually improves survival. By not screening, men with high-risk disease are going to miss out on potentially curative therapy.

Dr. Aronson. I think other endpoints are crucial to consider beyond just survival. Once patients have metastatic disease that can markedly impact their quality of life. Also, patients who are starting androgen deprivation therapy (ADT) have very significant issues with quality of life as well. I believe these other endpoints should also be considered by the USPSTF.

Jenna M. Houranieh, PharmD, BCOP. The American Cancer Society, ASCO (American Society of Clinical Oncology), NCCN (National Comprehensive Cancer Network), and the American Urological Association all had a different view on screening compared with the USPSTF that I think go more in line with some of the ways that we practice, because they take into consideration life expectancy, patients’ risks, and the age of screening as well.

Active Surveillance

Dr. Aronson. Active surveillance is now a wellestablished, reasonable approach to managing patients with low-risk prostate cancer. When we talk about the various treatment options, we always include a discussion of active surveillance and watchful waiting. Certainly, patients who have a Gleason score of 3+3, a low PSA (< 10) and low volume disease are ideal candidates for active surveillance. There is no established protocol for active surveillance, though there are a number of large series that report specific ways to go about doing it. The key issue for patients is to deemphasize the importance of the PSA, which is a very poor tool for monitoring progression of prostate cancer in men on active surveillance, and to focus on periodically obtaining prostate biopsies.

For patients with prostate cancer who have multiple medical problems and limited life expectancy, there is no reason to do biopsies on a regular basis. Watchful waiting would be more appropriate for these patients. One key issue, which is challenging right now, is that probably the best way to do active surveillance is with the more sophisticated biopsy technology that is now available. That includes both fusing magnetic resonance imaging (MRI) of the prostate into the ultrasound unit we are using to perform transrectal prostate biopsies. The more advanced biopsy units also provide the ability to perform same-site biopsies. There are specific coordinates at each site where a biopsy is performed so that we can go back to that same site on subsequent biopsies. Due to cost issues, these advanced biopsy units are not yet being used at a high frequency.

Dr. Nickols. The large ProtecT trial in the UK randomized men diagnosed with prostate cancer out of a PSA screening cohort to an active surveillance arm, a radical prostatectomy arm, and a radical radiation arm, and has a median of 10 years’ followup. Importantly, the endpoints of overall survival and prostate cancer specific survival were actually the same for all 3 arms, and were quite high. A little more than half of the patients who were on surveillance ended up getting delayed radical therapy of some kind within 10 years.

There was, however, a difference in metastasis-free survival and clinical progression, which were both higher in the active surveillance arm as compared to the treatment arms. Progression to metastatic disease was more than twice as high in the active surveillance arm than the other 2. Most of the patients who had progressed on the active surveillance arm were Gleason 7, and probably were not ideal candidates for active surveillance by today’s standards and would not normally be recommended active surveillance.

Androgen Deprivation Therapies

Dr. Houranieh. Androgen deprivation therapy plays a large role in prostate cancer management and is used in several areas of prostate cancer care. Androgen deprivation therapy can given be before, during or after radiation or alone in the metastatic setting. It's also continued along with chemotherapy in the more advanced stages. It's use is generally guided by our urologists and the duration of therapy is determined by the risk and stage of the cancer. It can be used for as little as a few months for lower risk, early stage disease or for a few years for higher risk disease. It can also be continued indefinitely for metastatic disease. Androgen deprivation therapy is a combination of 2 types of therapies, injectable LHRH (luteinizing hormone-releasing hormone) agonists and oral antiandrogens.

A number of products are available. The most commonly used LHRH agonist, at least at the Lexington VAMC in Kentucky, is leuprolide, which comes either in an intramuscular or subcutaneous formulation and can be given at different frequencies either monthly, every 3 months, or every 6 months.

There are also a number of antiandrogens available on the market. The most commonly used one is bicalutamide. It is generally the best tolerated and given once daily, as opposed to the other 2, which are either given twice or 3 times daily.

Dr. Nickols. We typically add ADT to radiation for patients with high-risk prostate cancer, defined as any of the following: A PSA ≥ 20, clinical T3 or higher disease, or Gleason score of ≥ 8. The addition of ADT to radiation in high-risk patients improves overall survival, prostate cancer survival, and biochemical recurrence-free survival. The backbone of this hormone therapy is usually a GnRH analogue like leuprolide.

The data are extensive, including many large phase 3 randomized trials of patients with highrisk prostate cancer treated with radiation plus or minus androgen suppression. Many of these trials were led by the big cooperative trial groups: the Radiation Therapy Oncology Group (RTOG), the European Organisation for Research and Treatment of Cancer (EORTC), and others. Looking
at all of the data, the answer to the general question of whether hormone therapy is beneficial is yes. The unknown question is what is the optimal duration for this concurrent and adjuvant hormone therapy. The optimal duration is probably somewhere between 1 and 3 years. That’s a large range, and clearly preferences of the patient and the comorbidities play a role in the decision of duration. The radiation doses were considerably lower than what is considered standard of care at this time in the trials that have established the use of concurrent and adjuvant hormone therapy with radiation, which needs to be taken in context.

For patients with localized intermediate-risk prostate cancer, a shorter course of hormone therapy is reasonable. The RTOG 9408 and DFCI 95096 trials showed that a 4- to 6-month course of ADT with RT in mostly intermediate-risk patients was better than RT alone. However, studies looking at the different comorbidities present in these patients showed that patients with less comorbidity actually benefit more from the addition of hormone therapy, which needs to be taken into account.

The benefit to the intermediate-risk patients is probably driven by the patients with unfavorable intermediate-risk disease, for example, with the primary Gleason 4 patterns, such as Gleason 4+3 patients rather than Gleason 3+4, patients with higher volume of prostate cancer, patients with multiple intermediate-risk features, etc. For the truly favorable intermediate-risk patients, low-volume disease, low PSA, and Gleason 3+4 pattern, the added value of concurrent ADT may be small.

The mechanism of why ADT may contribute to radiation efficacy may be explained by direct radio-sensitization: the transcription factor androgen receptor activates expression of many genes involved in DNA repair. Interfere with that, and you sensitize to radiation.

Dr. Graff. Of note, we don’t use ADT as the primary treatment for localized prostate cancer. This is for use in combination with radiation, in people with positive lymph nodes after surgery and in people with incurable prostate cancer.

Dr. Nickols. The question of whether or not to treat patients with localized high-risk prostate cancer with hormone therapy alone has been answered: The SPCG-7 and NCIC CTG PR3/MRC PR07 trials proved that adding radiation to long-term ADT improved survival in these patients.

The DFCI 95096 trial also showed that patients with a high level of comorbidities benefitted the least from concurrent hormone therapy; cardiovascular risks from the hormone therapy can offset the anticancer effect in these patients.

Analyses of the large randomized trials of radiation with or without hormones looking at the question of whether or not there was increased cardiovascular mortality in the patients that had hormone therapy did not show more cardiovascular mortality. Importantly, those trials were not enriched for patients with comorbidities that would set them up for this risk. One needs to weigh the benefits of adding hormones to radiation against the risks on a patient-to-patient basis.

Dr. Aronson. Another scenario where we used ADT is for patients whose cancer progressed after primary therapy; for example, when radical prostatectomy and RT are not successful for a patient. We see patients on a regular basis with a rising PSA after primary therapy. Our main goal is to avoid giving ADT to these patients as long as possible and only use it when it is clearly indicated.

The best measure that we typically use is the PSA doubling time. If the PSA doubling time, for example, is > 1 year, than we feel more confident in holding off on starting ADT and instead just monitoring the PSA. Adverse effects (AEs) of ADT are dramatic. We know that patients can get significant fatigue, gain weight, lose muscle mass, have an increased risk of diabetes mellitus, get hot flashes, and develop impotence and loss of libido. And now there are emerging data on an increased risk of Alzheimer disease. We use ADT but only when clearly indicated.

When I start patients on ADT, in addition to explaining the AEs, I also strongly suggest that, if their health allows, they walk at a brisk rate for at least 30 minutes daily and get on a regular weight training or a resistance training program to try to maintain muscle mass. They need to watch their diet more carefully because they are at increased risk for weight gain. And if they also can do balancing exercises, that would also be ideal. Typically, we also start patients on calcium and vitamin D as there is a risk for bone loss and osteoporosis, and we monitor their bone density.

Dr. Nickols. There’s another role for ADT. In patients who have a PSA recurrence after surgery, RT directed to the prostate bed and/or pelvic nodes is a potential curative therapy. There’s now some emerging evidence that analogous to the definitive radiation setting, the addition of hormone therapy to salvage radiation may be of value.

There were 2 recent trials published. The RTOG-9601 trial showed a benefit to the addition of bicalutamide for patients who had rising PSA after a surgery and were randomized to radiation that was directed to the prostate bed plus or minus 2 years of bicalutamide. The second trial, GETUG-AFU 16, was similar except that in this case the hormone therapy used was 6 months of the GnRH analogue leuprolide. The RTOG-9601 trial had positive outcomes in multiple endpoints, including survival. The GETUG trial is not as mature but had a biochemical improvement.

I don’t think the interpretation of this should be to use hormones with salvage radiation all the time. Importantly, in the RTOG 9601 trial, the patients that had the greatest benefit to the addition of concurrent hormone therapy were those that had a PSA of higher than 0.5 or 0.7. Most patients who get salvage radiation now get it at a much lower PSA, so we probably don’t want to overinterpret that data. And, of course, we have to wait for the GETUG-AFU data to mature more to see if there’s any hard clinical endpoints met
there. Notably, the incidence of gynecomastia in the bicalutamide arm of RTOG 9601 was near 70%. I discuss the addition of hormones with my patients who are getting salvage radiation and usually recommend it to the ones who have the high-risk features, those who would have gotten the concurrent hormones in the definitive setting, those with a PSA greater than 0.5 at the time of salvage, and those with a rapid PSA doubling time.

Dr. Houranieh. Androgen deprivation therapy includes use of LHRH agonists, like leuprolide and antiandrogens like bicalutamide. Some of the short-term AEs from androgen deprivation that we counsel patients on are things like tumor flare, hot flashes, erectile dysfunction, and injection site reactions. Some of the more long-term complications that we touch upon are osteoporosis, obesity, insulin resistance, increased risk of diabetes mellitus and cardiovascular events. We counsel patients on these adverse reactions and do our best with monitoring and prevention.

Dr. Nickols. The ProtecT trial also had some valuable patient-reported outcomes that were very carefully tracked. It confirmed what we already believe. The patients that had primary RT had the greatest negative impact on bowel function and on urinary irritative and obstructive symptoms. The patients who had surgery had the greatest negative impact on sexual function and on urinary incontinence. Obviously, active surveillance had the benefit of avoiding or postponing AEs of local therapy.

You can break up RT for localized disease, into 2 general approaches. The first is external beam radiation. This can be delivered as intensity-modulated radiotherapy (IMRT), which is the most common approach right now, typically stretched over more than 2 months of daily treatments. In addition, there is a newer technique called stereotactic body radiation therapy (SBRT), which has been applied to localized prostate cancer now for more than a decade. It’s efficacy was demonstrated first in low-risk patients as normally is the case. It has the advantage of convenience; it is just 5 treatment days total, which can be accomplished in a couple of weeks. And its convenient for patients who are commuting some distance. That’s really important for veterans, as radiotherapy is not available at all VAs.

At the West LA VAMC, we offer SBRT as a standard treatment for men with low and favorable intermediate risk prostate cancer. In addition, we offer it in the context of a clinical trial for patients with unfavorable intermediate- and high-risk prostate cancer.

