Prostate Cancer Treatment

Prostate Cancer Treatment

1 Introduction

Summary and Quick Facts

  • Prostate cancer is common and can often be treated effectively in its early stages. For many men, immediate treatment may not be necessary.
  • This protocol will help you understand the different stages of prostate cancer and what treatments may be needed. Learn about dietary and lifestyle changes, and supplements that may complement a treatment approach.
  • Various preparations of lycopene and green tea supplements have been shown to benefit men with prostate cancer in clinical trials.

Roughly one in five men in the United States will be diagnosed with prostate cancer during their lifetime (NCI 2017c; Pollock 2015). Although prostate cancer can be deadly if it spreads to other organs, it is quite treatable if detected early (NCI 2018b; McLeod 2004). Surgery, radiation, and medicines to block hormones are common treatment options (NCI 2018b; NCCN 2017b). Researchers are continually working to make these treatments better and improve outcomes for men with prostate cancer (Ho 2017; Counago 2017; Montgomery 2016; Roth 2008; Holmboe 2000).

Many medical innovations in prostate cancer diagnosis and treatment have emerged in recent years. Advanced imaging techniques such as multiparametric MRI have made diagnosis more accurate and treatment more precise (Ahmed 2017; Bagheri 2017). New blood tests provide patients and doctors with information to better select appropriate treatment strategies (Tosoian, Druskin 2017). Immunotherapy, which has been a huge advance for cancer care in general, is currently an active and promising area of prostate cancer research (Bilusic 2017; Schepisi 2017).

While much discussion centers around specific treatments and diagnostics for prostate cancer, one of the most important aspects of a man’s journey through this disease is his involvement in decisions related to his care. It is important that men take an active, informed role in their prostate cancer care (Baade 2012). Obtaining accurate information is critical for men with prostate cancer—one study found that men who had greater knowledge about their options had better quality-of-life six months after treatment (Orom 2016). A man should work closely with his medical team to discuss key considerations, such as:

  • What treatment options are available for the level of disease he has;
  • Whether to pursue aggressive treatment options, such as surgery or radiation, or a less aggressive approach, called active surveillance, in early prostate cancer; and
  • What are the potential risks and benefits of each treatment option.

This protocol will provide the information that patients and their loved ones need to be informed and active in decisions related to prostate health. You will learn about current tools for finding and diagnosing prostate cancer, and treatment options for all stages of the disease. This protocol also includes details on many promising new treatments being developed, as well as integrative, natural interventions that may complement conventional therapy.

This protocol focuses on prostate cancer treatment. More information about prevention is available in the Prostate Cancer Prevention protocol. Readers are encouraged to review both of these protocols, as well as other relevant cancer-related protocols:

2 Background

The Prostate Gland

The prostate gland is part of the male reproductive system and produces an important fluid component of semen. Prostatic fluid helps sperm travel through the female reproductive tract to the egg for fertilization (NCCN 2016b; Schjenken 2015).

The prostate is located just below the bladder and surrounds part of the urethra, the tube that carries urine out of the bladder (NCCN 2016b). Because the prostate sits adjacent to the rectum, it can be felt during a manual procedure called digital rectal exam.

The prostate gland needs testosterone to function properly (NCI 2017c). Testosterone and its metabolite dihydrotestosterone stimulate prostate growth, particularly during puberty (Wilczynski 2015).

Pre-cancerous and Non-cancerous Conditions of the Prostate

As men age, growth of the prostate can cause restriction or partial blockage of the urethra (NCI 2017a). This condition, called benign prostatic hyperplasia (BPH), is common in older men and is not a form of cancer. Prostatitis, or inflammation of the prostate, is another non-cancerous condition that is more common in younger men (Mayo Clinic 2016). Prostatitis is often caused by a bacterial infection, but other factors, including autoimmune processes, may also contribute (Mayo Clinic 2016; Vaidyanathan 2008).

Prostate cells can take on some of the features of cancer cells in a condition called prostatic intraepithelial neoplasia, or PIN, which is diagnosed via prostate biopsy (Voltaggio 2016; Packer 2016). High-grade PIN denotes cells that look abnormal and is considered precancerous. Men with multiple sites of high-grade PIN detected on biopsy are more than twice as likely to develop prostate cancer as men without PIN (Bjurlin 2014; Cicione 2016). Although estimates vary, the risk of prostate cancer after a diagnosis of multiple-site high-grade PIN may be higher than 30% (Cicione 2016).

Because of its precancerous nature, careful monitoring is often recommended in cases of high-grade PIN (Bjurlin 2014; Cicione 2016). Men with PIN may benefit from lifestyle and dietary changes and targeted supplements aimed at preventing cancer from developing (Cheetham 2011).

Prostate Cancer

Most prostate cancers are of a type called adenocarcinomas (NCCN 2016b). Adenocarcinomas develop in the prostate when normal glandular cells become cancerous (Packer 2016). Gene mutations accumulate and promote abnormal prostate cell division, eventually leading to cancer development. As the tumor progresses, it causes alterations in surrounding tissues, making its growth easier (Yu 2017; Levesque 2017).

When a tumor is no longer confined to the prostate gland, it may spread to other nearby structures, such as the seminal vesicles (Small 2015). It can also spread to the urethra, rectum, and bladder (Zardawi 2016; Abbas 2011; Hallemeier 2010). In later stages, prostate cancer is found in the lymph nodes and distant parts of the body such as the bones, lungs, or liver (Rycaj 2017; Macedo 2017). The disease does not progress in the same manner, nor at the same rate, in all men (Pollard 2017; Peisch 2017).

3 Causes and Risk Factors

The risk of prostate cancer, like many other forms of cancer, increases with age. Forty-year-old men have a 2.3% chance of being diagnosed with prostate cancer by age 60. For 70-year-old men, the 20-year risk of prostate cancer is 9.5% (CDC 2015).

African-American men have a higher risk of prostate cancer than Caucasian men (Wells 2010; Zhang 2013). In one study of almost three million servicemen, African Americans were nearly three times more likely to be diagnosed with prostate cancer (Wells 2010). According to the Centers for Disease Control and Prevention (CDC), about twice as many African Americans die from prostate cancer as Caucasians (CDC 2017). In contrast, Asian Americans have a lower risk of prostate cancer (Tran 2016; CDC 2017).

Men with a family history of prostate cancer and those who have specific gene mutations have an increased risk of prostate cancer (Helfand 2015; Chen 2017; Cheng 2017). For instance, mutations in the BRCA1 or BRCA2 genes increase prostate cancer risk (Lecarpentier 2017). The likelihood of developing prostate cancer before age 65 is more than eight-fold higher in men with mutations in the BRCA2 gene. The presence of BRCA2 gene mutations predict a lifetime prostate cancer risk of 30–40% and is associated with more aggressive forms of cancer. While BRCA1 mutations have also been correlated with increased prostate cancer risk, the relationship is not as strong as with BRCA2 mutations (Costa 2017; Mateo 2017).

Obesity may be associated with increased risk for advanced prostate cancer (Vidal 2017; Rundle 2017). In a large prospective study of over 25,000 men, obesity was associated with increased prostate cancer risk in non-Hispanic white men and African-American men, but the association was stronger in African-American men than men of other races (Barrington 2015).

Dietary factors have been linked to prostate cancer risk. Greater intake of red meat (especially that cooked at high temperatures) and animal fats have been linked to increased prostate cancer risk (Nelson 2014). On the other hand, a healthy diet has been linked to lower risk of prostate cancer and better outcomes in several studies. Studies have shown that a diet rich in plant-based foods may be protective against prostate cancer (Perez-Cornago, Travis 2017; Peisch 2017). For a more thorough evaluation of dietary prostate cancer risks, review the Prostate Cancer Prevention protocol, specifically, the section titled “Impact of Diet on Prostate Cancer Risk and Mortality.”

Research suggests that smoking is a risk factor for many cancers, including cancer of the prostate (Tang 2017; Sato 2017; Jones, Joshu 2016). Smokers are more likely to be diagnosed with more advanced prostate cancer (Ho 2014), develop fatigue while using docetaxel (Taxotere) (a chemotherapy drug commonly used to treat prostate cancer) (Bergin 2017), and have complications such as pneumonia and unplanned intubation after prostate surgery (Byun 2017).

Gonorrhea (a sexually transmitted infection) is associated with increased prostate cancer risk (Lian 2015; Wang, Chung 2017; Vazquez-Salas 2016).

4 Signs and Symptoms of Prostate Cancer

With the widespread use of prostate cancer screening tests, over 60% of men with prostate cancer may not have any symptoms at the time of diagnosis. Instead, the only sign of the disease may be an elevated prostate-specific antigen (PSA) level. For some men, the tumor can be felt during a digital rectal examination (Small 2015).

Men with more advanced prostate cancer may have symptoms such as urination difficulties, discomfort in the pelvic area, and blood in the semen (Mayo Clinic 2018). Cancer that has spread beyond the prostate to other organs can cause other symptoms such as bone pain (NCI 2018b).

5 Diagnosis

Screening Tests

PSA and digital rectal exam. Until about 2008, doctors recommended that most men over 50 be screened for prostate cancer yearly with a PSA test along with a digital rectal exam (NCI 2017d; USPSTF 2008; NCI 2018a). PSA is a protein produced by cells of the prostate gland (NCI 2018a; Malatesta 2000), and high blood levels of PSA are often seen in men with prostate cancer. However, PSA levels can also be elevated as a result of benign prostate conditions, such as prostatitis and BPH (USPSTF 2008; NCI 2018a).

