 The cancer is located on one side of the prostate. At this stage, the tumor is very small or found incidentally, possibly during surgery or by an elevated prostate-specific antigen (PSA) level. The Gleason score is low.

 The cancer is located only in the prostate but can be seen on imaging scans or felt during a digital rectal exam. The Gleason score may range from 2 to 10.

 The cancer has extended through the outer layer of the prostate and into surrounding tissues and may be found in the seminal vesicle but not in the lymph nodes. The Gleason score may range from 2 to 10.

 The cancer has spread to the lymph nodes near or far from the prostate or has spread to distant tissues or organs, such as the liver or bones. The Gleason score may range from 2 to 10.

 defines prostate cancer by grade based on the pathologist’s review of a biopsy or surgical specimen, with 1 being the least aggressive and 5 being the most aggressive. The grade of the most common tumor pattern is added to the grade of the second most common tumor pattern in the tissue examined to create the Gleason score. A Gleason score of 2 to 4 is considered low grade, 5 to 7 is intermediate grade and 8 to 10 is high grade.

Articles

Side Note

When diagnosing prostate cancer, doctors consider staging and grading. In grading, a score is assigned based on the Gleason grading system.

Medical Illustration: Prostate Cancer

Longer lives, fewer side effects, less overall toxicity: These are the treatment goals that men tend to share after being diagnosed with prostate cancer.

Although there are still mysteries to resolve, continual advances in treatment mean that these benchmarks are being met more and more effectively over time.

, we bring you a comprehensive overview of the latest techniques in prostate cancer treatment, from the strategies appropriate for the earliest phases of the disease to those applied in the latest stages. In a detailed timeline spanning back to the year 1904, we also offer a sense of just how far prostate cancer treatment has come.

For instance, in slow-growing localized disease, when active surveillance is an option, state-of-the-art imaging in the form of the highly accurate multiparametric MRI is becoming more available. In addition, there’s a growing understanding of biomarkers that can signal the presence of prostate cancer or its aggressiveness, helping to determine when the disease should be actively treated instead of carefully watched.

When men do step into the treatment arena, a prime concern is often finding a way to effectively fight the cancer without incurring the common side effects of urinary incontinence or sexual dysfunction.

For one man featured in these pages, that became possible through highdose- rate brachytherapy; in fact, shorter, higher-dose courses of therapy are being explored throughout the radiation realm. In the surgical suite, more and more doctors are turning to laparoscopic prostatectomy (in some cases robotic) as a less invasive alternative to open prostatectomy, and we also discuss surgical techniques on the horizon that may do more to prevent side effects by avoiding damage to the structures surrounding the prostate.

Perhaps the most notable recent advances in prostate cancer treatment are the six new medical agents approved since 2010, five of them based on their ability to improve patient survival. In addition to presenting information on these cutting-edge treatments, we discuss a variety of investigational drugs, including hormonal treatments galeterone (TOK-001) and ARN-509 and the immunotherapy Prostvac.

 mission to provide both education and inspiration for patients, survivors and caregivers during the cancer journey, we’ve filled this issue with facts and advice about every aspect of prostate cancer screening, diagnosis, treatment and research — and even some thoughts on living with side effects. Through guidance from leading oncologists and other decision-making tools, we hope to leave you better prepared to make choices about your own care – or at least to ask the questions that will help you determine the path that is right for you. As always, thank you for reading.

From the Chairman

Understanding state-of-the-art care helps patients with prostate cancer to choose treatments

Choosing the Right Path

After James Levy finished his high-dose-rate (HDR) brachytherapy to treat his localized prostate cancer, he celebrated by getting a tattoo that included the StandUp2Cancer logo, the date his treatment ended and the word “radioactive.” It was his way of acknowledging his successful treatment with this relatively new approach.

“I’m a big fan of HDR brachytherapy,” says Levy, of Richmond, Va. “I went in Friday and was back at work on Monday. There was nothing to it.”

HDR brachytherapy, which involves placing strong sources of radioactivity in or near the cancerous tissue for a few minutes and then removing them, joins other, more established forms of radiation as a treatment option.

These techniques include one other type of brachytherapy and many forms of external beam radiation therapy (EBRT), which sends beams of radiation into the prostate from outside the body. In addition, for men whose prostate cancer has metastasized to the bone, a fairly new radiopharmaceutical is available. These approaches give patients a variety of choices if they select radiation treatment as either a first-line or follow-up therapy.

The common variable that internal and external radiation share is their increasing ability to deliver higher doses to the prostate while reducing exposure to nearby healthy tissues. Nonetheless, the treatments can cause side effects, including temporary fatigue or later development of permanent urinary incontinence, bowel problems and erectile dysfunction, among others.