The other type of radiation therapy is brachytherapy in which the radiation is temporarily or permanently inserted into the target, the prostate. It is a good stand-alone option for men with low- or intermediate-risk prostate cancer. It has the advantage of being relatively fast in that it is done in a day, although it is more invasive than IMRT or SBRT, and certain anatomic features of the prostate and the patient’s baseline urinary function can limit its appropriateness in some patients.

There are some recent data of interest for the combination of brachytherapy and externalbeam radiation therapy (EBRT). The recently reported ASCENDE-RT trial randomized mostly high-risk patients to either EBRT with 1 year of androgen suppression or EBRT with a boost of brachytherapy to the prostate and 1 year of ADT.

The arm that got the brachytherapy boost actually had half the biochemical recurrence of the EBRT alone but had double the rate of grade 2 acute genitourinary toxicity and triple the rate of grade 3. Metastasis-free survival and other hard clinical endpoints will need longer follow-up, but the biochemical control was quite high: It was about 80% at 10 years out.

Dr. Aronson. For surgical approaches, many VAs now have the da Vinci robot system (Sunnyvale, CA). When we look at the key results, which examine cancer care and AEs, such as incontinence and impotence, there actually is no clear advantage over the open procedure that we previously used. That being said, with the robotic surgery, because we do it laparoscopically, there’s significantly less blood loss. The magnification is such that it is much easier to do the surgery. It’s also much easier on the surgeon’s body, given that you’re in an anatomically, ergonomically good position, and patients go home much sooner, typically on postoperative day 1 or postoperative day 2 with less morbidity following the procedure and a much quicker recovery.

Precision Medicine

Dr. Graff. Prostate cancer may not be cured, even after the best attempts at surgery or radiation. The medical oncologist is probably most utilized with people with incurable prostate cancer. Once it’s incurable, it develops tumors in the bones and lymph nodes most commonly, and we call it metastatic prostate cancer.

Right now we use mostly a once-size-fits-all approach. Everyone initially gets some form of castration therapy, usually medical castration with LHRH agonists. However, prostate cancer invariably becomes resistant to those maneuvers. We call that castration-resistant prostate cancer. That opens the door to 6 other treatments that can prolong survival in prostate cancer. Two of the treatments are hormonal (enzalutamide and abiraterone), 2 are chemotherapy (docetaxel and cabazitaxel), 1 is IV radiation with radium-223, and 1 is an immunotherapy (sipuleucel-T).

At this point, there’s not a lot of guidance about what to use when except that each of these therapies has unique AEs, so we may not use one of the therapies because it causes a lot of fatigue or it could cause seizures, for example, in a patient at risk for those. Sometimes the therapies are inappropriate. For example, with radium, you wouldn’t give it to a patient with a tumor in the liver.

We don’t have readily available companion diagnostics to help us narrow the selection. In 2015, there was an article in Cell that looked at men with metastatic castration-resistant prostate cancer. The tumors were biopsied and analyzed, and we found some surprising things, including certain mutations called DNA repair defects that could make them susceptible to a drug already approved in ovarian cancer, such as olaparib and rucaparib.

A subsequent study in the New England Journal of Medicine looked at patients with advanced prostate cancer whose cancers have these DNA repair defects. Those cancers were susceptible to the PARP (poly ADP ribose polymerase) inhibitor olaparib. That’s an example of where looking and sequencing a tumor could lead to a treatment selection. The PARP inhibitors are not yet approved in prostate cancer, but the Prostate Cancer Foundation is interested in supporting research that could help deliver appropriate therapies to veterans in particular whose cancers have certain markers.

So, we are biopsying patients’ tumors, looking at the mutations in their germline DNA, and matching patients to treatments and vice versa. The DNA repair defects is the one that’s probably under most active evaluation right now. Another example of a biomarker is the AR-V7, which is a mutation in the androgen receptor that renders the cancer resistant to enzalutamide and abiraterone.

Also, I have a study of pembrolizumab which is a PD-1 inhibitor, and I’ve seen some very good responses to that therapy. And we’re not yet sure how to identify prospectively those patients who are likely to respond.

Use of Imaging

Dr. Nickols. The sensitivity of technetium-99m bone scans and CT (computed tomography) scans is not good enough. Many patients that we classify as M0, but with clear evidence of disease with a rising PSA, will be more accurately classified as M1 when the imaging allows this to be the case.

I think prostate-specific membrane antigen positron emission tomography (PET), which is not approved at this time, is going to be of value. A lot of data are coming out of Europe and in the recurrence setting show that PET imaging can detect metastatic sites at PSA values as low as 0.2 with the per lesion sensitivity around 80% and a specificity upward of 97%. This is clearly far and away much better than anything we have now.

There’s going to be a whole cohort of patients that we literally can’t see now, patients with essentially minimally metastatic disease, and they will be revealed when the imaging gets there. And the question is what to do for these patients. Treating patients with a heavy metastatic disease burden is much different from treating patients who may have just one or a few areas of disease outside of their prostate. And we need new strategies for these patients. We are now looking at new treatment regimens for patients with limited metastatic disease burden. I think this is going to be important going forward.

It’s also worth asking: What is the role of local therapy in patients with advanced prostate cancer, patients with metastatic disease? If you look at the patients who were in a lot of the old trials, for example, the NCIC trial, that was adding radiation to hormone therapy for high-risk patients, about 25% of patients in that trial had a PSA > 50. That’s a lot. Many of those patients probably had occult metastases. And there are trials now looking at the role of local therapy in metastatic patients.

Another area of interest is precision oncology, which Dr. Graff touched on, is starting to play a big role in the metastatic setting, but what about the local setting? There are now genomic classifiers available to help with risk assessments, but we don’t yet have much in the way of predictive tools that help guide specific therapies in the localized setting. We know that patients, for example, who have germline BRCA1 or 2 mutations have a worse outcome, period, after local therapy; and right now it may play some into treatment decisions, but we don’t have tailored therapy yet in the localized setting at the molecular level. And I think this is something that we need to start looking at.

Dr. Aronson. The VA is a very rich environment for performing clinical research as well as translational research (bench to bedside). And for example, at the West Los Angeles VAMC, I think one of the key steps that we have taken, moving forward is now our urology, radiation oncology, and hematology-oncology research groups have now merged together. This allows us to not only combine our administrative resources but to really improve the ability for us to perform highquality research in our veterans. And so that’s a model which I think other VAs might consider pursuing, depending upon their circumstances.

Author Disclosures
Dr. Graff has received research support from Sanofi, Astellas, Merck, Janssen, and Bristol Myers Squibb; an honorarium from Astellas; travel support from Clovis and Sanofi; and has consulted for Bayer and Dendreon. No other authors report actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

PSA Screening

William J. Aronson, MD. I’m very encouraged that the U.S. Preventive Services Task Force (USPSTF) has recently drafted revised guidelines for screening men for prostate cancer in which they now are proposing a C grade for prostate specific antigen (PSA) screening in men aged < 70 years. In this age group they now propose an informed discussion with the patient regarding the pros and cons of screening (shared decision making). The USPSTF recommended against PSA screening in men aged ≥ 75 years in 2008 (D grade), and they recommended against PSA screening in all men in 2012 (D grade). Previously the USPSTF put a great deal of emphasis on the PLCO (Prostate, Lung, Colorectal, and Ovarian Screening Trial). In that trial, there was no difference in prostate cancer mortality between the study groups, but, it appears that up to 90% of men in the control group received PSA screening, therefore, invalidating the studies findings.

I still have serious concerns about giving a D grade for men aged > 70 years. Dr. Jim Hu from Cornell University recently published a study in JAMA Oncology and reported that men aged > 74 years now have twice the rate (12%) of presenting with metastatic disease at the time of diagnosis compared with men aged > 74 years prior to the 2008 USPSTF recommendations. In my view, otherwise healthy men with a good life expectancy, even if they’re aged > 70 years, should still have an informed discussion with their physician about getting PSA screening.

Julie N. Graff, MD. I completely agree with Dr. Aronson, and I would add that our veterans are a special group of patients who have risk factors that aren’t seen in the general population. For example, Agent Orange exposure, and I think the VA has not necessarily embraced those recommendations. I’d also add that people are living longer, and most of the men who die of prostate cancer are over the age of 80 years. We need to consider each patient individually and his life expectancy. It’s okay to diagnose someone with prostate cancer, and it’s important to have a conversation about how likely that cancer is to shorten his life and not just turn a blind eye to it.

Nicholas G. Nickols, MD, PhD. I don’t think there’s really anything clinically meaningful about PSA screening that can be gleaned from the PLCO trial. However, there was another trial that looked at PSA screening, the ERSPC (European Randomized Study of Screening for Prostate Cancer) trial, and had less contamination in the nonscreened arm and actually did ultimately show a 27% reduction in prostate cancer mortality in the screened men. We also know that local treatment in men with high-risk prostate cancer actually improves survival. By not screening, men with high-risk disease are going to miss out on potentially curative therapy.

Dr. Aronson. I think other endpoints are crucial to consider beyond just survival. Once patients have metastatic disease that can markedly impact their quality of life. Also, patients who are starting androgen deprivation therapy (ADT) have very significant issues with quality of life as well. I believe these other endpoints should also be considered by the USPSTF.

Jenna M. Houranieh, PharmD, BCOP. The American Cancer Society, ASCO (American Society of Clinical Oncology), NCCN (National Comprehensive Cancer Network), and the American Urological Association all had a different view on screening compared with the USPSTF that I think go more in line with some of the ways that we practice, because they take into consideration life expectancy, patients’ risks, and the age of screening as well.

Active Surveillance

Dr. Aronson. Active surveillance is now a wellestablished, reasonable approach to managing patients with low-risk prostate cancer. When we talk about the various treatment options, we always include a discussion of active surveillance and watchful waiting. Certainly, patients who have a Gleason score of 3+3, a low PSA (< 10) and low volume disease are ideal candidates for active surveillance. There is no established protocol for active surveillance, though there are a number of large series that report specific ways to go about doing it. The key issue for patients is to deemphasize the importance of the PSA, which is a very poor tool for monitoring progression of prostate cancer in men on active surveillance, and to focus on periodically obtaining prostate biopsies.

For patients with prostate cancer who have multiple medical problems and limited life expectancy, there is no reason to do biopsies on a regular basis. Watchful waiting would be more appropriate for these patients. One key issue, which is challenging right now, is that probably the best way to do active surveillance is with the more sophisticated biopsy technology that is now available. That includes both fusing magnetic resonance imaging (MRI) of the prostate into the ultrasound unit we are using to perform transrectal prostate biopsies. The more advanced biopsy units also provide the ability to perform same-site biopsies. There are specific coordinates at each site where a biopsy is performed so that we can go back to that same site on subsequent biopsies. Due to cost issues, these advanced biopsy units are not yet being used at a high frequency.

Dr. Nickols. The large ProtecT trial in the UK randomized men diagnosed with prostate cancer out of a PSA screening cohort to an active surveillance arm, a radical prostatectomy arm, and a radical radiation arm, and has a median of 10 years’ followup. Importantly, the endpoints of overall survival and prostate cancer specific survival were actually the same for all 3 arms, and were quite high. A little more than half of the patients who were on surveillance ended up getting delayed radical therapy of some kind within 10 years.

There was, however, a difference in metastasis-free survival and clinical progression, which were both higher in the active surveillance arm as compared to the treatment arms. Progression to metastatic disease was more than twice as high in the active surveillance arm than the other 2. Most of the patients who had progressed on the active surveillance arm were Gleason 7, and probably were not ideal candidates for active surveillance by today’s standards and would not normally be recommended active surveillance.