Controversy and new guidelines. Prostate cancer screening guidelines have been controversial (Wilt 2015; Etzioni 2014; Payton 2012; Tabayoyong 2015). As increasing numbers of men were being screened, critics became concerned that too many men were undergoing invasive diagnostic procedures only to find out they did not have cancer (NCI 2017d; USPSTF 2008; USPSTF 2017). A second concern was that some cancers detected during routine screening might not have become clinically significant in the man’s lifetime (Howrey 2013; Etzioni 2002; Andriole 2012).

In 2008, the United States Preventative Service Task Force (USPSTF) recommended against routine screening for men over 75 (USPSTF 2008). In 2012, they expanded this recommendation to men of all ages (Moyer 2012). A review of the literature from 2012 to 2016 found that the use of PSA testing had declined, and not as many prostate biopsies were being performed as previously (Lee, Mallin 2017).

As routine screening has declined, there are new concerns that men will be diagnosed in later and less treatable stages of prostate cancer (Lee, Mallin 2017; Eapen 2017; Fleshner 2017). The most recent draft of prostate cancer screening guidelines released by the USPSTF in 2017 states that “the decision about whether to be screened for prostate cancer should be an individual one” (Bibbins-Domingo 2017; USPSTF 2017). This statement highlights the importance of personal and informed decision-making when it comes to prostate cancer screening (Eapen 2017).

New screening tests. PSA testing and digital rectal exam have been the primary prostate cancer screening methods. Several variations of the basic PSA test, described below, have been developed to improve its usefulness (Saini 2016; Hatakeyama 2017).

The PSA level at a single time point may not be as informative as changes in PSA levels over time (Salman 2015; Adhyam 2012). PSA velocity measures how quickly PSA is rising, and PSA doubling time measures how long it takes for PSA levels to rise twofold (Ponholzer 2010; Loughlin 2014). Both doubling time and velocity have been primarily studied for monitoring prostate cancer after diagnosis. These tests can indicate how quickly a tumor is growing, whether the cancer has metastasized, and how the disease is responding to treatment (Howard 2017; Freiberger 2017; Vickers 2014).

Some PSA is free in the blood, and some is bound to, or complexed with, other proteins (NCI 2018a). The standard PSA test detects both forms, while a newer test measures free PSA, and complexed PSA can be calculated using these values (NCI 2018a; Brawer 1998; Brawer 2003). Complexed PSA, free PSA, and tests that include information about both may provide a more accurate reflection of prostate cancer activity than total PSA alone (Wang, Li 2017; Strittmatter 2011; NCI 2018a).

Another version of the PSA test looks at a precursor form of PSA called pro-PSA (Peyromaure 2005; Ito 2014; Ayyildiz 2014). This form of PSA may be better than total PSA at determining which men with borderline total PSA may really have cancer (Boegemann 2016). The Prostate Health Index (PHI) is a test that combines information from total PSA, free PSA, and pro-PSA (Loeb, Catalona 2014). This test was approved by the Food and Drug Administration (FDA) in 2012, for men age 50 and older with a total serum PSA between 4 and 10 ng/mL and a normal digital rectal exam, to reduce the number of unnecessary prostate biopsies (Loeb, Catalona 2014; Sartori 2014). One recent study found that total PSA was 47% accurate for identifying men with cancer while the PHI test was 72% accurate (Tosoian, Druskin 2017).

While some research has focused on improving the PSA test, other research has developed completely new tests. For the PCA3 test, for example, urine is collected after a digital rectal exam (NCI 2018a; Martignano 2017). The cells in the urine are tested for the prostate cancer-specific gene PCA3 (Hessels 2003). PCA3 testing is not currently used as a general screening test. Instead, for men with high PSA levels but no cancer detected in a biopsy, PCA3 testing can help determine which men should have a repeat biopsy and which should be monitored using active surveillance (Rubio-Briones 2017; Wang, Chen 2017; Galasso 2010).

Diagnostic Tests

Doctors diagnose prostate cancer by examining tissue from a biopsy (Bjurlin 2014; NCCN 2016b; Small 2015). The biopsy is most often collected through the wall of the rectum. Typically, at least 12 cores (different areas) of tissue are removed to check all areas of the prostate (NCCN 2016b). Some men experience adverse effects or complications such as soreness, infection, or bleeding after prostate biopsy (NCCN 2016b; Bjurlin 2014; Jones, Radtke 2016).

Imaging techniques are commonly used during the biopsy procedure (Woodrum 2017). Transrectal ultrasonography uses sound waves to produce images of the prostate (NCI 2018b). The doctor uses these images to ensure biopsy samples are obtained from the targeted regions of the prostate (NCCN 2016b).

Doctors may also use magnetic resonance imaging (MRI) along with transrectal ultrasonography (Marks 2013; Woodrum 2017; NCI 2018b; Jambor 2017). MRI images are taken before the procedure to assess the patient’s risk of prostate cancer, possibly preventing unnecessary biopsies (Porpiglia 2017; Ahmed 2017). If a biopsy is needed, these highly sensitive MRI images can be used to identify the region of the prostate to target (NCCN 2016b), improving diagnosis of more dangerous forms of cancer (Bjurlin 2017). In a study that enrolled 601 men who were scheduled for prostate biopsy, MRI-guided biopsy identified greater than 30% more cases of high-grade prostate cancer than traditional biopsy methods (Meng 2016).

Prognostic Assessment

A prognostic test can help guide treatment decisions by providing information on how aggressive a tumor is or how likely it is to spread (Terada 2017). Tissue obtained during biopsy or surgery is analyzed by a pathologist who assesses the characteristics of the cells and determines the Gleason score (Litwin 2017). The Gleason scoring system has been used for decades to indicate how aggressive a tumor is and guide treatment decisions (Chen 2016; Slager 2003; Wright 2009; Humphrey 2004).

The Gleason Score

The Gleason score is an established system for grading tumors and plays an important role in treatment selection. To determine the Gleason score, a pathologist first analyzes tumor cells in a biopsy or surgery sample under a microscope to determine how much they differ from normal cells and express this as a number between one and five (NCI 2018b). Lower numbers indicate that the characteristics of the cells are closer to those of normal cells and higher numbers indicate that the cells have more cancerous characteristics. The pathologist assigns a number, or a grade, to the two areas that make up most of the tumor. The sum of these two numbers is called the Gleason score. The Gleason score can range from 2 to 10 (although only Gleason scores of 6 – 10 are reported clinically in most cases) (NCCN 2016c; ACS 2017). Also, the individual numbers are usually provided (such as 3+4=7). The number listed first is the grade that is most common in the tumor (ACS 2017).

Tumors that are Gleason score 6 or lower are likely to grow slowly and may not require invasive treatment right away (NCCN 2016b). Patients with higher Gleason score tumors have a worse prognosis and may benefit from more aggressive treatment plans (NCCN 2017b). In 2014, new guidelines were released for grouping patients by Gleason score (Gordetsky 2016; Epstein 2017):

  • Grade Group 1 = Gleason score ≤ 6
  • Grade Group 2 = Gleason score 3 + 4 = 7
  • Grade Group 3 = Gleason score 4 + 3 = 7
  • Grade Group 4 = Gleason score 8
  • Grade Group 5 = Gleason scores 9 and 10

This new grouping system was validated in a study in over 20,000 men undergoing radical prostatectomy. Using PSA levels alone as the measure of recurrence, the rates of 5-year survival without recurrence in men in Groups 1, 2, 3, 4, and 5 were 96%, 88%, 63%, 48%, and 26%, respectively (Epstein 2016).

A commonly used system of staging is called the TNM system. The “T” component describes how much the tumor has grown in and around the prostate gland; the “N” component of staging indicates whether the cancer has spread to lymph nodes; and the “M” component indicates whether the cancer has metastasized (NCCN 2016b; Small 2015).

After being diagnosed with prostate cancer, patients typically undergo further testing to determine whether the cancer has spread to the lymph nodes and other organs (ie, to assess their TNM status) (Bhindi 2017; Rodgers 2017). Selecting which type of additional testing is appropriate depends on each man’s clinical status. Men with higher PSA values or Gleason scores or larger tumors may be candidates for additional imaging such as a bone scan with technetium-99m, pelvic computed tomography (CT) scan, or pelvic MRI to check for cancer spread (NCCN 2016b). Men whose PSA is above 10‒20 ng/mL are often advised to undergo the technetium-99m bone scan. The American College of Radiology has developed guidelines to help guide the selection of imaging tests for men with prostate cancer, based on variables such as “T” stage, Gleason score, PSA level, and number of positive biopsy cores (National Guideline 2016).

One challenge with both MRI and CT scans is they have a relatively high rate of inaccurately identifying the extent of the disease, which may lead to a suboptimal course of treatment. The development of techniques such as multiparametric MRI and sophisticated types of positron emission tomography (PET) scans has expanded the repertoire of tools available to physicians for use during prostate cancer evaluation (Bednarova 2017; Fulgham 2017). Results from these tests can be used to assess cancer stage and guide treatment decisions (NCCN 2017b; NCCN 2016b; Bhindi 2017; Rodgers 2017). Other techniques combining PET and MRI technologies have been investigated; these newer modalities may improve treatment planning in the near future (Eiber 2013). However, as previously mentioned, each man’s clinical status and unique situation must be taken into consideration when determining which testing strategies are optimal.