For Levy, 57, who completed treatment about a year ago, side effects have not been an issue. “I’ve had none of the common long-term effects, like incontinence, erectile dysfunction or bowel issues,” says Levy. This is likely because of HDR’s ability to direct radiation specifically at the tumor and avoid nearby tissue and organs — and its short duration.

To treat his localized prostate cancer, James Levy chose high-dose-rate brachytherapy, and has not experienced any long-term side effects. [Photo by Liza Bishop, VCU Massey Cancer Center]

While that outcome is compelling, HDR may not be right for everyone. In fact, sifting through possibilities to arrive at the best radiation option for each patient can be challenging, says James B. Yu, a radiation oncologist at Yale University School of Medicine in New Haven, Conn. The decision, he says, is as individual as the man and his cancer.

“It depends on what you’re looking at — cure rates or complications,” he says. “Patients care about some complications more than others, such as erectile dysfunction, so the choice of treatment is intensely personal.”

Questions about the relative value of newer radiation methods may, in particular, give men pause.

For instance, in administering EBRT, “Physicians are looking at shortening the number of radiation treatments by increasing the dose per treatment,” Yu explains. He says there continues to be concern that giving more intense radiation treatments, even if there aren’t as many, could be more toxic overall. Adding to the confusion is that current research is mixed, highlighting “the complexity of comparing these treatments and saying that one is better than the other.”

Yu urges patients to learn as much as they can about the pros and cons of various treatments before making a decision, and to discuss any questions they might have with their health care providers. Levy agrees, adding that “the Internet makes it possible to become really well-informed.”

For men with localized prostate cancer (meaning it hasn’t spread outside the gland), often the first step after diagnosis is choosing between active surveillance (particularly for lower-grade tumors, as indicated by the level of prostate-specific antigen [PSA] in a man’s blood and the Gleason score doctors use to describe aggressiveness); surgery to remove the prostate gland (called a radical prostatectomy), or radiation therapy. If a man has localized prostate cancer and plans to undergo treatment, he should know that surgery and radiation are considered equally effective when it comes to preventing the advancement of the disease, according to the American Cancer Society (ACS).

One option for men with locally advanced prostate cancer (in which lymph nodes or other nearby tissues are involved) is radiation therapy plus hormonal therapy, which several studies have shown is more effective at fighting the cancer than hormonal therapy alone. In addition, men with this condition and a higher risk of recurrence should be informed that radiation therapy after a radical prostatectomy decreases their risk of cancer recurrence or progression, according to national guidelines issued in May 2013. Issued jointly by the American Society for Radiation Oncology and the American Urological Association, the guidelines also state that doctors should offer “salvage radiotherapy” to patients whose PSA levels rise, or who have a local recurrence after prostatectomy but show no evidence of distant metastases.

In 2015, the National Comprehensive Cancer Network (NCCN) issued new guidelines for patients. These guidelines recommend EBRT as a staple of treatment for men with various stages of the disease: as a first-line treatment for those at low risk for developing metastatic disease and who are expected to live 10 years after diagnosis; as a first-line or adjuvant therapy for many categories of men at intermediate risk, and for many groups of men with high-risk disease.

Most radiation options fall under the umbrella of EBRT, which is typically administered over a seven- to nine-week period, according to the ACS. Among EBRT therapies, intensity modulated radiation therapy (IMRT) is the most common and has been adopted extensively over the past 15 years. This approach uses a machine that moves around the patient, shaping the beams and aiming them from several angles. In this way, the dose of radiation can be adjusted, directing higher doses to the places where there are cancerous cells.

Other high-tech options include three-dimensional conformal radiation therapy (3D-CRT), image-guided radiation therapy and intensity-modulated arc therapy. The shared element among these therapies is a careful mapping of the exact size, shape and location of the prostate gland and tumor using imaging tests, such as computed tomography and magnetic resonance imaging scans or X-rays. This information helps doctors determine precisely where to aim higher and lower doses of radiation for maximum effectiveness and minimum side effects. One recent comparative study showed that IMRT offers a disease-control advantage over 3D-CRT.

Stereotactic body radiation therapy (SBRT), which is often referred to by the names of the machines that administer the radiation, including CyberKnife, Gamma Knife and X-Knife, is a form of EBRT that delivers large doses of radiation to the prostate. Although the benefit of SBRT is that its entire treatment course is days and not several weeks, some studies have shown side effects to be worse with this form of therapy.