Androgen Deprivation Therapies

Dr. Houranieh. Androgen deprivation therapy plays a large role in prostate cancer management and is used in several areas of prostate cancer care. Androgen deprivation therapy can given be before, during or after radiation or alone in the metastatic setting. It's also continued along with chemotherapy in the more advanced stages. It's use is generally guided by our urologists and the duration of therapy is determined by the risk and stage of the cancer. It can be used for as little as a few months for lower risk, early stage disease or for a few years for higher risk disease. It can also be continued indefinitely for metastatic disease. Androgen deprivation therapy is a combination of 2 types of therapies, injectable LHRH (luteinizing hormone-releasing hormone) agonists and oral antiandrogens.

A number of products are available. The most commonly used LHRH agonist, at least at the Lexington VAMC in Kentucky, is leuprolide, which comes either in an intramuscular or subcutaneous formulation and can be given at different frequencies either monthly, every 3 months, or every 6 months.

There are also a number of antiandrogens available on the market. The most commonly used one is bicalutamide. It is generally the best tolerated and given once daily, as opposed to the other 2, which are either given twice or 3 times daily.

Dr. Nickols. We typically add ADT to radiation for patients with high-risk prostate cancer, defined as any of the following: A PSA ≥ 20, clinical T3 or higher disease, or Gleason score of ≥ 8. The addition of ADT to radiation in high-risk patients improves overall survival, prostate cancer survival, and biochemical recurrence-free survival. The backbone of this hormone therapy is usually a GnRH analogue like leuprolide.

The data are extensive, including many large phase 3 randomized trials of patients with highrisk prostate cancer treated with radiation plus or minus androgen suppression. Many of these trials were led by the big cooperative trial groups: the Radiation Therapy Oncology Group (RTOG), the European Organisation for Research and Treatment of Cancer (EORTC), and others. Looking
at all of the data, the answer to the general question of whether hormone therapy is beneficial is yes. The unknown question is what is the optimal duration for this concurrent and adjuvant hormone therapy. The optimal duration is probably somewhere between 1 and 3 years. That’s a large range, and clearly preferences of the patient and the comorbidities play a role in the decision of duration. The radiation doses were considerably lower than what is considered standard of care at this time in the trials that have established the use of concurrent and adjuvant hormone therapy with radiation, which needs to be taken in context.

For patients with localized intermediate-risk prostate cancer, a shorter course of hormone therapy is reasonable. The RTOG 9408 and DFCI 95096 trials showed that a 4- to 6-month course of ADT with RT in mostly intermediate-risk patients was better than RT alone. However, studies looking at the different comorbidities present in these patients showed that patients with less comorbidity actually benefit more from the addition of hormone therapy, which needs to be taken into account.

The benefit to the intermediate-risk patients is probably driven by the patients with unfavorable intermediate-risk disease, for example, with the primary Gleason 4 patterns, such as Gleason 4+3 patients rather than Gleason 3+4, patients with higher volume of prostate cancer, patients with multiple intermediate-risk features, etc. For the truly favorable intermediate-risk patients, low-volume disease, low PSA, and Gleason 3+4 pattern, the added value of concurrent ADT may be small.

The mechanism of why ADT may contribute to radiation efficacy may be explained by direct radio-sensitization: the transcription factor androgen receptor activates expression of many genes involved in DNA repair. Interfere with that, and you sensitize to radiation.

Dr. Graff. Of note, we don’t use ADT as the primary treatment for localized prostate cancer. This is for use in combination with radiation, in people with positive lymph nodes after surgery and in people with incurable prostate cancer.

Dr. Nickols. The question of whether or not to treat patients with localized high-risk prostate cancer with hormone therapy alone has been answered: The SPCG-7 and NCIC CTG PR3/MRC PR07 trials proved that adding radiation to long-term ADT improved survival in these patients.

The DFCI 95096 trial also showed that patients with a high level of comorbidities benefitted the least from concurrent hormone therapy; cardiovascular risks from the hormone therapy can offset the anticancer effect in these patients.

Analyses of the large randomized trials of radiation with or without hormones looking at the question of whether or not there was increased cardiovascular mortality in the patients that had hormone therapy did not show more cardiovascular mortality. Importantly, those trials were not enriched for patients with comorbidities that would set them up for this risk. One needs to weigh the benefits of adding hormones to radiation against the risks on a patient-to-patient basis.

Dr. Aronson. Another scenario where we used ADT is for patients whose cancer progressed after primary therapy; for example, when radical prostatectomy and RT are not successful for a patient. We see patients on a regular basis with a rising PSA after primary therapy. Our main goal is to avoid giving ADT to these patients as long as possible and only use it when it is clearly indicated.

The best measure that we typically use is the PSA doubling time. If the PSA doubling time, for example, is > 1 year, than we feel more confident in holding off on starting ADT and instead just monitoring the PSA. Adverse effects (AEs) of ADT are dramatic. We know that patients can get significant fatigue, gain weight, lose muscle mass, have an increased risk of diabetes mellitus, get hot flashes, and develop impotence and loss of libido. And now there are emerging data on an increased risk of Alzheimer disease. We use ADT but only when clearly indicated.

When I start patients on ADT, in addition to explaining the AEs, I also strongly suggest that, if their health allows, they walk at a brisk rate for at least 30 minutes daily and get on a regular weight training or a resistance training program to try to maintain muscle mass. They need to watch their diet more carefully because they are at increased risk for weight gain. And if they also can do balancing exercises, that would also be ideal. Typically, we also start patients on calcium and vitamin D as there is a risk for bone loss and osteoporosis, and we monitor their bone density.

Dr. Nickols. There’s another role for ADT. In patients who have a PSA recurrence after surgery, RT directed to the prostate bed and/or pelvic nodes is a potential curative therapy. There’s now some emerging evidence that analogous to the definitive radiation setting, the addition of hormone therapy to salvage radiation may be of value.

There were 2 recent trials published. The RTOG-9601 trial showed a benefit to the addition of bicalutamide for patients who had rising PSA after a surgery and were randomized to radiation that was directed to the prostate bed plus or minus 2 years of bicalutamide. The second trial, GETUG-AFU 16, was similar except that in this case the hormone therapy used was 6 months of the GnRH analogue leuprolide. The RTOG-9601 trial had positive outcomes in multiple endpoints, including survival. The GETUG trial is not as mature but had a biochemical improvement.

I don’t think the interpretation of this should be to use hormones with salvage radiation all the time. Importantly, in the RTOG 9601 trial, the patients that had the greatest benefit to the addition of concurrent hormone therapy were those that had a PSA of higher than 0.5 or 0.7. Most patients who get salvage radiation now get it at a much lower PSA, so we probably don’t want to overinterpret that data. And, of course, we have to wait for the GETUG-AFU data to mature more to see if there’s any hard clinical endpoints met
there. Notably, the incidence of gynecomastia in the bicalutamide arm of RTOG 9601 was near 70%. I discuss the addition of hormones with my patients who are getting salvage radiation and usually recommend it to the ones who have the high-risk features, those who would have gotten the concurrent hormones in the definitive setting, those with a PSA greater than 0.5 at the time of salvage, and those with a rapid PSA doubling time.

Dr. Houranieh. Androgen deprivation therapy includes use of LHRH agonists, like leuprolide and antiandrogens like bicalutamide. Some of the short-term AEs from androgen deprivation that we counsel patients on are things like tumor flare, hot flashes, erectile dysfunction, and injection site reactions. Some of the more long-term complications that we touch upon are osteoporosis, obesity, insulin resistance, increased risk of diabetes mellitus and cardiovascular events. We counsel patients on these adverse reactions and do our best with monitoring and prevention.

Dr. Nickols. The ProtecT trial also had some valuable patient-reported outcomes that were very carefully tracked. It confirmed what we already believe. The patients that had primary RT had the greatest negative impact on bowel function and on urinary irritative and obstructive symptoms. The patients who had surgery had the greatest negative impact on sexual function and on urinary incontinence. Obviously, active surveillance had the benefit of avoiding or postponing AEs of local therapy.

You can break up RT for localized disease, into 2 general approaches. The first is external beam radiation. This can be delivered as intensity-modulated radiotherapy (IMRT), which is the most common approach right now, typically stretched over more than 2 months of daily treatments. In addition, there is a newer technique called stereotactic body radiation therapy (SBRT), which has been applied to localized prostate cancer now for more than a decade. It’s efficacy was demonstrated first in low-risk patients as normally is the case. It has the advantage of convenience; it is just 5 treatment days total, which can be accomplished in a couple of weeks. And its convenient for patients who are commuting some distance. That’s really important for veterans, as radiotherapy is not available at all VAs.

At the West LA VAMC, we offer SBRT as a standard treatment for men with low and favorable intermediate risk prostate cancer. In addition, we offer it in the context of a clinical trial for patients with unfavorable intermediate- and high-risk prostate cancer.

The other type of radiation therapy is brachytherapy in which the radiation is temporarily or permanently inserted into the target, the prostate. It is a good stand-alone option for men with low- or intermediate-risk prostate cancer. It has the advantage of being relatively fast in that it is done in a day, although it is more invasive than IMRT or SBRT, and certain anatomic features of the prostate and the patient’s baseline urinary function can limit its appropriateness in some patients.

There are some recent data of interest for the combination of brachytherapy and externalbeam radiation therapy (EBRT). The recently reported ASCENDE-RT trial randomized mostly high-risk patients to either EBRT with 1 year of androgen suppression or EBRT with a boost of brachytherapy to the prostate and 1 year of ADT.

The arm that got the brachytherapy boost actually had half the biochemical recurrence of the EBRT alone but had double the rate of grade 2 acute genitourinary toxicity and triple the rate of grade 3. Metastasis-free survival and other hard clinical endpoints will need longer follow-up, but the biochemical control was quite high: It was about 80% at 10 years out.

Dr. Aronson. For surgical approaches, many VAs now have the da Vinci robot system (Sunnyvale, CA). When we look at the key results, which examine cancer care and AEs, such as incontinence and impotence, there actually is no clear advantage over the open procedure that we previously used. That being said, with the robotic surgery, because we do it laparoscopically, there’s significantly less blood loss. The magnification is such that it is much easier to do the surgery. It’s also much easier on the surgeon’s body, given that you’re in an anatomically, ergonomically good position, and patients go home much sooner, typically on postoperative day 1 or postoperative day 2 with less morbidity following the procedure and a much quicker recovery.

Precision Medicine

Dr. Graff. Prostate cancer may not be cured, even after the best attempts at surgery or radiation. The medical oncologist is probably most utilized with people with incurable prostate cancer. Once it’s incurable, it develops tumors in the bones and lymph nodes most commonly, and we call it metastatic prostate cancer.

Right now we use mostly a once-size-fits-all approach. Everyone initially gets some form of castration therapy, usually medical castration with LHRH agonists. However, prostate cancer invariably becomes resistant to those maneuvers. We call that castration-resistant prostate cancer. That opens the door to 6 other treatments that can prolong survival in prostate cancer. Two of the treatments are hormonal (enzalutamide and abiraterone), 2 are chemotherapy (docetaxel and cabazitaxel), 1 is IV radiation with radium-223, and 1 is an immunotherapy (sipuleucel-T).

At this point, there’s not a lot of guidance about what to use when except that each of these therapies has unique AEs, so we may not use one of the therapies because it causes a lot of fatigue or it could cause seizures, for example, in a patient at risk for those. Sometimes the therapies are inappropriate. For example, with radium, you wouldn’t give it to a patient with a tumor in the liver.

We don’t have readily available companion diagnostics to help us narrow the selection. In 2015, there was an article in Cell that looked at men with metastatic castration-resistant prostate cancer. The tumors were biopsied and analyzed, and we found some surprising things, including certain mutations called DNA repair defects that could make them susceptible to a drug already approved in ovarian cancer, such as olaparib and rucaparib.