Importantly, given the numerous and complex strategies available for investigating the extent of prostate cancer, it is important that each patient undergo careful and thoughtful evaluation. Some experienced physicians have noted that lack of attention to detail in assessing a man’s clinical status may lead to inaccurate TNM staging and thus suboptimal treatment. Men in the midst of prostate cancer diagnosis and staging should ask lots of questions of their medical team and be sure they are confident that sufficient detail is being gathered to carefully plan their treatment.

Nomograms are tools that combine available clinical information from large numbers of patients and use mathematical calculations to estimate an individual’s risk of various events. In the case of prostate cancer, these events may include the spread (metastasis) of prostate cancer or mortality after specific treatments. Nomograms, when used appropriately by knowledgeable clinicians, can help individualize the treatment decision-making process (NCCN 2016b; Beauval 2017; Kim 2017; Lowrance 2009; Caras 2014). Nomograms can be informative about many aspects of prostate cancer care, including estimating the need for biopsy and the choice for adjuvant therapy (Caras 2014). However, because it is difficult to standardize these assessments (ie, different nomograms are appropriate for different patients), practitioners may prefer different nomograms or interpret them slightly differently.

In recent years, imaging studies, such as MRI, have been incorporated into prostate cancer nomograms (Caras 2014). Several research studies have revealed that incorporating multiparametric MRI into nomograms could improve their predictive value (Watson 2016). While nomograms may be very useful in addressing a specific question, they also have several shortcomings (eg, cost), and they are not perfectly accurate. Moreover, nomograms are only valid if used on a treatment population that is similar to the population from which the nomogram data were collected (Caras 2014). Given the complexity of properly employing nomograms, they may be underutilized, even though they have demonstrated value when used appropriately. Men in the treatment-planning stages of prostate cancer management should ask their care team whether these valuable tools have been incorporated into the decision-making process for their care.

6 Conventional Treatment

When diagnostic and staging information are available, the patient and his medical team can begin to consider treatment options (NCCN 2017b; Gillessen 2017; Small 2015) (see Table 1). For some men with early-stage disease or tumors with a low Gleason score, an approach called active surveillance can be considered. In active surveillance, no treatment is administered and the prostate cancer is monitored carefully (Wilt 2017; Garisto 2017). If treatment is deemed necessary, surgery and various forms of radiation are common initial options (NCCN 2016b; NCCN 2017b; Small 2015). Those with more advanced disease or disease that has recurred after initial treatment may want to consider options such as chemotherapy, hormonal therapy, or immunotherapy (NCCN 2016b; Small 2015; NCCN 2017a).

Table 1: Initial Treatment Options Based on Disease Stage and Risk

Type of Prostate Cancer

Characteristics

Treatment Options

Low-risk disease

Small tumors confined to prostate
Gleason score ≤ 6
Gleason grade group 1
PSA < 10 ng/mL

  • Active surveillance
  • Radical prostatectomy
  • Radiation (EBRT or brachytherapy)

Intermediate-risk disease

Larger tumors confined to prostate
Gleason score = 7
Gleason grade group 2–3
PSA = 10–20 ng/mL

  • Active surveillance
  • Radical prostatectomy
  • EBRT, sometimes with hormone therapy
  • Brachytherapy

High-risk disease

Tumors that have grown beyond the prostate to local structures
Gleason score ≥ 8
Gleason grade group 4–5
PSA > 20 ng/mL

  • Radical prostatectomy, sometimes with hormone therapy
  • EBRT, typically with hormone therapy
  • EBRT plus brachytherapy, typically with hormone therapy

Progressive disease after initial therapy

Disease progression detected by PSA, digital rectal examination, or imaging

  • Radical prostatectomy for those previously treated with radiation
  • EBRT for those previously treated surgically
  • Brachytherapy
  • Hormone therapy
  • Cryotherapy
  • High-intensity focused ultrasound

Metastatic disease

Tumors that have grown beyond the prostate to the bladder, rectum, lymph nodes, or distant organs

  • Hormone therapy
  • Sipuleucel-T (Provenge)
  • Chemotherapy
  • Radiation therapy to metastases
  • Treatments for pain and other symptoms

 EBRT=External beam radiation therapy; PSA=Prostate specific antigen
(Small 2015; NCCN 2017b)

Active Surveillance

Treatments such as surgery and radiation are invasive, with potential side effects and complications (Wilt 2017; Lee 2015). Men with low-risk prostate cancer have a good chance of living full lives without being affected by the disease, even without active treatment (Wilt 2017; Hamdy 2016). Unnecessary treatment for men with low-risk disease is often referred to as overtreatment (Loeb, Bjurlin 2014; Daskivich 2011).

Active surveillance is a regimen of regular monitoring with PSA, digital rectal examination, and repeat biopsies (Garisto 2017; NCCN 2017b). With regular testing, the patient’s risk status can be monitored. If anything suspicious is detected, additional tests or an active treatment approach can be considered.

One recent study followed 731 men with prostate cancer who were randomly assigned to either active surveillance or surgery. After almost 20 years, there were no significant differences in rates of prostate cancer-related deaths or deaths from any cause in the two groups. Surgery was associated with more adverse events than surveillance, while surveillance was associated with increased likelihood of treatment for disease progression (Wilt 2017).

Another recent trial compared active surveillance, surgery, and radiation therapy in 1,643 men with low-risk prostate cancer. After an average of 10 years of follow-up, there were very few prostate cancer-related deaths in all three groups. Metastases were more common, but still rare (about 6%), in the active surveillance group compared to the other two groups (Hamdy 2016).

Patients under active surveillance may benefit from implementing dietary and lifestyle practices associated with prostate health. For example, both healthy diet and exercise can reduce the risk of disease progression during active surveillance (Galvao 2016). Supplements such as omega-3 fatty acids and vitamin D may also be helpful (Marshall 2012; Moreel 2014). In addition, new molecular tests such as Oncotype Dx and Promark may help patients and their medical teams feel more confident in the selection of active surveillance (Albala 2016; Ross 2016). (See the Novel and Emerging Strategies section of this protocol).

Deciding Among Treatment Options in Newly Diagnosed Prostate Cancer

When men are first diagnosed with prostate cancer, they, along with their medical team, face the task of deciding which initial treatment approach is right for them. The patient’s risk group plays a major role in this decision (Small 2015; NCCN 2017b). 

But what about men for whom two or more options are equally appropriate? Some studies indicate that a patient’s treatment preferences may be overshadowed by their doctor’s recommendations (Scherr 2017). This suggests the value of talking with more than one type of prostate cancer specialist during the decision-making process. Radiation oncologists, who do not perform surgery, and urologists, who are surgeons, may present treatment options differently (Kim 2014; Jang 2010).

Patients can develop realistic expectations by asking questions when they meet with their medical team. Lack of complete information frequently leads men to underestimate their life expectancy with active surveillance and overestimate the gain in life expectancy with surgery or radiation (Xu 2016). Patients who discuss the risks and benefits of all treatment options with their medical team tend to be more satisfied with their ultimate decision (Davison 2003; Holmes 2017).

Online resources and advocacy groups can also help men stay involved and informed. Some decision aids have been specifically designed to support men through this process (Gorawara-Bhat 2017; Christie 2015), and men who use these tools are better able to ask critical questions about the treatments recommended by their medical team (Holmes-Rovner 2017; Jones, Hollen 2016).

Radical Prostatectomy

One common treatment option for prostate cancer is a type of surgery called radical prostatectomy (NCCN 2016b). Radical prostatectomy is mainly used when cancer is believed to be confined to the prostate gland (NCCN 2017b). According to the CDC, about 138,000 radical prostatectomies were performed in the United States in 2010 (CDC 2010).

During the procedure, the prostate gland is removed along with the seminal vesicles and sometimes other affected tissues in the region (NCCN 2016b; NCI 2018b). In the most common form of prostatectomy, called retropubic prostatectomy, lymph nodes can be removed if necessary, and nerves required for erection can be spared if they are not affected by the cancer (NCI 2018b; NCCN 2016b; Tosoian 2012; Masterson 2006; Goyal 2007).

Prostatectomies can also be performed laparoscopically to shorten recovery time. In this procedure, surgical tools are inserted through several small incisions. Laparoscopic surgery can be conducted using robotic arms to make very careful cuts, thereby reducing the risk of damage to healthy tissues (NCCN 2016b; Ku 2017). One study reported that robotic-assisted surgery was more effective than unassisted laparoscopic surgery at preventing PSA level rises that could indicate recurrence (Lee, Seo 2017).

Most men experience short-term urinary incontinence or sexual dysfunction after surgery (NCCN 2016b). Improvements in surgical techniques have reduced the number of men who experience long-term complications (Small 2015; Wallis 2017). The risk of long-term problems varies greatly based on individual characteristics, extent of the cancer, and skill of the surgeon (Goldenberg 2017). For instance, older patients or those whose nerves have been affected by the cancer are more likely to experience long-term erectile problems after surgery (NCCN 2016b).

Radiation Therapy

Men with prostate cancer that has not spread to surrounding tissues are commonly treated with radiation therapy. Radiation is also a valuable tool for recurrent disease and disease that has spread to lymph nodes (Small 2015; NCCN 2017b; NCCN 2016b). Radiation destroys cancer cells but can also cause damage to nearby healthy cells (NCI 2010).

External-beam radiation therapy uses a machine to deliver beams of photons to the prostate gland (NCCN 2016b). The radiation is carefully targeted to the cancer cells using digital imaging (NCI 2018b). Intensity-modulated radiation therapy is an advanced form of radiation that uses many carefully-calculated doses applied from various angles. This approach decreases the doses of radiation that reach normal organs and tissues. Intensity-modulated external-beam radiation has become the standard modality of radiation therapy for prostate cancer (Moon 2017).

Stereotactic body radiation therapy is a type of intensity-modulated radiation therapy used in recent years to treat men with localized prostate cancer. One advantage of this approach is that the treatment can be completed in about five visits (NCCN 2016b; Koskela 2017). Although this approach is a safe and effective way to treat prostate cancer, trials are currently under way to compare stereotactic body radiation therapy with other approaches (Kishan 2017; Kim 2016).

Intensity-modulated radiation therapy uses photon beams to irradiate the prostate, while a form of radiation therapy called proton therapy uses proton beams (NCCN 2016b). Proton beams release most of a dose of radiation at a specified depth. This may allow the use of higher doses of radiation without causing side effects involving nearby organs such as the bladder and rectum (Moon 2017). One recent study that enrolled 1,375 patients treated with proton therapy found that PSA levels remained low five years after treatment in 99%, 91%, and 86% of low-, intermediate-, and high-risk patients, respectively (Takagi 2017). Although this method is promising, long-term studies comparing it to intensity-modulated radiation therapy are needed (Magnuson 2017; Moon 2017).

Brachytherapy is another option for men with some early stage prostate cancers (NCCN 2017b). Brachytherapy involves the use of radiation-emitting devices called seeds that are about the size of a grain of rice. Using imaging techniques to guide placement, 40 to 100 seeds are implanted permanently or temporarily within the prostate. Because the radiation is delivered directly into the tumor, the dose of radiation can be high with minimal risk to healthy tissues (NCCN 2016b; Stish 2017). For patients with higher-risk cancer, brachytherapy can be combined with external beam radiation therapy and hormonal therapy (NCCN 2017b; Hannoun-Levi 2017).

Radiation therapy can cause short-term and long-term urinary, bowel, and sexual function symptoms (Lee 2015). External beam radiation therapy can also cause damage to the skin (NCCN 2016b). When data from many studies were analyzed together, patients treated with radiation were found to be more likely to have bowel symptoms, but less likely to have urinary or sexual function problems, compared with patients treated with surgery (Lardas 2017; Wallis 2017). New devices such as the SpaceOAR Hydrogel System, which creates a physical space between the prostate and rectum during radiation therapy, may increase protection of healthy tissues (Hamstra 2017; Wolf 2015; Augmenix 2017).

Refer to the Cancer Radiation Therapy protocol for more general information.

Cryotherapy

Cryotherapy, also called cryosurgery or cryoablation, is a newer treatment in which argon gas is sent through very thin needles into the prostate to freeze the tumor (NCCN 2016b). Cryotherapy is an option that is typically considered when radiation fails to completely destroy the cancer (NCCN 2017b); however, existing data on cryotherapy as an initial treatment are encouraging (Bahn 2012; Garcia-Barreras 2017; Durand 2014). One study compared cryotherapy with external beam radiation in men with newly diagnosed cancer that had not spread beyond the prostate. There was no difference between the two approaches in prostate cancer survival, and patients who received cryotherapy had fewer positive biopsies after three years (Donnelly 2010).  

One innovative physician, Gary Onik, MD, has had success treating localized prostate cancer with focused cryotherapy. The approach taken by Dr. Onik and his team involves carefully mapping the location of cancer in the process via a technique called three-dimensional prostate-mapping biopsy. Then, after the tumors have been precisely located, patients are treated with focal cryoablation, in which targeted cryotherapy is applied to the cancerous tissue. Dr. Onik’s team conducted a study in which they used this technique on 46 men. 

Impressively, biochemical disease-free survival was 89% after 10 years of follow-up, and the rate of biochemical disease-free survival did not differ by initial risk group. (This is important because men with higher-risk prostate cancer usually have a higher rate of recurrence and death from prostate cancer). Moreover, local recurrence was considerably less common in the group who underwent three-dimensional prostate mapping (4%) compared with those who underwent transrectal ultrasound (TRUS, 33%) (Onik 2014). A more comprehensive review of Dr. Onik’s pioneering work is available in the June, 2016 issue of Life Extension Magazine®, in an article titled “Major Advance in Screening and Treating Prostate Cancer.”

Hormone Therapy

Because androgens (male sex hormones) stimulate the growth of some prostate cancers, various types of hormone therapies are used to interfere with their actions (NCCN 2016b). Some hormone therapies stop the body from producing androgens, mainly testosterone, while others block the effect of testosterone on cancer cells (NCCN 2016b; NCI 2018b). Hormone therapy is a valuable tool used in all stages of prostate cancer except early low-risk disease (NCCN 2017b).

Hormone therapies targeting luteinizing hormone-releasing hormone (LHRH) prevent the testicles from making testosterone. Leuprolide (Lupron), goserelin (Zoladex), histrelin (Vantas), triptorelin (Trelstar), buserelin (Suprefact), and degarelix (Firmagon) are examples of such medications (NCCN 2016b; NCI 2018b). Another hormonal strategy for reducing testosterone is the use of certain forms of estrogens. Surgical removal of the testicles (orchiectomy) is used in some cases to dramatically reduce the amount of testosterone in the body (NCCN 2017b). 

Ketoconazole (Nizoral), a well-known antifungal medication, is sometimes used for its ability to inhibit production of testosterone at several locations, including the adrenal glands (NLM 2017; NCCN 2016a; NCI 2018b). Abiraterone (Zytiga) is another androgen synthesis inhibitor approved by the FDA in 2012 for use in men with metastatic castration-resistant prostate cancer, a term referring to prostate cancer that has progressed despite testosterone-lowering therapy (Maluf 2012). Abiraterone plus the corticosteroid prednisone is used either before or after chemotherapy, and may be combined with other hormone therapy (NCI 2013; Fizazi 2012; James 2017; Fizazi 2017).

Antiandrogens block testosterone receptors on tumor cells. Bicalutamide (Casodex), flutamide, nilutamide (Nilandron), and enzalutamide (Xtandi) are examples of antiandrogens (NCCN 2016b; NCCN 2017b).

The side effects of hormone therapy can vary from patient to patient and depend on the exact therapy used (NCCN 2016b). In general, hormone therapies can cause erectile dysfunction, hot flashes, mood changes, weight gain, loss of muscle, breast growth, and fatigue (NCCN 2016b; NCI 2018b; Gilbert 2017). Long-term use of hormone therapies can weaken the patient’s bones and increase the risk of diabetes and heart disease (NCCN 2016b; Gupta 2017; Thomsen 2017). 

Chemotherapy

Chemotherapy is an option for men with castration-resistant metastatic cancers (NCCN 2017b). Docetaxel is a well-established and commonly used chemotherapy drug in prostate cancer treatment regimens. Newer data on docetaxel suggest the drug may also help men with tumors that still respond to hormone therapy (in other words, are not castration-resistant), particularly those with metastases or high-risk non-metastatic cancer (NCCN 2017b; Patrikidou 2017; Puente 2017; James 2016). In the CHAARTED trial, docetaxel extended average survival by slightly over one year in men being treated with hormone therapy (Sweeney 2015). Common side effects of docetaxel include diarrhea, nausea, vomiting, and loss of appetite; fatigue and weakness; low white blood cell counts and fever; numbness, tingling, or burning in the hands and feet; hair loss; and mouth sores (NCCN 2016b; Bergin 2017; ACS 2016).

In 2010, the FDA approved the chemotherapy drug cabazitaxel (Jevtana) for men whose cancer is progressing despite previous treatment with a regimen containing docetaxel (NCCN 2017b; Eisenberger 2017). Researchers are investigating how to manage the side effects, optimize the dose, and select the right patients for this drug (Eisenberger 2017; Patel 2017). Mitoxantrone (Novantrone) is another FDA-approved chemotherapy drug available for patients who cannot tolerate docetaxel or cabazitaxel (NCCN 2017b).

Refer to the Chemotherapy protocol for more general information.

Immunotherapy

As of late 2017, the only FDA-approved immunotherapy for prostate cancer is sipuleucel-T (NCCN 2016b; Silvestri 2016). Sipuleucel-T is a treatment option for men with metastatic castration-resistant prostate cancer. White blood cells from the patient are treated in the lab with a protein that helps them recognize and attack cancer cells. The cells are then returned to the patient’s body (Virgo 2017; NCI 2018b). In a randomized controlled trial, men treated with sipuleucel-T lived about four months longer than controls (Small 2006). In a recent phase-II clinical trial, sipuleucel-T caused a greater antitumor immune response when the treatment occurred before hormone therapy (Antonarakis 2017). Further studies will be needed to determine whether this therapy can be more effective before the development of castration-resistant disease.

Treatment of Bone Metastases

In addition to general prostate cancer treatments such as chemotherapy and hormone therapy, there are several options that specifically treat bone metastases. External beam radiation can be targeted to the bones (NCCN 2017b). Radiopharmaceuticals such as radium-223 naturally accumulate in areas of the bone with metastases and destroy cancer cells (NCI 2018b; Sartor 2014). Other drugs, such as denosumab (Prolia) and zoledronate (Aclasta), strengthen bones affected by cancer or weakened through cancer treatment and can help prevent fractures (Traboulsi 2017; Hegemann 2017; Israeli 2008).