A subsequent study in the New England Journal of Medicine looked at patients with advanced prostate cancer whose cancers have these DNA repair defects. Those cancers were susceptible to the PARP (poly ADP ribose polymerase) inhibitor olaparib. That’s an example of where looking and sequencing a tumor could lead to a treatment selection. The PARP inhibitors are not yet approved in prostate cancer, but the Prostate Cancer Foundation is interested in supporting research that could help deliver appropriate therapies to veterans in particular whose cancers have certain markers.

So, we are biopsying patients’ tumors, looking at the mutations in their germline DNA, and matching patients to treatments and vice versa. The DNA repair defects is the one that’s probably under most active evaluation right now. Another example of a biomarker is the AR-V7, which is a mutation in the androgen receptor that renders the cancer resistant to enzalutamide and abiraterone.

Also, I have a study of pembrolizumab which is a PD-1 inhibitor, and I’ve seen some very good responses to that therapy. And we’re not yet sure how to identify prospectively those patients who are likely to respond.

Use of Imaging

Dr. Nickols. The sensitivity of technetium-99m bone scans and CT (computed tomography) scans is not good enough. Many patients that we classify as M0, but with clear evidence of disease with a rising PSA, will be more accurately classified as M1 when the imaging allows this to be the case.

I think prostate-specific membrane antigen positron emission tomography (PET), which is not approved at this time, is going to be of value. A lot of data are coming out of Europe and in the recurrence setting show that PET imaging can detect metastatic sites at PSA values as low as 0.2 with the per lesion sensitivity around 80% and a specificity upward of 97%. This is clearly far and away much better than anything we have now.

There’s going to be a whole cohort of patients that we literally can’t see now, patients with essentially minimally metastatic disease, and they will be revealed when the imaging gets there. And the question is what to do for these patients. Treating patients with a heavy metastatic disease burden is much different from treating patients who may have just one or a few areas of disease outside of their prostate. And we need new strategies for these patients. We are now looking at new treatment regimens for patients with limited metastatic disease burden. I think this is going to be important going forward.

It’s also worth asking: What is the role of local therapy in patients with advanced prostate cancer, patients with metastatic disease? If you look at the patients who were in a lot of the old trials, for example, the NCIC trial, that was adding radiation to hormone therapy for high-risk patients, about 25% of patients in that trial had a PSA > 50. That’s a lot. Many of those patients probably had occult metastases. And there are trials now looking at the role of local therapy in metastatic patients.

Another area of interest is precision oncology, which Dr. Graff touched on, is starting to play a big role in the metastatic setting, but what about the local setting? There are now genomic classifiers available to help with risk assessments, but we don’t yet have much in the way of predictive tools that help guide specific therapies in the localized setting. We know that patients, for example, who have germline BRCA1 or 2 mutations have a worse outcome, period, after local therapy; and right now it may play some into treatment decisions, but we don’t have tailored therapy yet in the localized setting at the molecular level. And I think this is something that we need to start looking at.

Dr. Aronson. The VA is a very rich environment for performing clinical research as well as translational research (bench to bedside). And for example, at the West Los Angeles VAMC, I think one of the key steps that we have taken, moving forward is now our urology, radiation oncology, and hematology-oncology research groups have now merged together. This allows us to not only combine our administrative resources but to really improve the ability for us to perform highquality research in our veterans. And so that’s a model which I think other VAs might consider pursuing, depending upon their circumstances.

Author Disclosures
Dr. Graff has received research support from Sanofi, Astellas, Merck, Janssen, and Bristol Myers Squibb; an honorarium from Astellas; travel support from Clovis and Sanofi; and has consulted for Bayer and Dendreon. No other authors report actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

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This article (part 2 of 2) focuses on the treatment of prostate cancer in seniors. Part 1 provided an overview of prostate cancer epidemiology, pathology, and screening in senior patients.

There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Recently, the International Society of Geriatric Oncology assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.

Patient Evaluation

The practice guidelines of the National Comprehensive Cancer Network (NCCN) recommend using life expectancy in determining treatment.¹ Prostate cancer is considered to be an indolent disease, and active therapy may be more harmful than beneficial to older patients whose life expectancy is limited because of treatment-related sequelae. Therefore, an accurate estimation of life expectancy is important in devising treatment strategies for older patients.

Age should not be the only factor in determining the life expectancy of patients, because life expectancy varies widely based on the patient’s health status, including preexisting comorbidities. Chronologic life expectancy can be found in the Social Security Administration’s life tables. Individual life expectancy is then projected by adding 50% to or deducting 50% from the chronologic life expectancy for men in the highest and lowest quartile of health, respectively. The life expectancy from the life tables can be applied with no addition or subtraction for men in the middle 2 quartiles of health status (Figure 1).²

Geriatric Assessment

Despite the increasing incidence of prostate cancer in older adults, no particular guidelines for its management exist. Compared with younger patients, older
patients with prostate cancer need to weigh the benefits of treatment vs the risks to avoid any potential adverse treatment-related quality of life (QOL) decreases. Clearly, for some patients there are no significant benefits from treatment (eg, improved survival).

The Comprehensive Geriatric Assessment has been created to properly assess aging in correlation to individual and patient-centered biologic and clinical metrics.
Following extensive literature reviews, the International Society of Geriatric Oncology (SIOG) Prostate Cancer Working Group recognized that the most important prognostic factors in evaluating health status in elderly patients with prostate cancer include comorbidities, functional dependence, and nutrition status.³ An important prognosticator of survival in prostate cancer is preexisting comorbidities. The Cumulative Illness Rating Scale-Geriatrics (CIRS-G) is considered the best metric currently available in assessing a patient’s death risk unrelated to cancer.

Another important factor influencing survival of older patients with prostate cancer is the patient’s level of independent activity. Independent functioning is evaluated
using (1) activities of daily living (ADL); and (2) the instrumental activities of daily living (IADL).^4-6

Health Status Subgroups

The SIOG recommendation for prostate cancer treatment in older patients is based on a complete assessment of existing comorbidities of patients using the CIRS-G,
IADL, and ADL scales as well as the nutritional status of each patient.^3,7-9 Based on these prognostic tools, the SIOG classifies the health status of elderly patients with prostate cancer into 4 prognostic health status categories: healthy, vulnerable, frail, and terminal.^10,11

Patient Characteristics

Older patients generally present with highrisk prostate cancer at diagnosis.^12,13 However, older patients are less likely to be treated with curative intent, resulting in
lower overall and disease-specific survivals. Nearly 40% of deaths due to prostate cancer occur in patients aged ≥ 75 years and 31% in the group aged ≥ 85 years.^12,14 Recent reports have demonstrated that curative radiotherapy or surgery improved survival outcomes as well as QOL in the elderly, comparable with those seen in younger patients.

Bechis and colleagues analyzed the relationship between survival of older patients with high-risk cancer and curative local therapy.¹⁵ Treatment modalities included radical prostatectomy, external-beam radiation therapy (EBRT), watchful waiting/active surveillance, and other modalities, including primary androgen deprivation therapy (ADT). The findings were: (1) older patients more frequently presented with high-risk disease as age increased; (2) therapeutic approaches varied but were based mainly on age at diagnosis rather than on cancer risk factors (Figures 2 and 3); and (3) ADT was used more frequently in older patients compared with its use in younger patients, irrespective of the risk score, including patients with high-risk disease.

Older patients were less likely to receive radical therapy, especially surgical treatment, regardless of risk category. Forty-four percent of patients aged > 70 years with high-risk disease died of any cause at a median 5.7 years, and 21% died of prostate cancer; whereas 47% of patients aged > 75 years with high-risk disease died at a median of 5.3 years, and 20% of those died of prostate cancer.

When older patients with high-risk disease received curative local therapy, however, the mortality rate decreased.

In a study by Sun and colleagues, 4,561 senior patients who received radical prostatectomy therapy were classified into 3 age groups (aged < 60 years, aged 60 to 70 years, and aged > 70 years) based on the year of surgery (before or after 2000). Therapy outcomes were compared among the 3 groups.¹⁶ The researchers found that seniors aged > 70 years who presented with high-risk disease had poorer therapeutic outcomes. A diagnosis of advancedstage cancer and a Gleason score > 7 were more often made in patients aged > 70 years vs that of their younger counterparts. They also found greater risk of failures for these patients in biochemical recurrence, distant metastasis, and disease-specific survivals.

Most clinicians typically ruled out active treatment based on chronologic age alone, without considering existing comorbidities and overall life expectancy. According
to a study by Daskivich and colleagues, only 16% of patients aged > 75 years were aggressively treated, whereas 84% of patients aged < 55 years received aggressive curative therapy, using radical prostatectomy, radiation therapy, or brachytherapy.¹⁷

Therapeutic Approaches

Current NCCN guidelines recommend active surveillance as an option for men with low- and intermediate-risk disease with a < 10-year life expectancy and the only option for men with a < 20-year life expectancy and a very low-risk of prostate cancer (stage T1c, Gleason ≤ 6, prostate specific antigen [PSA] < 10 ng/mL, < 3 positive cores, < 50% core involvement, and PSA density < 0.15 ng/mL²). Patients who are older and have significant comorbidities should be managed with active surveillance rather than with active treatment. In the practice setting, however, studies indicated that a substantial number of older men with limited life expectancy still received aggressive treatment for low-risk cancer. Active treatment tended to decrease with age but was still common among men aged > 80 years: 25% received active local therapy, 36% received primary ADT, and only 39% received no active treatment.¹⁸

Surgery

Surgical treatment is an active therapeutic option for some patients with localized disease. Mortalities were reduced using prostatectomy vs watchful waiting, including disease-specific mortality and rates of metastasis. As newer techniques develop, laparoscopic prostatectomy may be able to provide excellent therapeutic
outcomes with quick surgical recovery times and possibly less postoperative nerve damage. Compared with younger patients, older patients experienced comparable
outcomes after surgical therapy.19-21 Despite encouraging surgical outcomes, however, surgery is not generally offered to patients aged > 70 years because
of the presumed high risks related to possible surgical complications.

Radiation Therapies

External-beam radiation therapy has been a well-established, standard mode of radiotherapy for the past several decades, among various radiation modalities, including brachytherapy (high- and low-dose radioactive seed implant therapy), cyber-knife therapy, and proton therapy. If indicated, EBRT rather than surgery is generally suggested as an active treatment for patients with localized prostate cancer. In general, EBRT and radical prostatectomy are comparable in survival
outcomes, but EBRT is preferred for older patients because it is noninvasive.^21,22 Conventional EBRT technique has gradually progressed over the past several decades, advancing to 3D conformal radiotherapy, intensity-modulated radiation therapy (IMRT), image-guided radiotherapy, and then most recently to RapidArc radiation therapy.

RapidArc radiotherapy is an advanced form of IMRT that increases dose conformity and significantly shortens daily treatment times. In contrast to the static conventional IMRT technique (requiring repeated stops to deliver radiation through a 360° rotation of the therapy machine around the patient), RapidArc radiotherapy continues to deliver radiation therapy to the targeted tumor lesion with no interruption while the therapy machine is rotating around the patient. Accordingly, radiation therapy time is much shorter (up to 8 times faster) compared with conventional IMRT radiotherapy.

Systemic Therapy

Androgen-deprivation therapy can slow cancer growth, as it inhibits androgen production, blocks androgen action, or both. For localized prostate cancers with intermittent- and high-risk for recurrence, radiation therapy combined with ADT (eg, leuprolide, goserelin, triptorelin) reduces mortality of patients compared with ADT alone. In addition, hormone therapy is used for advanced, recurrent, or metastatic prostate cancers.

Most advanced and roughly one-fifth of biologically recurrent cancers ultimately convert to castrationresistant prostate cancer and may potentially benefit from nonhormonal systemic chemotherapy. Docetaxel with or without prednisone is the agent of choice for castration-resistant symptomatic metastatic prostate cancer. Cabazitaxel is a secondgeneration taxane and approved for castration-resistantmetastatic prostate cancer. Other systemic drugs (hormonal) for chemotherapy-naïve, metastatic castration-resistant prostate cancer are abiraterone (androgen synthesis inhibitor) and enzalutamide (anti-androgen).

Low-Risk Prostate Cancers

Active surveillance would be a reasonable management option for older patients with low-risk, localized prostate cancer and limited life expectancy of < 10 years. Albertsen and colleagues reported that patients with welldifferentiated prostate cancer and limited life expectancy have little chance of death due to prostate cancer but are more likely die of other causes, such as preexisting comorbidities.²³ Bill-Axelson and colleagues reported a very similar cancer-specific mortality rate of only 2.5% for patients with well-differentiated prostate cancer who are receiving either active therapy or active surveillance.²⁴ In another study, Krakowsky and colleagues reported a 97% 10-year cancer-specific survival rate in 450 patients with a median age of 70 years, and in a randomized study, Holmberg and colleagues reported no differences in overall survival for patients aged > 65 years who were randomized to surgery or watchful waiting for early-stage prostate cancer.^25,26

The literature consistently reports cancer-specific survival rates approaching 100% for patients with low-risk prostate cancer. The main concern regarding aggressive
therapy for older patients with low-risk cancer and significant comorbidities, as well as limited life expectancy, is the real possibility of overtreatment and the resultant high risk of treatment-related complications and loss in QOL. For example, surgery can lead to varying degrees of incontinence, and radiation can lead to rectal bleeding from proctitis, both severely impacting patients’ QOL.

High-Risk Prostate Cancers

Older patients with high-risk prostate cancer generally do not receive curative therapy. Bechis and colleagues examined the influence of age on disease-specific mortality.¹⁵ They found that patients aged > 75 years were more likely to be diagnosed with high-risk prostate cancer and treated with conservative therapy, such as ADT or watchful waiting, often resulting in death. They also found that the choice of therapy in older patients was based primarily on age rather than on comorbidities or other disease factors. Trends for such undertreatment were most evident in healthy seniors with high-risk cancer. The undertreatment of older patients with lower comorbidities contributes to the higher disease-specific mortality seen in the elderly population. Such healthy older patients were often overlooked solely because of their age and might have been denied the opportunity to receive curative and life-saving therapy early.

Summary

Most prostate cancers develop in older patients, and nearly one-fourth of prostate cancers are diagnosed in patients who are aged > 75 years. In addition, older patients show a higher tendency to present with highrisk prostate cancer. Furthermore, older patients have a higher risk of death compared with that of younger
patients, although many of them still die of causes other than prostate cancer. The most important prognostic factors in older patients, as recognized by the SIOG Prostate Cancer Working Group, included comorbidities, dependence status, and nutrition status. Management decisions for older patients with prostate cancer should be individualized and formulated based on remaining life expectancy, the patient’s functional performance and health status, as well as coexisting comorbidities and patient-specific prognostic characteristics of the prostate cancer, such as stage, Gleason score, and PSA values.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations— including indications, contraindications, warnings, and adverse effects—before administering pharmacologic
therapy to patients.

Click here to read the digital edition.

This article (part 2 of 2) focuses on the treatment of prostate cancer in seniors. Part 1 provided an overview of prostate cancer epidemiology, pathology, and screening in senior patients.

There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Recently, the International Society of Geriatric Oncology assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.

Patient Evaluation

The practice guidelines of the National Comprehensive Cancer Network (NCCN) recommend using life expectancy in determining treatment.¹ Prostate cancer is considered to be an indolent disease, and active therapy may be more harmful than beneficial to older patients whose life expectancy is limited because of treatment-related sequelae. Therefore, an accurate estimation of life expectancy is important in devising treatment strategies for older patients.

Age should not be the only factor in determining the life expectancy of patients, because life expectancy varies widely based on the patient’s health status, including preexisting comorbidities. Chronologic life expectancy can be found in the Social Security Administration’s life tables. Individual life expectancy is then projected by adding 50% to or deducting 50% from the chronologic life expectancy for men in the highest and lowest quartile of health, respectively. The life expectancy from the life tables can be applied with no addition or subtraction for men in the middle 2 quartiles of health status (Figure 1).²

Geriatric Assessment

Despite the increasing incidence of prostate cancer in older adults, no particular guidelines for its management exist. Compared with younger patients, older
patients with prostate cancer need to weigh the benefits of treatment vs the risks to avoid any potential adverse treatment-related quality of life (QOL) decreases. Clearly, for some patients there are no significant benefits from treatment (eg, improved survival).

The Comprehensive Geriatric Assessment has been created to properly assess aging in correlation to individual and patient-centered biologic and clinical metrics.
Following extensive literature reviews, the International Society of Geriatric Oncology (SIOG) Prostate Cancer Working Group recognized that the most important prognostic factors in evaluating health status in elderly patients with prostate cancer include comorbidities, functional dependence, and nutrition status.³ An important prognosticator of survival in prostate cancer is preexisting comorbidities. The Cumulative Illness Rating Scale-Geriatrics (CIRS-G) is considered the best metric currently available in assessing a patient’s death risk unrelated to cancer.

Another important factor influencing survival of older patients with prostate cancer is the patient’s level of independent activity. Independent functioning is evaluated
using (1) activities of daily living (ADL); and (2) the instrumental activities of daily living (IADL).^4-6

Health Status Subgroups

The SIOG recommendation for prostate cancer treatment in older patients is based on a complete assessment of existing comorbidities of patients using the CIRS-G,
IADL, and ADL scales as well as the nutritional status of each patient.^3,7-9 Based on these prognostic tools, the SIOG classifies the health status of elderly patients with prostate cancer into 4 prognostic health status categories: healthy, vulnerable, frail, and terminal.^10,11

Patient Characteristics

Older patients generally present with highrisk prostate cancer at diagnosis.^12,13 However, older patients are less likely to be treated with curative intent, resulting in
lower overall and disease-specific survivals. Nearly 40% of deaths due to prostate cancer occur in patients aged ≥ 75 years and 31% in the group aged ≥ 85 years.^12,14 Recent reports have demonstrated that curative radiotherapy or surgery improved survival outcomes as well as QOL in the elderly, comparable with those seen in younger patients.

Bechis and colleagues analyzed the relationship between survival of older patients with high-risk cancer and curative local therapy.¹⁵ Treatment modalities included radical prostatectomy, external-beam radiation therapy (EBRT), watchful waiting/active surveillance, and other modalities, including primary androgen deprivation therapy (ADT). The findings were: (1) older patients more frequently presented with high-risk disease as age increased; (2) therapeutic approaches varied but were based mainly on age at diagnosis rather than on cancer risk factors (Figures 2 and 3); and (3) ADT was used more frequently in older patients compared with its use in younger patients, irrespective of the risk score, including patients with high-risk disease.

Older patients were less likely to receive radical therapy, especially surgical treatment, regardless of risk category. Forty-four percent of patients aged > 70 years with high-risk disease died of any cause at a median 5.7 years, and 21% died of prostate cancer; whereas 47% of patients aged > 75 years with high-risk disease died at a median of 5.3 years, and 20% of those died of prostate cancer.

When older patients with high-risk disease received curative local therapy, however, the mortality rate decreased.

In a study by Sun and colleagues, 4,561 senior patients who received radical prostatectomy therapy were classified into 3 age groups (aged < 60 years, aged 60 to 70 years, and aged > 70 years) based on the year of surgery (before or after 2000). Therapy outcomes were compared among the 3 groups.¹⁶ The researchers found that seniors aged > 70 years who presented with high-risk disease had poorer therapeutic outcomes. A diagnosis of advancedstage cancer and a Gleason score > 7 were more often made in patients aged > 70 years vs that of their younger counterparts. They also found greater risk of failures for these patients in biochemical recurrence, distant metastasis, and disease-specific survivals.

Most clinicians typically ruled out active treatment based on chronologic age alone, without considering existing comorbidities and overall life expectancy. According
to a study by Daskivich and colleagues, only 16% of patients aged > 75 years were aggressively treated, whereas 84% of patients aged < 55 years received aggressive curative therapy, using radical prostatectomy, radiation therapy, or brachytherapy.¹⁷

Therapeutic Approaches

Current NCCN guidelines recommend active surveillance as an option for men with low- and intermediate-risk disease with a < 10-year life expectancy and the only option for men with a < 20-year life expectancy and a very low-risk of prostate cancer (stage T1c, Gleason ≤ 6, prostate specific antigen [PSA] < 10 ng/mL, < 3 positive cores, < 50% core involvement, and PSA density < 0.15 ng/mL²). Patients who are older and have significant comorbidities should be managed with active surveillance rather than with active treatment. In the practice setting, however, studies indicated that a substantial number of older men with limited life expectancy still received aggressive treatment for low-risk cancer. Active treatment tended to decrease with age but was still common among men aged > 80 years: 25% received active local therapy, 36% received primary ADT, and only 39% received no active treatment.¹⁸

Surgery

Surgical treatment is an active therapeutic option for some patients with localized disease. Mortalities were reduced using prostatectomy vs watchful waiting, including disease-specific mortality and rates of metastasis. As newer techniques develop, laparoscopic prostatectomy may be able to provide excellent therapeutic
outcomes with quick surgical recovery times and possibly less postoperative nerve damage. Compared with younger patients, older patients experienced comparable
outcomes after surgical therapy.19-21 Despite encouraging surgical outcomes, however, surgery is not generally offered to patients aged > 70 years because
of the presumed high risks related to possible surgical complications.

Radiation Therapies

External-beam radiation therapy has been a well-established, standard mode of radiotherapy for the past several decades, among various radiation modalities, including brachytherapy (high- and low-dose radioactive seed implant therapy), cyber-knife therapy, and proton therapy. If indicated, EBRT rather than surgery is generally suggested as an active treatment for patients with localized prostate cancer. In general, EBRT and radical prostatectomy are comparable in survival
outcomes, but EBRT is preferred for older patients because it is noninvasive.^21,22 Conventional EBRT technique has gradually progressed over the past several decades, advancing to 3D conformal radiotherapy, intensity-modulated radiation therapy (IMRT), image-guided radiotherapy, and then most recently to RapidArc radiation therapy.

RapidArc radiotherapy is an advanced form of IMRT that increases dose conformity and significantly shortens daily treatment times. In contrast to the static conventional IMRT technique (requiring repeated stops to deliver radiation through a 360° rotation of the therapy machine around the patient), RapidArc radiotherapy continues to deliver radiation therapy to the targeted tumor lesion with no interruption while the therapy machine is rotating around the patient. Accordingly, radiation therapy time is much shorter (up to 8 times faster) compared with conventional IMRT radiotherapy.

Systemic Therapy

Androgen-deprivation therapy can slow cancer growth, as it inhibits androgen production, blocks androgen action, or both. For localized prostate cancers with intermittent- and high-risk for recurrence, radiation therapy combined with ADT (eg, leuprolide, goserelin, triptorelin) reduces mortality of patients compared with ADT alone. In addition, hormone therapy is used for advanced, recurrent, or metastatic prostate cancers.

Most advanced and roughly one-fifth of biologically recurrent cancers ultimately convert to castrationresistant prostate cancer and may potentially benefit from nonhormonal systemic chemotherapy. Docetaxel with or without prednisone is the agent of choice for castration-resistant symptomatic metastatic prostate cancer. Cabazitaxel is a secondgeneration taxane and approved for castration-resistantmetastatic prostate cancer. Other systemic drugs (hormonal) for chemotherapy-naïve, metastatic castration-resistant prostate cancer are abiraterone (androgen synthesis inhibitor) and enzalutamide (anti-androgen).