Participating in a Clinical Trial

Some men may want to consider participating in a clinical trial. Many of the treatments described in the “Novel and Emerging Strategies” and “Integrative Interventions” sections are currently being tested. It is important to recognize that treatments under investigation might have significant side effects or might not be effective (NCI 2018b; Vieweg 2007). Whether the tested treatment is successful or not, all clinical trials help inform future patient care. Men who want to learn more about ongoing clinical trials can consult with their medical team. The following online resources may also be helpful:

  1. National Comprehensive Cancer Network (NCCN): https://www.nccn.org/patients/resources/clinical_trials/find_trials.aspx
  2. National Cancer Institute: https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/trial-guide
  3. American Cancer Society: https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/clinical-trials-matching-service-find-trial.html

Testosterone Replacement Therapy and Prostate Cancer

Testosterone deficiency affects up to a quarter of men over 40. The signs and symptoms of this condition can be severe and the long-term effects can be damaging. Men with low testosterone may experience reduced sexual function, depression, decreased muscle mass, increased fat mass, and weakened bones (Golla 2017). Supplemental testosterone, or testosterone replacement therapy, can improve many of these symptoms (Hackett 2016).

Historically, medical professionals warned against testosterone replacement for men who have, or have had, prostate cancer due to concern that it might stimulate cancer growth. Current research, however, shows that restoring normal testosterone levels with supplemental testosterone does not increase prostate cancer risk (Hackett 2016; Golla 2017; Debruyne 2017) and may be safe in some prostate cancer patients (Nguyen 2016).

Some data suggest that testosterone use may be safe during active surveillance (Golla 2017; Ory 2016; Morgentaler 2011). Moreover, emerging evidence even alludes to the idea that testosterone replacement during prostate cancer treatment may be less problematic than previously thought, although this is very controversial and still preliminary (Golla 2017). One early study measured serum testosterone levels in men who were candidates for active surveillance but opted for radical prostatectomy instead. Prostate tissue examination revealed that those with low testosterone had a greater chance of having more extensive disease than biopsy results had indicated (Ferro 2017); however, cause and effect is not clear. Two reviews of current research concluded that, in men with a history of prostate cancer, testosterone replacement therapy improved quality of life and did not appear to increase risk of disease progression or recurrence (Nguyen 2016; Pastuszak 2016).

More general information about testosterone replacement is provided in the Male Hormone Restoration protocol.

7 Novel and Emerging Strategies

Improvements to Conventional Treatments

Commonly used treatments such as radical prostatectomy, radiation, and hormone therapy are constantly being reviewed and refined to improve patient survival and quality of life (NCCN 2017b). For example, identifying patient groups that are most likely to benefit from specific treatments is an active area of research. Recent clinical data suggest radical prostatectomy might be helpful even for men with advanced or high-risk disease (Weiner 2017; Gandaglia 2017; O'Shaughnessy 2017). Surgery may be particularly effective in this patient group when used in conjunction with radiation therapy (Fahmy 2017; NCCN 2017b).

Researchers are also developing new evidence regarding the optimal order and combinations of various treatments. As described earlier, docetaxel may be more effective when used before resistance to testosterone-lowering therapy develops (Estevez 2016). Other research is addressing issues such as which hormone therapy should be used first and when it should be started (Moul 2015; Dijkstra 2016; Ho 2017; Chu 2015).

Finally, new medications for treating prostate cancer are being studied. A newer second generation of hormone therapies is in development (Wadosky 2016; Bambury 2016; Petrunak 2017). Seviteronel, also known as VT-464, is an androgen synthesis inhibitor that is undergoing fast-track review by the FDA for approval in patients with metastatic castration-resistant disease (Norris 2017; Teply 2016; Pharmacutical Technology 2017). Apalutamide is a new androgen receptor blocker granted priority review by the FDA in late 2017 based on promising results from the phase-III SPARTAN trial. The priority review is for use in men with nonmetastatic castration-resistant prostate cancer; the FDA’s opinion is expected by April, 2018 (Smith 2016; Broderick 2017).

High-Intensity Focused Ultrasound

High-intensity focused ultrasound (HIFU) is being tested in men with newly diagnosed prostate cancer and those with cancer recurrence after radiation (NCCN 2017b; Golbari 2017; Garcia-Barreras 2017; Crouzet 2017). In this approach, ultrasound is focused on the tumor and its concentrated energy destroys the targeted tumor cells (NCCN 2016b; NCI 2018b; Kim 2008; Malietzis 2013).

HIFU is currently approved by the FDA for prostate tissue ablation, but is not specifically approved as a treatment for prostate cancer (Nelson 2015). HIFU may cause fewer side effects than radical prostatectomy, and initial studies suggest it may be equally effective in low-risk patients; however, more research is needed (Garcia-Barreras 2017; Kanthabalan 2017; Jones 2017; Albisinni 2017).

Vascular-Targeted Photodynamic Therapy

Vascular-targeted photodynamic therapy involves injection of a photosensitizing, or light-sensitizing, drug. Small laser fibers are inserted into the prostate to activate the drug locally, and the activated drug destroys blood vessels supporting the tumor (NCCN 2016b).

A phase-III clinical trial evaluated vascular-targeted photodynamic therapy in men with low-risk prostate cancer. Side effects were rare, and fewer men in the photodynamic therapy group (about 30%) than the active surveillance group (about 60%) had disease progression after two years (Azzouzi 2017). Moreover, almost half of the patients that underwent photodynamic therapy, compared with only 14% in the active surveillance group, had a cancer-free biopsy sample two years after treatment (Stone 2017).

Targeted Therapies

Targeted therapies are designed to block or inhibit specific molecules that help cancer grow. Olaparib (Lynparza) is a type of drug that interferes with a protein called poly ADP ribose polymerase, or PARP, that helps cancer cells repair their DNA (NCCN 2017b). Olaparib and other PARP inhibitors may be effective treatments for men with tumors that rely on this DNA repair function (Ramakrishnan Geethakumari 2017).

In a phase-II clinical trial, 88% of patients with defects in tumor DNA-repair genes responded to olaparib (Mateo 2015). Researchers are developing tests to identify patients who are likely to respond to olaparib and other targeted drugs (Goodall 2017). In 2016, the FDA granted olaparib “breakthrough therapy” designation for metastatic castration-resistant prostate cancer, which ensures its rapid review (Ramakrishnan Geethakumari 2017; Helleday 2016).

Another emerging therapy targets prostate-specific membrane antigen, or PSMA, which is highly concentrated on the surface of prostate cancer cells. Agents called PSMA ligands bind PSMA and carry a radioactive substance to destroy the prostate cancer cells (Eiber 2017; Kulkarni 2016).

In a recent study, 145 patients with advanced prostate cancer were treated with a PSMA ligand. Forty-five percent had reductions of at least 50% in their PSA levels (Rahbar 2017). Two other studies found PSA levels decreased in about 80–90% of patients after treatment with PSMA-directed radiotherapy (Baum 2016; Brauer 2017).

Immunotherapy

Immunotherapy, an approach that uses the patient’s own immune system to fight cancer, was named the “cancer advance of the year” by the American Society of Clinical Oncology in both 2016 and 2017 (Madan, Gulley 2017; Rijnders 2017; Burstein 2017; Dizon 2016). Sipuleucel-T was one of the first FDA-approved immunotherapies (Madan, Gulley 2017).

Cancer vaccines deliver a cancer-specific protein to the body and direct the immune system to target cells that contain that protein (Sayour 2017). A vaccine developed for prostate cancer called PROSTVAC was designed to trigger the immune system to attack cells that have PSA on their surface (Mandl 2014; DiPaola 2015). Phase I – II clinical trials of PROSTVAC in combination with other anti-cancer agent, are ongoing as of early 2018. Results of these trials will help establish the utility of PROSTVAC for treating prostate cancer (Madan 2017; Fong 2017; Gulley 2017). Several other vaccine approaches are also currently being tested in earlier stage clinical trials (Lilleby 2017; Heery 2016; Yoshimura 2016).

Checkpoint inhibitors are another class of immunotherapy agents. These drugs were developed in response to the discovery of immune checkpoint proteins, which tumor cells engage to deactivate immune cells (Azoury 2015; Dyck 2017). Checkpoint inhibitors interfere with this process, allowing the patient’s immune system to continue fighting the tumor (Rijnders 2017; Madan, Gulley 2017; Popovic 2017). In a small study testing the checkpoint inhibitor pembrolizumab (Keytruda) in patients with metastatic castration-resistant prostate cancer, three of 10 patients experienced rapid and dramatic PSA level reductions (Graff 2016). Similarly remarkable responses to the checkpoint inhibitors nivolumab (Opdivo) and ipilimumab (Yervoy) have been described in case reports (Basnet 2017; Cabel 2017). Additional clinical trials will help determine which patients are most likely to benefit from checkpoint-inhibitor immunotherapy (Popovic 2017). 

Chimeric antigen receptor (CAR)-modified T-cell immunotherapy involves taking the patient’s T cells, genetically engineering the T cells to produce receptors that direct them to the cancer cells, and returning these CAR T cells to the patient’s body (NCI 2017b). In a phase-I clinical trial, 50% and 70% reductions in PSA levels were seen in two of five patients treated with CAR T-cell therapy (Junghans 2016). Promising results from animal models of prostate cancer using CAR T-cell therapy provide a foundation for further investigation (Kloss 2013; Gade 2005; Ma 2014; Zuccolotto 2014).

More information is available in the Cancer Immunotherapy protocol.

Screening, Diagnostic, and Prognostic Tests

Many men with slightly or moderately high PSA levels do not have cancer detected in their biopsy or do not have an aggressive form that needs treatment (Thompson 2004; Saini 2016). Several new tests are being developed to help men with moderate PSA level elevations decide whether to have a biopsy (Dani 2017; Carlsson 2017). A composite test called 4Kscore uses measurements of four different proteins in the blood along with clinical information about the patient to predict the likelihood that the cancer will spread within the next 15–20 years (Punnen 2015; Zappala 2017; Stattin 2015). A meta-analysis of published data concluded that the diagnostic accuracy of this test is similar to that of the FDA-approved Prostate Health Index (Russo 2017).

Genetic markers from cells in urine collected after a digital rectal exam may be useful predictors of cancer aggressiveness (Martignano 2017). In a trial with 1,077 participants, combined measurement of the gene markers TMPRSS2:ERG and PCA3 improved the ability to identify men at low risk for aggressive disease compared with PSA testing alone (Sanda 2017). Researchers examining genetic markers in urine samples from 905 participants with prostate cancer found two other markers (HOXC6 and DLX1 mRNA levels) that could help identify those with high-grade cancer (Van Neste 2016). These genetic tests could someday play a role in avoiding unnecessary biopsies (Martignano 2017).

New tests are also being developed to analyze tissue obtained through biopsy. The tissue may look healthy under a microscope, but certain molecular changes could indicate that a nearby cancer was missed by the biopsy needles. ConfirmMdx (Stewart 2013; Partin 2016) and the Prostate Core Mitomic Test (PCMT) (Robinson 2010; Legisi 2016) are two examples of commercially available tissue tests. Patients testing negative with these tests may opt for fewer or less frequent repeat biopsies (Wojno 2014; Legisi 2016).

Prostate tissue obtained through biopsy or surgery can be analyzed with new tests that may provide information on how aggressively the cancer should be treated:

  • Decipher has been assessed in over 2,000 patients and may predict the risk of metastasis (Nguyen 2017; Spratt 2017).
  • Oncotype DX Prostate Cancer Assay may provide information on tumor aggressiveness for men with clinically low-risk disease facing the choice between active surveillance or treatment (Brand 2016).
  • Prolaris and Promark may help prevent overtreatment by identifying men who are unlikely to benefit from more aggressive treatment (Cuzick 2015; Tosoian, Chappidi 2017; Koch 2016; Blume-Jensen 2015; Peabody 2017).

Although these tests are available and covered by Medicare for eligible patients, long-term and randomized trials are needed to confirm and compare their value (McMahon 2017; Metmark Genetics 2016).

Developments in imaging may improve diagnosis and assessment of prognosis. Positron emission tomography, or PET, provides information on how tissues and organs are functioning by measuring processes such as glucose metabolism and blood flow. PET scans use molecules called tracers that associate with cancers (Bednarova 2017). Researchers are working to understand how results from PET scans using various tracers can inform and improve treatment decisions (Dietlein 2017; Nanni 2016).

Repurposing Existing Drugs

Some drugs that are approved for the treatment of other diseases may be useful for treating prostate cancer. Much of the evidence supporting the potential benefits of these drugs comes from observational rather than clinical trials; however, several controlled trials are either underway or are being planned. The completion of such trials will help clarify whether there is a role for these repurposed drugs in prostate cancer treatment.

Statins are a category of cholesterol-lowering drugs. Among men with prostate cancer, those with high cholesterol levels are more likely to have high-grade and metastatic prostate cancer (Schnoeller 2017; Thysell 2010). In addition, men using statins to manage cholesterol have a lower risk of advanced prostate cancer and higher rate of prostate cancer survival (Alfaqih 2017). Several mechanisms by which statins may combat prostate cancer have been proposed, including modulation of cholesterol-signaling pathways in prostate tumors (cholesterol is the precursor to androgens, so statins may reduce androgen bioavailability in prostate cancer cells). Statins may also influence enzymes that participate in cell migration and tumor progression. Randomized controlled trials are needed to determine whether adding statins to prostate cancer treatment leads to better outcomes (Mucci 2017).

Preliminary data suggest aspirin may reduce prostate cancer recurrence (Smith 2017), prostate cancer-related death (Jacobs 2014), or death from any cause (Zhou 2017). The ADD-ASPIRIN trial is recruiting over 2,000 patients with prostate cancer to further test whether aspirin can prevent cancer recurrence (Coyle 2016).

The diabetes drug metformin may slow prostate cancer growth (Whitburn 2017; Sarmento-Cabral 2017). Metformin has been shown to enhance the ability of hormone therapy and radiation therapy to destroy prostate cancer cells in the lab and prostate tumors in mice (Colquhoun 2012; Whitburn 2017; Zhang 2014; Liu 2017). In one study in 44 men with metastatic prostate cancer, metformin (1,000 mg twice daily) stabilized the disease and extended PSA doubling time in a significant number of participants (Rothermundt 2014).

8 Dietary and Lifestyle Considerations

In addition to the information presented here, readers should also review the Prostate Cancer Prevention protocol, as it contains additional information about the potential role of diet and lifestyle factors in preventing prostate cancer.

Exercise and Body Weight

Regular exercise and maintaining a healthy body weight has been associated with better outcomes and quality of life for prostate cancer patients (Peisch 2017). A higher body mass index (BMI) has been associated with increased risk of aggressive prostate cancer (Xie, Zhang 2017). In one large observational trial, 5,158 men with prostate cancer were followed for several decades. In this study, long-term weight gain of more than 30 pounds was associated with a roughly 60% increased risk of prostate cancer-related death among non-smokers (Dickerman 2017; Perez-Cornago, Appleby 2017).

A meta-analysis of data on 1,199 participants from 32 clinical trials concluded that resistance exercise counters losses of muscle mass and strength associated with prostate cancer and its treatments (Keilani 2017). Another meta-analysis, which combined data from 1,574 participants in 16 randomized controlled trials, found exercise improved quality of life and reduced fatigue caused by prostate cancer (Bourke 2016). In one study with 25 patients, improved fitness was associated with slower rises in PSA levels (Hvid 2016). Additional studies are needed to address whether exercise programs can slow disease progression and improve survival (Hart 2017).

Exercise may be particularly helpful for patients on hormone therapy. Meta-analyses have shown that exercise improves some of the negative side effects attributed to hormone therapy, including muscle weakness, fatigue, weight gain, and sexual dysfunction (Yunfeng 2017; Baguley 2017). Results from one study suggest that, among patients on hormone therapy, those with the highest levels of fatigue may be the most likely to benefit from starting an exercise program (Taaffe 2017).

Diet

Emerging evidence suggests a diet emphasizing fruits, vegetables, and whole grains may contribute to reduced prostate cancer risk and improved prognosis and quality of life in prostate cancer patients (Carmody 2008; Nguyen 2006; Saxe 2001). In addition, preliminary evidence suggests specific foods, such as tomato sauce, cruciferous vegetables, olive oil, nuts, fish, and coffee, may be associated with lower risk of prostate cancer progression (Peisch 2017).

The Mediterranean diet is high in cancer-fighting phytonutrients, mainly from fruits, vegetables, whole grains, and olive oil, and has been associated with reduced risk of prostate cancer and prostate cancer-related death (Capurso 2017). In one study, men in the highest 25% of intake of cruciferous vegetables, such as broccoli, cabbage, and cauliflower, had about 60% reduced risk of prostate cancer progression compared with men whose intake was in the lowest 25% of the distribution (Richman 2012; Kirsh 2007). An association between higher fruit and vegetable consumption in general and increased prostate cancer survival has also been noted (Taborelli 2017).

Saturated fats, meat, and dairy may contribute to the development and progression of prostate cancer (Peisch 2017). One study noted that Swedish men with localized prostate cancer whose daily diet included at least three servings of high-fat milk were six times more likely to die of the disease; those reporting low-fat milk intake showed an associated borderline reduction in prostate cancer death (Downer 2017). Reducing saturated fat and increasing fruit and vegetable intake has been observed to prevent PSA level increases in men previously treated for prostate cancer (Hebert 2012).

Eating more fruits and vegetables and less red meat and saturated fat may also reduce prostate cancer risk and improve outcomes for some men with prostate cancer (Ballon-Landa 2018; Wilson 2016). Processed red meat and red meat cooked at high temperatures may be especially problematic and should be minimized (Wilson 2016).

A low ratio of omega-6 to omega-3 fatty acids in the diet may benefit prostate cancer patients (Apte 2013; Aronson 2011). In a group of 525 Swedish men with prostate cancer, the 25% of participants with the highest intake of the omega-3 fatty acid docosahexaenoic acid (DHA) and total marine fatty acids were 40% less likely to die of prostate cancer (Epstein 2012).