Low-Risk Prostate Cancers

Active surveillance would be a reasonable management option for older patients with low-risk, localized prostate cancer and limited life expectancy of < 10 years. Albertsen and colleagues reported that patients with welldifferentiated prostate cancer and limited life expectancy have little chance of death due to prostate cancer but are more likely die of other causes, such as preexisting comorbidities.²³ Bill-Axelson and colleagues reported a very similar cancer-specific mortality rate of only 2.5% for patients with well-differentiated prostate cancer who are receiving either active therapy or active surveillance.²⁴ In another study, Krakowsky and colleagues reported a 97% 10-year cancer-specific survival rate in 450 patients with a median age of 70 years, and in a randomized study, Holmberg and colleagues reported no differences in overall survival for patients aged > 65 years who were randomized to surgery or watchful waiting for early-stage prostate cancer.^25,26

The literature consistently reports cancer-specific survival rates approaching 100% for patients with low-risk prostate cancer. The main concern regarding aggressive
therapy for older patients with low-risk cancer and significant comorbidities, as well as limited life expectancy, is the real possibility of overtreatment and the resultant high risk of treatment-related complications and loss in QOL. For example, surgery can lead to varying degrees of incontinence, and radiation can lead to rectal bleeding from proctitis, both severely impacting patients’ QOL.

High-Risk Prostate Cancers

Older patients with high-risk prostate cancer generally do not receive curative therapy. Bechis and colleagues examined the influence of age on disease-specific mortality.¹⁵ They found that patients aged > 75 years were more likely to be diagnosed with high-risk prostate cancer and treated with conservative therapy, such as ADT or watchful waiting, often resulting in death. They also found that the choice of therapy in older patients was based primarily on age rather than on comorbidities or other disease factors. Trends for such undertreatment were most evident in healthy seniors with high-risk cancer. The undertreatment of older patients with lower comorbidities contributes to the higher disease-specific mortality seen in the elderly population. Such healthy older patients were often overlooked solely because of their age and might have been denied the opportunity to receive curative and life-saving therapy early.

Summary

Most prostate cancers develop in older patients, and nearly one-fourth of prostate cancers are diagnosed in patients who are aged > 75 years. In addition, older patients show a higher tendency to present with highrisk prostate cancer. Furthermore, older patients have a higher risk of death compared with that of younger
patients, although many of them still die of causes other than prostate cancer. The most important prognostic factors in older patients, as recognized by the SIOG Prostate Cancer Working Group, included comorbidities, dependence status, and nutrition status. Management decisions for older patients with prostate cancer should be individualized and formulated based on remaining life expectancy, the patient’s functional performance and health status, as well as coexisting comorbidities and patient-specific prognostic characteristics of the prostate cancer, such as stage, Gleason score, and PSA values.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations— including indications, contraindications, warnings, and adverse effects—before administering pharmacologic
therapy to patients.

Click here to read the digital edition.

This article (part 2 of 2) focuses on the treatment of prostate cancer in seniors. Part 1 provided an overview of prostate cancer epidemiology, pathology, and screening in senior patients.

There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Recently, the International Society of Geriatric Oncology assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.

Patient Evaluation

The practice guidelines of the National Comprehensive Cancer Network (NCCN) recommend using life expectancy in determining treatment.¹ Prostate cancer is considered to be an indolent disease, and active therapy may be more harmful than beneficial to older patients whose life expectancy is limited because of treatment-related sequelae. Therefore, an accurate estimation of life expectancy is important in devising treatment strategies for older patients.

Age should not be the only factor in determining the life expectancy of patients, because life expectancy varies widely based on the patient’s health status, including preexisting comorbidities. Chronologic life expectancy can be found in the Social Security Administration’s life tables. Individual life expectancy is then projected by adding 50% to or deducting 50% from the chronologic life expectancy for men in the highest and lowest quartile of health, respectively. The life expectancy from the life tables can be applied with no addition or subtraction for men in the middle 2 quartiles of health status (Figure 1).²

Geriatric Assessment

Despite the increasing incidence of prostate cancer in older adults, no particular guidelines for its management exist. Compared with younger patients, older
patients with prostate cancer need to weigh the benefits of treatment vs the risks to avoid any potential adverse treatment-related quality of life (QOL) decreases. Clearly, for some patients there are no significant benefits from treatment (eg, improved survival).

The Comprehensive Geriatric Assessment has been created to properly assess aging in correlation to individual and patient-centered biologic and clinical metrics.
Following extensive literature reviews, the International Society of Geriatric Oncology (SIOG) Prostate Cancer Working Group recognized that the most important prognostic factors in evaluating health status in elderly patients with prostate cancer include comorbidities, functional dependence, and nutrition status.³ An important prognosticator of survival in prostate cancer is preexisting comorbidities. The Cumulative Illness Rating Scale-Geriatrics (CIRS-G) is considered the best metric currently available in assessing a patient’s death risk unrelated to cancer.

Another important factor influencing survival of older patients with prostate cancer is the patient’s level of independent activity. Independent functioning is evaluated
using (1) activities of daily living (ADL); and (2) the instrumental activities of daily living (IADL).^4-6

Health Status Subgroups

The SIOG recommendation for prostate cancer treatment in older patients is based on a complete assessment of existing comorbidities of patients using the CIRS-G,
IADL, and ADL scales as well as the nutritional status of each patient.^3,7-9 Based on these prognostic tools, the SIOG classifies the health status of elderly patients with prostate cancer into 4 prognostic health status categories: healthy, vulnerable, frail, and terminal.^10,11

Patient Characteristics

Older patients generally present with highrisk prostate cancer at diagnosis.^12,13 However, older patients are less likely to be treated with curative intent, resulting in
lower overall and disease-specific survivals. Nearly 40% of deaths due to prostate cancer occur in patients aged ≥ 75 years and 31% in the group aged ≥ 85 years.^12,14 Recent reports have demonstrated that curative radiotherapy or surgery improved survival outcomes as well as QOL in the elderly, comparable with those seen in younger patients.

Bechis and colleagues analyzed the relationship between survival of older patients with high-risk cancer and curative local therapy.¹⁵ Treatment modalities included radical prostatectomy, external-beam radiation therapy (EBRT), watchful waiting/active surveillance, and other modalities, including primary androgen deprivation therapy (ADT). The findings were: (1) older patients more frequently presented with high-risk disease as age increased; (2) therapeutic approaches varied but were based mainly on age at diagnosis rather than on cancer risk factors (Figures 2 and 3); and (3) ADT was used more frequently in older patients compared with its use in younger patients, irrespective of the risk score, including patients with high-risk disease.

Older patients were less likely to receive radical therapy, especially surgical treatment, regardless of risk category. Forty-four percent of patients aged > 70 years with high-risk disease died of any cause at a median 5.7 years, and 21% died of prostate cancer; whereas 47% of patients aged > 75 years with high-risk disease died at a median of 5.3 years, and 20% of those died of prostate cancer.

When older patients with high-risk disease received curative local therapy, however, the mortality rate decreased.

In a study by Sun and colleagues, 4,561 senior patients who received radical prostatectomy therapy were classified into 3 age groups (aged < 60 years, aged 60 to 70 years, and aged > 70 years) based on the year of surgery (before or after 2000). Therapy outcomes were compared among the 3 groups.¹⁶ The researchers found that seniors aged > 70 years who presented with high-risk disease had poorer therapeutic outcomes. A diagnosis of advancedstage cancer and a Gleason score > 7 were more often made in patients aged > 70 years vs that of their younger counterparts. They also found greater risk of failures for these patients in biochemical recurrence, distant metastasis, and disease-specific survivals.

Most clinicians typically ruled out active treatment based on chronologic age alone, without considering existing comorbidities and overall life expectancy. According
to a study by Daskivich and colleagues, only 16% of patients aged > 75 years were aggressively treated, whereas 84% of patients aged < 55 years received aggressive curative therapy, using radical prostatectomy, radiation therapy, or brachytherapy.¹⁷

Therapeutic Approaches

Current NCCN guidelines recommend active surveillance as an option for men with low- and intermediate-risk disease with a < 10-year life expectancy and the only option for men with a < 20-year life expectancy and a very low-risk of prostate cancer (stage T1c, Gleason ≤ 6, prostate specific antigen [PSA] < 10 ng/mL, < 3 positive cores, < 50% core involvement, and PSA density < 0.15 ng/mL²). Patients who are older and have significant comorbidities should be managed with active surveillance rather than with active treatment. In the practice setting, however, studies indicated that a substantial number of older men with limited life expectancy still received aggressive treatment for low-risk cancer. Active treatment tended to decrease with age but was still common among men aged > 80 years: 25% received active local therapy, 36% received primary ADT, and only 39% received no active treatment.¹⁸

Surgery

Surgical treatment is an active therapeutic option for some patients with localized disease. Mortalities were reduced using prostatectomy vs watchful waiting, including disease-specific mortality and rates of metastasis. As newer techniques develop, laparoscopic prostatectomy may be able to provide excellent therapeutic
outcomes with quick surgical recovery times and possibly less postoperative nerve damage. Compared with younger patients, older patients experienced comparable
outcomes after surgical therapy.19-21 Despite encouraging surgical outcomes, however, surgery is not generally offered to patients aged > 70 years because
of the presumed high risks related to possible surgical complications.

Radiation Therapies

External-beam radiation therapy has been a well-established, standard mode of radiotherapy for the past several decades, among various radiation modalities, including brachytherapy (high- and low-dose radioactive seed implant therapy), cyber-knife therapy, and proton therapy. If indicated, EBRT rather than surgery is generally suggested as an active treatment for patients with localized prostate cancer. In general, EBRT and radical prostatectomy are comparable in survival
outcomes, but EBRT is preferred for older patients because it is noninvasive.^21,22 Conventional EBRT technique has gradually progressed over the past several decades, advancing to 3D conformal radiotherapy, intensity-modulated radiation therapy (IMRT), image-guided radiotherapy, and then most recently to RapidArc radiation therapy.

RapidArc radiotherapy is an advanced form of IMRT that increases dose conformity and significantly shortens daily treatment times. In contrast to the static conventional IMRT technique (requiring repeated stops to deliver radiation through a 360° rotation of the therapy machine around the patient), RapidArc radiotherapy continues to deliver radiation therapy to the targeted tumor lesion with no interruption while the therapy machine is rotating around the patient. Accordingly, radiation therapy time is much shorter (up to 8 times faster) compared with conventional IMRT radiotherapy.

Systemic Therapy

Androgen-deprivation therapy can slow cancer growth, as it inhibits androgen production, blocks androgen action, or both. For localized prostate cancers with intermittent- and high-risk for recurrence, radiation therapy combined with ADT (eg, leuprolide, goserelin, triptorelin) reduces mortality of patients compared with ADT alone. In addition, hormone therapy is used for advanced, recurrent, or metastatic prostate cancers.

Most advanced and roughly one-fifth of biologically recurrent cancers ultimately convert to castrationresistant prostate cancer and may potentially benefit from nonhormonal systemic chemotherapy. Docetaxel with or without prednisone is the agent of choice for castration-resistant symptomatic metastatic prostate cancer. Cabazitaxel is a secondgeneration taxane and approved for castration-resistantmetastatic prostate cancer. Other systemic drugs (hormonal) for chemotherapy-naïve, metastatic castration-resistant prostate cancer are abiraterone (androgen synthesis inhibitor) and enzalutamide (anti-androgen).

Low-Risk Prostate Cancers

Active surveillance would be a reasonable management option for older patients with low-risk, localized prostate cancer and limited life expectancy of < 10 years. Albertsen and colleagues reported that patients with welldifferentiated prostate cancer and limited life expectancy have little chance of death due to prostate cancer but are more likely die of other causes, such as preexisting comorbidities.²³ Bill-Axelson and colleagues reported a very similar cancer-specific mortality rate of only 2.5% for patients with well-differentiated prostate cancer who are receiving either active therapy or active surveillance.²⁴ In another study, Krakowsky and colleagues reported a 97% 10-year cancer-specific survival rate in 450 patients with a median age of 70 years, and in a randomized study, Holmberg and colleagues reported no differences in overall survival for patients aged > 65 years who were randomized to surgery or watchful waiting for early-stage prostate cancer.^25,26

The literature consistently reports cancer-specific survival rates approaching 100% for patients with low-risk prostate cancer. The main concern regarding aggressive
therapy for older patients with low-risk cancer and significant comorbidities, as well as limited life expectancy, is the real possibility of overtreatment and the resultant high risk of treatment-related complications and loss in QOL. For example, surgery can lead to varying degrees of incontinence, and radiation can lead to rectal bleeding from proctitis, both severely impacting patients’ QOL.

High-Risk Prostate Cancers

Older patients with high-risk prostate cancer generally do not receive curative therapy. Bechis and colleagues examined the influence of age on disease-specific mortality.¹⁵ They found that patients aged > 75 years were more likely to be diagnosed with high-risk prostate cancer and treated with conservative therapy, such as ADT or watchful waiting, often resulting in death. They also found that the choice of therapy in older patients was based primarily on age rather than on comorbidities or other disease factors. Trends for such undertreatment were most evident in healthy seniors with high-risk cancer. The undertreatment of older patients with lower comorbidities contributes to the higher disease-specific mortality seen in the elderly population. Such healthy older patients were often overlooked solely because of their age and might have been denied the opportunity to receive curative and life-saving therapy early.

Summary

Most prostate cancers develop in older patients, and nearly one-fourth of prostate cancers are diagnosed in patients who are aged > 75 years. In addition, older patients show a higher tendency to present with highrisk prostate cancer. Furthermore, older patients have a higher risk of death compared with that of younger
patients, although many of them still die of causes other than prostate cancer. The most important prognostic factors in older patients, as recognized by the SIOG Prostate Cancer Working Group, included comorbidities, dependence status, and nutrition status. Management decisions for older patients with prostate cancer should be individualized and formulated based on remaining life expectancy, the patient’s functional performance and health status, as well as coexisting comorbidities and patient-specific prognostic characteristics of the prostate cancer, such as stage, Gleason score, and PSA values.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations— including indications, contraindications, warnings, and adverse effects—before administering pharmacologic
therapy to patients.

Click here to read the digital edition.

Prostate cancer is the most common cancer and the second leading cause of cancer deaths in men. The incidence of prostate cancer continues to rise. Roughly 220,800 men were expected to be newly diagnosed with prostate cancer in 2015.¹ As the population ages and overall life expectancy increases, prostate cancer is likely to become a growing health care burden, especially because prostate cancer is primarily a disease of elderly males.

There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Fortunately, the International Society of Geriatric Oncology recently assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.

This article (part 1 of 2) provides a brief overview of prostate cancer epidemiology, pathology and screening in senior patients. The second part (to be published in August 2015) will focus on treatment.

Epidemiology

Currently more than 2 million men are estimated to have prostate cancer in the U.S. About 18% to 20% of U.S. males have a lifetime risk of developing prostate
cancer. Prostate cancer is mainly a disease of seniors aged between 60 and 70 years—the median age of prostate cancer at diagnosis is about 65 to 68 years. About 65% of new prostate cancers are diagnosed in males aged ‹ 65 years and 25% in males > aged 75 years.² Most older patients with prostate cancer do not die of prostate cancer.

As the life expectancy of the general population increases, the risk of developing prostate cancer among seniors is also expected to proportionally rise. Historically, the cancer-specific mortality rate of prostate cancer in patients aged > 70 years was only 29% if managed either with active surveillance or hormonal manipulation.

Prevalence of Incidental Prostate Cancer

There is an abrupt age-dependent increase of prostate cancer incidence from the 5th decade of life on. Furthermore, there is a 1 in 3 chance of incidental prostate cancer in men aged between 60 to 69 years and a 46% prevalence in men aged > 70 years. Yin and colleagues found that 12% of patients in their study group harbored incidental, preclinical prostate cancer.^3-5 The increasing prostate cancer incidence showed a strong and clear correlation with advancing age (Figure 1).

The lifetime probability of being diagnosed with prostate cancer also increases significantly with age.^6,7 Patients with a life expectancy of < 5 years are unlikely
to benefit from cancer screening and may be more likely to experience complications and potential treatment-related harm as a result of screening. Therefore, estimating the patient’s residual life expectancy is a critical factor in the decision-making process for patients with prostate cancer. Life expectancy can differ, depending on various factors besides age, such as health, functional status, and medical comorbidities. The estimated age-related life expectancy for seniors has gradually increased over the previous 5 decades.⁸

Risk Factors

There are several risk factors for prostate cancer: age, race, and ethnicity; genetic factors; environmental and socioeconomic status; dietary status; and others. However, these factors may play only a limited role in the risk of prostate cancer, and a cautious approach and careful interpretation are required for their application in clinical practice.^9,10

1. Age. There is a sudden and dramatic increase in the prevalence of prostate cancer with advancing age. Prostate cancer is rarely diagnosed in men aged < 40 years, but thereafter, the incidence of prostate cancer climbs steadily.¹¹ Surprisingly, subclinical microscopic prostate cancer was found at autopsy (death from unrelated causes) in a majority of senior males in their eighth decade of life.³
2. Race/ethnicity. Epidemiologic studies in the U.S. found the highest incidence of prostate cancer in African American men (incidence rate of 235 per 100,000 African American vs 150 per 100,000 white men). Also, African American men tended to present with higher grades and stages of prostate cancer. There were much lower incidence rates of prostate cancer in Asian Americans and Pacific Islanders, Hispanics, and American Indian and Alaska Natives (90 per 100,000, 126 per 100,000, and 78 per 100,000, respectively).^9,10
3. Diet. According to researchers, the western diet may be an important risk factors for prostate cancer. However, the actual relationship between obesity and prostate cancer is somewhat unclear, and any correlation is at present highly controversial. Some investigators have postulated that obesity can contribute to the development of prostate cancer; other studies have clearly established that obese patients, once diagnosed with prostate cancer, have inferior outcomes irrespective of the treatment modality used. Other studies, however, have suggested that certain hormonal profiles related to obesity may be protective against the development of prostate cancer.^12,13

Pathologic Evaluation

The original Gleason Grading System was devised based on the careful analysis of the cellular pattern of tumor architecture, using a 5-point scale: Tumor cells similar to normal-appearing prostate tissue were designated Gleason 1, 2, and 3; whereas cells/glands appearing abnormal were designated Gleason 4 and 5. The total Gleason score is the sum of the 2 most representative patterns, applied to both prostatectomy and needle biopsy specimens. The main differences from the original Gleason system, proposed by the 2005 International Society of Urological Pathology Modified Gleason System, are summarized in Table 1.

Early Detection and Screening

Although prostate cancer screening with prostate-specific antigen (PSA) detects many prostate cancer cases, concerns surrounding universal screening include the potential for overdiagnosis and overtreatment, along with the real possibility for adverse effects and complications from treatment. In addition, the recommendations for prostate cancer screening are not consistent among the various national health organizations. The American Cancer Society (ACS) recommends having an informed discussion between the health care provider and patient about the possible benefits and harms of screening. The discussion should not be initiated in men aged < 50 years (or aged < 45 years in men with high-risk features), and there is no need for screening in men with a life expectancy of < 10 years.

Prostate cancer screening may detect cancers that would not have become clinically significant. This is even more likely to be true when life expectancy decreases. Informed screening decisions in senior adults should be made according to the individual’s values and preferences in addition to the estimated outcomes and possible harms as a result of screening. The National Comprehensive Cancer Network offers similar recommendation to the ACS Screening Guidelines (Table 2).

Screening Recommendations for Seniors

There have been no generally recognized guidelines on prostate cancer screening for seniors, although recently, Konety and colleagues published “The Iowa Prostate Cancer Consensus” for elderly prostate cancer patients (Table 3).¹⁷ The consensus includes:

• More prostate cancers are detected at an earlier stage, but many of them would never become clinically apparent in most patients’ life times
• A reduced mortality (either overall or disease specific) from screening is not proven during the course of 10-year follow-up
• Harms related to diagnostic and therapeutic procedures develop early and remain for an extended period, causing a negative impact on quality of life
• The small benefits of screening leading up to a prostatectomy are seen only after 12 years of follow-up and may be limited to a certain population group of
  patients who are aged < 65 years
• Current recommendations discourage the routine screening of seniors with short life expectancies (< 10 years) and depend on existing comorbidities and disease group risk

Conclusion

Prostate cancer is the most common cancer in American men and the second most common cause of cancer death. Prostate cancer is almost twice as common among African Americans vs whites, and much less common in Asian Americans and Pacific Islanders, Hispanics, American Indian and Alaska Natives. Prostate cancer is generally a cancer of older seniors, and nearly 80% of seniors are estimated to harbor subclinical prostate cancer by their eighth decade of life.⁸ Prostate cancer screening is not universally recommended, and major professional associations support an informed, evidence-based, shared decision-making process between medical professionals and patients. This decision should include the careful consideration of patients’ life expectancy and existing medical comorbidities, always weighing the potential benefits against the possible screening and treatment-related harms.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Prostate cancer is the most common cancer and the second leading cause of cancer deaths in men. The incidence of prostate cancer continues to rise. Roughly 220,800 men were expected to be newly diagnosed with prostate cancer in 2015.¹ As the population ages and overall life expectancy increases, prostate cancer is likely to become a growing health care burden, especially because prostate cancer is primarily a disease of elderly males.

There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Fortunately, the International Society of Geriatric Oncology recently assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.

This article (part 1 of 2) provides a brief overview of prostate cancer epidemiology, pathology and screening in senior patients. The second part (to be published in August 2015) will focus on treatment.

Epidemiology

Currently more than 2 million men are estimated to have prostate cancer in the U.S. About 18% to 20% of U.S. males have a lifetime risk of developing prostate
cancer. Prostate cancer is mainly a disease of seniors aged between 60 and 70 years—the median age of prostate cancer at diagnosis is about 65 to 68 years. About 65% of new prostate cancers are diagnosed in males aged ‹ 65 years and 25% in males > aged 75 years.² Most older patients with prostate cancer do not die of prostate cancer.

As the life expectancy of the general population increases, the risk of developing prostate cancer among seniors is also expected to proportionally rise. Historically, the cancer-specific mortality rate of prostate cancer in patients aged > 70 years was only 29% if managed either with active surveillance or hormonal manipulation.

Prevalence of Incidental Prostate Cancer

There is an abrupt age-dependent increase of prostate cancer incidence from the 5th decade of life on. Furthermore, there is a 1 in 3 chance of incidental prostate cancer in men aged between 60 to 69 years and a 46% prevalence in men aged > 70 years. Yin and colleagues found that 12% of patients in their study group harbored incidental, preclinical prostate cancer.^3-5 The increasing prostate cancer incidence showed a strong and clear correlation with advancing age (Figure 1).