Carotenoids are plant pigments with documented health benefits, including some anti-cancer properties (Aghajanpour 2017). In one study, low circulating carotenoid levels were associated with more high-grade prostate cancers (Nordstrom 2016). In a study in men with recurrent prostate cancer participating in a 6-month program to improve diet and lifestyle, those with higher blood levels of carotenoids, including lycopene (a red pigment found in foods like tomatoes), had lower PSA levels at the end of the study (Antwi 2015). Cooked tomatoes are an especially rich source of lycopene (Story 2010). Higher consumption of lycopene has been correlated with a lower rate of prostate cancer diagnosis, especially lethal cancer (Chen 2013; Zu 2014).

Several population studies have shown that drinking coffee is associated with reduced risk of prostate cancer, especially lethal prostate cancer (Wang 2016; Pounis 2017; Wilson 2011; Peisch 2017). In a study of 630 men diagnosed with prostate cancer, those who drank an average of four cups of coffee per day or more had a 59% lower risk of cancer recurrence than those who drank one cup per day or less (Geybels 2013).

Smoking

Smoking may be particularly harmful for men diagnosed with prostate cancer (Peisch 2017). Smokers are more likely to be diagnosed with aggressive disease and 61% more likely to die from the disease as compared to never smokers (Kenfield 2011). In a study of over 2,000 men, those who were smokers at the time of radiation therapy were more than twice as likely to die from their disease (Steinberger 2015). Other studies have found that smokers treated with radical prostatectomy were more likely to have rising PSA levels after treatment (Rieken 2015) and die earlier than non-smokers (Curtis 2017). Smokers have also been found to be more likely to experience treatment-related fatigue during chemotherapy with docetaxel (Bergin 2017) and complications after prostatectomy (Byun 2017).

9 Integrative Interventions

Vitamin D

In laboratory studies, vitamin D interferes with several cancer processes (Pdq Integrative 2017; Abu El Maaty 2017; Moukayed 2017). For instance, laboratory data suggest vitamin D can prevent cancer cells from metastasizing (Hsu 2011). Several animal studies have shown that under some conditions vitamin D can control tumor growth (Pdq Integrative 2017; Mordan-McCombs 2010; Ajibade 2014). In addition, vitamin D can boost the immune system, possibly helping it identify and destroy cancer cells (Pandolfi 2017).

Several studies have explored whether vitamin D can help fight prostate cancer in humans (Brandstedt 2016; Xie, Chen 2017). In one study, serum vitamin D levels were analyzed before diagnosis in 1,000 patients with prostate cancer. Those with higher vitamin D levels were significantly less likely to die from the disease (Mondul 2016). In another study, short-term supplementation with high-dose vitamin D for three to eight weeks lowered PSA levels (Wagner 2013). As part of another study, 52 men with low-risk prostate cancer being monitored with active surveillance took 4,000 IU vitamin D3 daily for one year. In 55% of the men, the prostate cancer was less extensive at the end of the study than at the beginning based on biopsy analysis (Marshall 2012). Vitamin D supplementation improved PSA test results in two additional studies (Srinivas 2009; Newsom-Davis 2009).

Hormone therapy can weaken the bones of prostate cancer patients, but supplemental vitamin D may help prevent fractures in these patients (Ottanelli 2015; Dueregger 2014). A study examining factors associated with bone preservation in prostate cancer patients using hormone therapies found that those taking vitamin D supplements experienced less bone loss in their lower-back vertebrae (Alibhai 2013).

Green Tea

Green tea and its catechins, including epigallocatechin gallate or EGCG, may be helpful in fighting prostate cancer. In laboratory studies, EGCG slowed prostate tumor growth and caused cancer cells to die (Li 2014; Lin 2015). EGCG may also interfere with hormone signaling in prostate cancer cells (Ren 2000; Siddiqui 2011; Lee 2012).

Several human trials have suggested green tea and its catechins can prevent prostate cancer, particularly in men with high-grade prostatic intraepithelial neoplasia, or PIN, a precancerous condition (Pdq Integrative 2017; Jacob 2017). In a placebo-controlled trial, PSA levels decreased in men diagnosed with high-grade PIN taking 400 mg EGCG daily (Kumar 2015); furthermore, no toxic effects were seen after one year of EGCG supplementation at this dose (Kumar 2016). In a meta-analysis of multiple studies in men with high-grade PIN, taking green tea catechins reduced the rate of progression to prostate cancer from 23.1% to 7.6% (Cui 2017).

In a randomized trial, 113 men diagnosed with prostate cancer were assigned to drink six cups per day of green tea, black tea, or water for at least three weeks prior to prostatectomy. PSA levels significantly decreased in the group taking green tea (Henning 2015). In another trial, taking a green tea catechin supplement providing 800 mg EGCG daily was found to decrease levels of PSA and some other cancer markers in the blood in men with biopsy-confirmed prostate cancer awaiting prostatectomy (McLarty 2009).

Fish Oil and Omega-3 Fatty Acids

Oily fish are high in omega-3 polyunsaturated fatty acids (Ruxton 2004). These fatty acids have many health benefits and may even slow the growth of prostate cancer (Li 2014; Berquin 2011; Aucoin 2017). In laboratory and animal studies, omega-3 fatty acids were found to inhibit inflammation, interfere with blood vessel growth in tumors, and cause cancer cells to die (Spencer 2009; Gu 2013). Mice with prostate cancer whose only source of fat was fish oil survived longer than control mice fed diets with olive oil, corn oil, or animal fat (Lloyd 2013). Further analysis found that omega-3 fatty acids had beneficial effects on several types of cancer-fighting immune cells in the mice (Liang 2016). 

In a study that included more than 290,000 men, those who reported high fish and high omega-3 fatty acid intake on diet questionnaires at the beginning of the study were significantly less likely to die from prostate cancer during approximately 20 years of follow up (Bosire 2013). In a randomized trial, men scheduled for radical prostatectomy ate either a low-fat diet supplemented with 5 grams of fish oil daily or a traditional Western diet. Prostate cancer cells exposed to blood taken from the men eating the low-fat plus fish oil diet showed decreased growth in the laboratory (Aronson 2011). A second analysis of this same study found that pro-inflammatory marker levels were decreased and scores on a prognostic test were more favorable in the patients eating the low-fat plus fish oil diet (Galet 2014). In a study in men with low-risk prostate cancer undergoing active surveillance, higher tumor levels of omega-3 fatty acids, particularly the marine omega-3 fatty acid eicosapentaenoic acid (EPA), were associated with reduced risk of prostate cancer progression (Moreel 2014).

Flaxseed is a plant source of omega-3 fatty acids and fiber, as well as a class of polyphenols called lignans that have weak estrogenic activity (Kajla 2015). In one study, 25 men awaiting surgery for prostate cancer ate a low-fat diet supplemented with 30 grams of ground flaxseeds per day. Several tests indicated that the diet may have reduced cancer cell survival and proliferation (Demark-Wahnefried 2001). In a larger follow-up study, a similar group of patients ate either 30 grams ground flaxseeds per day, a low-fat diet, a low-fat diet plus 30 grams ground flaxseeds per day, or a control diet. Flaxseed supplementation, even without the context of a low-fat diet, was associated with molecular changes that may indicate that cancer cells were dividing more slowly (Demark-Wahnefried 2008).

Lycopene

As described in the “Dietary and Lifestyle Considerations” section, lycopene may help reduce risks of prostate cancer. Beneficial cancer-fighting effects of lycopene have been demonstrated in laboratory studies (Pdq Integrative 2017; Lin 2015). Small clinical studies in humans have shown that supplemental lycopene is safe and may reduce prostate cancer cell activity (Pdq Integrative 2017; Kumar 2008).

In a randomized controlled trial, men being treated with surgical removal of the testicles had a more consistent decrease in PSA levels if they were taking 4 mg per day of supplemental lycopene (Ansari 2003). Another randomized trial found that taking 30 mg lycopene per day reduced levels of markers of tumor growth in men newly diagnosed with localized prostate cancer (Kucuk 2001). In addition, men with intermediate-risk prostate cancer who ate tomato products providing 30 mg lycopene daily had significant decreases in PSA levels after three weeks (Paur 2017).

Pomegranate

Pomegranate contains a number of compounds that combat free radicals, and extracts from pomegranate interfere with cancer cell division in laboratory research (Pdq Integrative 2017). In a study designed to simulate consumption of one to two pomegranate fruits per day in an average adult human, mice injected with prostate cancer cells drank either plain water or water with pomegranate extract. Tumor onset was later and tumor growth was slower in the mice receiving the pomegranate extract (Malik 2005). In a study using experimental mice bred to be highly susceptible to prostate cancer, the same dose of pomegranate extract prevented metastasis and increased survival (Adhami 2012). Several other animal studies have shown similar results (Seeram 2007; Sartippour 2008; Albrecht 2004).

Pomegranate products have also been tested in human studies. In one trial, the average PSA doubling time increased from 15 months to 54 months in men with rising PSA levels after surgery or radiation therapy who drank eight ounces of pomegranate juice daily. Prostate cancer cells exposed to blood taken from patients treated in this study did not divide as rapidly and were more likely to die (Pantuck 2006). A randomized trial in a similar patient population found that doses of 1 and 3 grams of pomegranate extract per day extended PSA doubling time by 58% and 43%, respectively, an effect that was statistically the same for the two doses (Paller 2013).