The lifetime probability of being diagnosed with prostate cancer also increases significantly with age.^6,7 Patients with a life expectancy of < 5 years are unlikely
to benefit from cancer screening and may be more likely to experience complications and potential treatment-related harm as a result of screening. Therefore, estimating the patient’s residual life expectancy is a critical factor in the decision-making process for patients with prostate cancer. Life expectancy can differ, depending on various factors besides age, such as health, functional status, and medical comorbidities. The estimated age-related life expectancy for seniors has gradually increased over the previous 5 decades.⁸

Risk Factors

There are several risk factors for prostate cancer: age, race, and ethnicity; genetic factors; environmental and socioeconomic status; dietary status; and others. However, these factors may play only a limited role in the risk of prostate cancer, and a cautious approach and careful interpretation are required for their application in clinical practice.^9,10

1. Age. There is a sudden and dramatic increase in the prevalence of prostate cancer with advancing age. Prostate cancer is rarely diagnosed in men aged < 40 years, but thereafter, the incidence of prostate cancer climbs steadily.¹¹ Surprisingly, subclinical microscopic prostate cancer was found at autopsy (death from unrelated causes) in a majority of senior males in their eighth decade of life.³
2. Race/ethnicity. Epidemiologic studies in the U.S. found the highest incidence of prostate cancer in African American men (incidence rate of 235 per 100,000 African American vs 150 per 100,000 white men). Also, African American men tended to present with higher grades and stages of prostate cancer. There were much lower incidence rates of prostate cancer in Asian Americans and Pacific Islanders, Hispanics, and American Indian and Alaska Natives (90 per 100,000, 126 per 100,000, and 78 per 100,000, respectively).^9,10
3. Diet. According to researchers, the western diet may be an important risk factors for prostate cancer. However, the actual relationship between obesity and prostate cancer is somewhat unclear, and any correlation is at present highly controversial. Some investigators have postulated that obesity can contribute to the development of prostate cancer; other studies have clearly established that obese patients, once diagnosed with prostate cancer, have inferior outcomes irrespective of the treatment modality used. Other studies, however, have suggested that certain hormonal profiles related to obesity may be protective against the development of prostate cancer.^12,13

Pathologic Evaluation

The original Gleason Grading System was devised based on the careful analysis of the cellular pattern of tumor architecture, using a 5-point scale: Tumor cells similar to normal-appearing prostate tissue were designated Gleason 1, 2, and 3; whereas cells/glands appearing abnormal were designated Gleason 4 and 5. The total Gleason score is the sum of the 2 most representative patterns, applied to both prostatectomy and needle biopsy specimens. The main differences from the original Gleason system, proposed by the 2005 International Society of Urological Pathology Modified Gleason System, are summarized in Table 1.

Early Detection and Screening

Although prostate cancer screening with prostate-specific antigen (PSA) detects many prostate cancer cases, concerns surrounding universal screening include the potential for overdiagnosis and overtreatment, along with the real possibility for adverse effects and complications from treatment. In addition, the recommendations for prostate cancer screening are not consistent among the various national health organizations. The American Cancer Society (ACS) recommends having an informed discussion between the health care provider and patient about the possible benefits and harms of screening. The discussion should not be initiated in men aged < 50 years (or aged < 45 years in men with high-risk features), and there is no need for screening in men with a life expectancy of < 10 years.

Prostate cancer screening may detect cancers that would not have become clinically significant. This is even more likely to be true when life expectancy decreases. Informed screening decisions in senior adults should be made according to the individual’s values and preferences in addition to the estimated outcomes and possible harms as a result of screening. The National Comprehensive Cancer Network offers similar recommendation to the ACS Screening Guidelines (Table 2).

Screening Recommendations for Seniors

There have been no generally recognized guidelines on prostate cancer screening for seniors, although recently, Konety and colleagues published “The Iowa Prostate Cancer Consensus” for elderly prostate cancer patients (Table 3).¹⁷ The consensus includes:

• More prostate cancers are detected at an earlier stage, but many of them would never become clinically apparent in most patients’ life times
• A reduced mortality (either overall or disease specific) from screening is not proven during the course of 10-year follow-up
• Harms related to diagnostic and therapeutic procedures develop early and remain for an extended period, causing a negative impact on quality of life
• The small benefits of screening leading up to a prostatectomy are seen only after 12 years of follow-up and may be limited to a certain population group of
  patients who are aged < 65 years
• Current recommendations discourage the routine screening of seniors with short life expectancies (< 10 years) and depend on existing comorbidities and disease group risk

Conclusion

Prostate cancer is the most common cancer in American men and the second most common cause of cancer death. Prostate cancer is almost twice as common among African Americans vs whites, and much less common in Asian Americans and Pacific Islanders, Hispanics, American Indian and Alaska Natives. Prostate cancer is generally a cancer of older seniors, and nearly 80% of seniors are estimated to harbor subclinical prostate cancer by their eighth decade of life.⁸ Prostate cancer screening is not universally recommended, and major professional associations support an informed, evidence-based, shared decision-making process between medical professionals and patients. This decision should include the careful consideration of patients’ life expectancy and existing medical comorbidities, always weighing the potential benefits against the possible screening and treatment-related harms.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.

Prostate cancer is the most common cancer and the second leading cause of cancer deaths in men. The incidence of prostate cancer continues to rise. Roughly 220,800 men were expected to be newly diagnosed with prostate cancer in 2015.¹ As the population ages and overall life expectancy increases, prostate cancer is likely to become a growing health care burden, especially because prostate cancer is primarily a disease of elderly males.

There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Fortunately, the International Society of Geriatric Oncology recently assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.

This article (part 1 of 2) provides a brief overview of prostate cancer epidemiology, pathology and screening in senior patients. The second part (to be published in August 2015) will focus on treatment.

Epidemiology

Currently more than 2 million men are estimated to have prostate cancer in the U.S. About 18% to 20% of U.S. males have a lifetime risk of developing prostate
cancer. Prostate cancer is mainly a disease of seniors aged between 60 and 70 years—the median age of prostate cancer at diagnosis is about 65 to 68 years. About 65% of new prostate cancers are diagnosed in males aged ‹ 65 years and 25% in males > aged 75 years.² Most older patients with prostate cancer do not die of prostate cancer.

As the life expectancy of the general population increases, the risk of developing prostate cancer among seniors is also expected to proportionally rise. Historically, the cancer-specific mortality rate of prostate cancer in patients aged > 70 years was only 29% if managed either with active surveillance or hormonal manipulation.

Prevalence of Incidental Prostate Cancer

There is an abrupt age-dependent increase of prostate cancer incidence from the 5th decade of life on. Furthermore, there is a 1 in 3 chance of incidental prostate cancer in men aged between 60 to 69 years and a 46% prevalence in men aged > 70 years. Yin and colleagues found that 12% of patients in their study group harbored incidental, preclinical prostate cancer.^3-5 The increasing prostate cancer incidence showed a strong and clear correlation with advancing age (Figure 1).

The lifetime probability of being diagnosed with prostate cancer also increases significantly with age.^6,7 Patients with a life expectancy of < 5 years are unlikely
to benefit from cancer screening and may be more likely to experience complications and potential treatment-related harm as a result of screening. Therefore, estimating the patient’s residual life expectancy is a critical factor in the decision-making process for patients with prostate cancer. Life expectancy can differ, depending on various factors besides age, such as health, functional status, and medical comorbidities. The estimated age-related life expectancy for seniors has gradually increased over the previous 5 decades.⁸

Risk Factors

There are several risk factors for prostate cancer: age, race, and ethnicity; genetic factors; environmental and socioeconomic status; dietary status; and others. However, these factors may play only a limited role in the risk of prostate cancer, and a cautious approach and careful interpretation are required for their application in clinical practice.^9,10

1. Age. There is a sudden and dramatic increase in the prevalence of prostate cancer with advancing age. Prostate cancer is rarely diagnosed in men aged < 40 years, but thereafter, the incidence of prostate cancer climbs steadily.¹¹ Surprisingly, subclinical microscopic prostate cancer was found at autopsy (death from unrelated causes) in a majority of senior males in their eighth decade of life.³
2. Race/ethnicity. Epidemiologic studies in the U.S. found the highest incidence of prostate cancer in African American men (incidence rate of 235 per 100,000 African American vs 150 per 100,000 white men). Also, African American men tended to present with higher grades and stages of prostate cancer. There were much lower incidence rates of prostate cancer in Asian Americans and Pacific Islanders, Hispanics, and American Indian and Alaska Natives (90 per 100,000, 126 per 100,000, and 78 per 100,000, respectively).^9,10
3. Diet. According to researchers, the western diet may be an important risk factors for prostate cancer. However, the actual relationship between obesity and prostate cancer is somewhat unclear, and any correlation is at present highly controversial. Some investigators have postulated that obesity can contribute to the development of prostate cancer; other studies have clearly established that obese patients, once diagnosed with prostate cancer, have inferior outcomes irrespective of the treatment modality used. Other studies, however, have suggested that certain hormonal profiles related to obesity may be protective against the development of prostate cancer.^12,13

Pathologic Evaluation

The original Gleason Grading System was devised based on the careful analysis of the cellular pattern of tumor architecture, using a 5-point scale: Tumor cells similar to normal-appearing prostate tissue were designated Gleason 1, 2, and 3; whereas cells/glands appearing abnormal were designated Gleason 4 and 5. The total Gleason score is the sum of the 2 most representative patterns, applied to both prostatectomy and needle biopsy specimens. The main differences from the original Gleason system, proposed by the 2005 International Society of Urological Pathology Modified Gleason System, are summarized in Table 1.

Early Detection and Screening

Although prostate cancer screening with prostate-specific antigen (PSA) detects many prostate cancer cases, concerns surrounding universal screening include the potential for overdiagnosis and overtreatment, along with the real possibility for adverse effects and complications from treatment. In addition, the recommendations for prostate cancer screening are not consistent among the various national health organizations. The American Cancer Society (ACS) recommends having an informed discussion between the health care provider and patient about the possible benefits and harms of screening. The discussion should not be initiated in men aged < 50 years (or aged < 45 years in men with high-risk features), and there is no need for screening in men with a life expectancy of < 10 years.

Prostate cancer screening may detect cancers that would not have become clinically significant. This is even more likely to be true when life expectancy decreases. Informed screening decisions in senior adults should be made according to the individual’s values and preferences in addition to the estimated outcomes and possible harms as a result of screening. The National Comprehensive Cancer Network offers similar recommendation to the ACS Screening Guidelines (Table 2).

Screening Recommendations for Seniors

There have been no generally recognized guidelines on prostate cancer screening for seniors, although recently, Konety and colleagues published “The Iowa Prostate Cancer Consensus” for elderly prostate cancer patients (Table 3).¹⁷ The consensus includes:

• More prostate cancers are detected at an earlier stage, but many of them would never become clinically apparent in most patients’ life times
• A reduced mortality (either overall or disease specific) from screening is not proven during the course of 10-year follow-up
• Harms related to diagnostic and therapeutic procedures develop early and remain for an extended period, causing a negative impact on quality of life
• The small benefits of screening leading up to a prostatectomy are seen only after 12 years of follow-up and may be limited to a certain population group of
  patients who are aged < 65 years
• Current recommendations discourage the routine screening of seniors with short life expectancies (< 10 years) and depend on existing comorbidities and disease group risk

Conclusion

Prostate cancer is the most common cancer in American men and the second most common cause of cancer death. Prostate cancer is almost twice as common among African Americans vs whites, and much less common in Asian Americans and Pacific Islanders, Hispanics, American Indian and Alaska Natives. Prostate cancer is generally a cancer of older seniors, and nearly 80% of seniors are estimated to harbor subclinical prostate cancer by their eighth decade of life.⁸ Prostate cancer screening is not universally recommended, and major professional associations support an informed, evidence-based, shared decision-making process between medical professionals and patients. This decision should include the careful consideration of patients’ life expectancy and existing medical comorbidities, always weighing the potential benefits against the possible screening and treatment-related harms.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to read the digital edition.