Cruciferous Vegetable Isothiocyanates

Cruciferous vegetables such as cabbage, broccoli, cauliflower, collard greens, arugula, Brussels sprouts, and kale contain phytochemicals called glucosinolates. During food preparation, chewing, and digestion, glucosinolates are broken down into isothiocyanatets (eg, sulforaphane) and other bioactive compounds called indoles (eg, indole-3-carbinol). The cruciferous-vegetable-breakdown products have some compelling anti-prostate-cancer properties (Novio 2016; Watson 2013). Epidemiological studies have found correlations between greater intake of cruciferous vegetables and reduced risk of prostate cancer (Watson 2013). A small clinical study in which 20 men with prostate cancer took an isothiocyanate-rich broccoli extract for up to 20 weeks showed that PSA doubling time increased during treatment (Alumkal 2015). A meta-analysis of observational studies found that cruciferous vegetable consumption was associated with a roughly 20% relative prostate cancer risk reduction among men who ate the most cruciferous vegetables versus those who ate the least (Liu 2012). As of the time of this writing in early 2018, four clinical trials examining different cruciferous vegetable derivatives or preparations are pending publication of results.

Cranberry

Cranberries are a rich source of phytonutrients known to boost the immune system and fight infection, and laboratory and clinical data suggest cranberry products may be useful for cancer patients (Weh 2016). In several laboratory studies, various preparations of cranberry juice have been shown to interfere with cancer cell division and signals that boost cancer growth (Weh 2016; Deziel 2012; Deziel 2010). In an animal model of prostate cancer, a purified proanthocyanidin-rich extract from cranberries significantly slowed prostate tumor growth (Ferguson 2006).

In a controlled clinical trial, 64 participants scheduled for radical prostatectomy took either 1,500 mg per day of cranberry fruit powder or placebo for at least 21 days prior to surgery. Average PSA levels decreased by 22.5% in the group taking cranberry and increased by 0.9% in the placebo group (Student 2016).

Some studies have addressed whether cranberry can help relieve urinary symptoms in men treated for prostate cancer. Urinary tract infections are a common side effect of radiation therapy (Flannigan 2014; Bonetta 2012). Cranberry extract can interfere with the ability of bacteria to stick to tissue in the urinary tract (Weh 2016; Sobota 1984; Hisano 2012). In a randomized controlled trial in 370 men undergoing radiation therapy, those receiving 200 mg cranberry extract daily had a lower rate of urinary tract infections than those receiving placebo (8.7% vs. 24.2%) (Bonetta 2012). A large follow-up study confirmed these results in a group of 924 participants (Bonetta 2017). In a separate study, cranberry extracts protected men being treated with radiation therapy from another common side effect—inflammation of the bladder (Hamilton 2015).

Isoflavones

Soy isoflavones such as genistein have been studied extensively for their anti-inflammatory and estrogen-modulating effects (Danciu 2017). Laboratory data on prostate cancer cells suggest isoflavones may reduce inflammation and interfere with signals that promote blood vessel growth in tumors (Swami 2009; Rabiau 2010). Genistein has been shown to slow prostate tumor cell proliferation in laboratory and animal models (Ajdzanovic 2013; Wang 2004; El Touny 2009). Findings from other studies suggest isoflavones may make prostate cancer cells more sensitive to radiation therapy (Raffoul 2007; Singh-Gupta 2010).

In a randomized controlled trial, 32 patients with rising PSA levels after prostate cancer treatment added two slices of soy-enriched bread, providing 34 mg of isoflavones per slice, or a placebo bread to their daily diet. Reduced levels of markers of inflammation and suppressed cancer-promoting immune activity were seen in those receiving isoflavones in their bread (Lesinski 2015). In another randomized trial including 54 patients scheduled for prostatectomy, those who received 30 mg genistein per day had a 7.8% drop in PSA levels versus a 4.4% increase in the placebo group (Lazarevic 2011). Two small open trials using isoflavone-containing soy beverages noted reductions in PSA level increases in participants with rising post-treatment PSA levels (Kwan 2010; Pendleton 2008).

Some clinical trials have found that isoflavones do not affect PSA levels or other health parameters (deVere White 2010; Hamilton-Reeves 2013). Inconsistencies in preparations, doses, participant characteristics, and treatment durations make it difficult to draw conclusions. Future research into the effects of soy and isoflavones on prostate cancer outcomes is needed.

Modified Citrus Pectin

Pectin is an indigestible carbohydrate that is especially abundant in the peels and pulp of citrus fruits. Modified citrus pectin (MCP) is pectin that has been chemically modified to break into smaller carbohydrate chains that can be absorbed into the blood. Studies have shown that these small bits of MCP inhibit a molecule called galectin-3. Cancer cells use galectin-3 during metastasis, and inhibiting galectin-3 may impede cancer cells’ ability to spread (Leclere 2013; Zhang 2018; Jiang 2013).

Indeed, findings from a study using a rat model of prostate cancer suggest oral MCP may reduce metastases. Although nearly all untreated rats had metastases after 30 days, only about half of the rats drinking water containing MCP had metastases (Pienta 1995).

In a small clinical trial, 10 men with rising PSA levels after treatment for prostate cancer received 14.4 grams per day of MCP for 12 months; PSA doubling times increased in seven of the 10 men (Guess 2003). Another open trial tested the effects of MCP supplementation, at 15 grams per day, in participants with a variety of advanced solid cancers. MCP led to improved quality of life and disease stabilization in 20.7% of the 29 participants who completed eight weeks of supplementation. One participant with metastatic prostate cancer had a remarkable response, with a 50% decreased PSA level, improved quality of life, and decreased pain at 16 weeks (Azémar 2007). An ongoing clinical trial is evaluating the effect of MCP, at a dose of 4.8 grams three times per day, on PSA levels (Keizman 2017).

Laboratory research suggests MCP may prevent tumor growth and spread by interfering with cell-cell interaction and adherence (Leclere 2013). MCP and a similar product called fractionated pectin powder have also been shown to cause cell death in prostate cancer cell cultures (Jackson 2007; Yan 2010).

Curcumin

Curcumin, a carotenoid pigment extracted from the spice turmeric, has well-established anti-inflammatory and oxidative stress-reducing effects. In laboratory studies, curcumin interfered with cancer growth signals, decreased androgen receptor activity, reduced production of PSA, and slowed tumor growth (Li 2014; Lin 2015; Goel 2010; Rivera 2017). In one trial, 36 patients with castration-resistant prostate cancer and rising PSA levels were given 6,000 mg curcumin per day while undergoing treatment with docetaxel and prednisone. Positive PSA responses were noted in 59% of participants (Mahammedi 2016). Another study with 85 participants found that a combination of curcumin and soy isoflavones markedly reduced PSA levels in men with high PSA levels and negative biopsies (Ide 2010).

Zinc

Healthy prostate cells accumulate zinc to accomplish their normal cellular functions. In contrast, prostate cancer cells have depleted zinc stores, which makes them less susceptible to cell death (Costello 2016; Eidelman 2017; Franz 2013). When prostate cancer cells are treated with zinc in the laboratory, they begin to die (Feng 2002). In a group of over 35,000 men, those taking higher amounts of supplemental zinc were observed to be significantly less likely to be diagnosed with advanced prostate cancer (Gonzalez 2009). Another observational study in 525 men noted that those with higher dietary zinc intake around the time of their prostate cancer diagnosis had a lower risk of dying from prostate cancer (Epstein 2011).

Melatonin

Melatonin, a hormone best known for its role in regulating sleep, is also emerging as a promising anti-cancer agent. Evidence to date has shown that melatonin can interfere with cancer initiation, progression, and metastasis (Reiter 2017). In an observational study, men with higher levels of melatonin metabolites in their urine were found to be significantly less likely to have prostate cancer, especially advanced prostate cancer (Tai 2016). When rodents with prostate cancer were treated with supplemental melatonin, blood vessel growth was inhibited and the tumors grew more slowly (Paroni 2014; Xi 2001; Siu 2002; Mayo 2017). Melatonin may fight prostate cancer by interfering with androgen receptor signaling (Reiter 2017). Melatonin has also been shown to decrease glucose metabolism in prostate cancer cells, reducing cancer cells’ ATP production (ATP is a key cellular-energy-storage compound) (Hevia 2017). Melatonin may also enhance cancer cells’ sensitivity to conventional anti-cancer drugs, possibly complementing standard therapy (Reiter 2017).

Milk Thistle and Silymarin

Milk thistle (Silybum marianum) has been used for thousands of years as an herbal remedy for liver disorders. One of the main active ingredients in the seeds and fruit of milk thistle is a flavonoid complex called silymarin (Vue 2016; Abenavoli 2010; Vaknin 2008). Many studies have tested the effects of silymarin on rodents with prostate cancer and on prostate cancer cells in the laboratory. For example, one component of silymarin, called silibinin, reduced the creation of new blood vessels in tumors and slowed tumor growth in mice with prostate cancer (Deep 2017). In another study, silibinin made prostate tumors in mice more sensitive to the effects of radiation yet protected healthy tissues from radiation damage (Nambiar 2015).

Silibinin is being tested in clinical trials for breast cancer (Lazzeroni 2016), hepatitis C infection (Braun 2015), and liver cancer (Siegel 2014). In six patients with prostate cancer awaiting prostatectomy, taking 13 grams daily of a preparation of silibinin led to high levels of silibinin in the blood; however, levels were very low in the prostate tissue obtained during surgery (Flaig 2010). Recent studies have explored variations in the silibinin compound that may be more potent and may reach the prostate tissue more effectively (Vue 2017; Manivannan 2017).

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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