Another promising, yet controversial, form of EBRT is proton beam therapy, which aims protons (the heavy, positive parts of atoms) at tumors and releases their energy after traveling a specific distance, thereby causing less damage to tissues they pass through. Although research is inconclusive about whether proton therapy reduces sexual complications, one study did find that men aged 60 or younger treated with this modality experienced little sexual dysfunction; in comparison with the findings of other studies cited in the paper, the amount of dysfunction was comparable to that in populations treated with EBRT in general, but better than that in men treated with prostatectomy.

LDR AND HDR Brachytherapy Round Out Options

But other research has suggested limited advantages of proton therapy. A 2012 study comparing IMRT with proton therapy found that the newer therapy was no more effective in getting cancer in check. In addition, experts warn that proton beam therapy is not only more expensive than other forms of radiation (primarily due to costly machinery), but also might not be the best choice to treat prostate cancer because “critical structures, such as the rectum and urethra, will still get radiation no matter how perfect your particle is,” Yu explains.

Men with early stage, slow-growing tumors who would prefer fewer radiation treatments — or even just a single treatment &mdash; might be candidates for traditional brachytherapy, which places radioactive seeds directly, and permanently, into the prostate gland during a short surgical procedure. Radiation is then delivered slowly, for months, at a low-dose rate (LDR); eventually, the seeds lose their radioactivity.

HDR brachytherapy, a newer approach, is administered through temporary catheters, in which a high-activity source is placed for just minutes to deliver HDR radiation.

[Photo by Liza Bishop, VCU Massey Cancer Center]

Experts have placed some caveats on these treatments. Current guidelines from the NCCN recommend that brachytherapy as a standalone treatment be limited to low-risk or intermediate-risk cases. And for now, HDR is usually reserved for cancers that are progressing.

“Only when you need to deliver a big radiobiological punch — like when the disease is aggressive &mdash; do you go with HDR, typically not for early-stage prostate cancer,” says Dorin Todor, director of the brachytherapy program at Virginia Commonwealth University’s Massey Cancer Center in Richmond. “I think this is where brachytherapy combined with EBRT really shines.

These rules of thumb may be changing, though. According to Todor, “There are ongoing clinical trials trying to prove the equivalence between LDR treatments and one large fraction of HDR for early-stage prostate cancer. Both have the advantage of being a ‘one-stop shop,’ but during HDR, radiation is delivered for only 10 to 15 minutes, as opposed to months or years.”

Radiation can also be delivered directly to bone metastases via radiopharmaceuticals — drugs that contain radioactive elements &mdash; in patients with advanced prostate cancer. These drugs are a particularly useful approach when multiple areas of bone are involved. They can shrink painful lesions and improve quality of life with less exposure to normal tissue.

In May 2013, the U.S. Food and Drug Administration approved Xofigo (radium-223) to treat bone metastases, and a study published in July 2013 in 

 showed that those receiving Xofigo had improved median overall survival (14.9 months) compared with those on placebo (11.3 months).

Although there are many radiation treatment options, with the guidelines continuing to evolve, Levy is pleased that he chose HDR brachytherapy for his localized tumor.

“I didn’t want to take any chances,” he says. “Two days of treatment meant that I would likely not have any problems down the road.”

Features

New advances in radiation treatment enable higher doses with less damage to nearby tissue.

Scanning the Horizon: Advances in Radiation Treatment for Prostate Cancer

As time moves on, we are seeing continual developments in the diagnosis and treatment of prostate cancer, with several recent developments of particular interest.

Yet unanswered questions persist, and some of the most controversial concern screening for the disease. How much does screening for the level of prostate-specific antigen (PSA) in a man’s blood — which may indicate the presence of prostate cancer — help men overall, and how should we balance screening programs with our concern about the unnecessary diagnosis and treatment of slow-growing cases of the disease?

The medical and scientific communities are working to resolve these questions. Some suggest changing screening eligibility requirements or raising the PSA level — or the rate of change in levels over time &mdash; that are considered high enough to warrant testing for prostate cancer. Are there specific factors upon which to selectively screen certain individuals? Another hope is that the discovery of various biomarkers may lead to a more definitive test for prostate cancer &mdash; or better yet, help us determine more clearly which prostate cancers are indolent and which are aggressive. Until that happens, we grapple with the issue of whether PSA screening is a worthwhile alternative.

Similar questions spill over into the treatment arena when prostate cancer is caught early. If a man is told to “watch and wait,” is knowing about his disease worth the stress that knowledge can cause? For those who choose treatment for this stage of disease, are outcomes good enough to warrant the common side effects that can result, including urinary incontinence and erectile dysfunction?

In more advanced cases, when treatment is more definitively necessary, we often turn to strategies that have been with us for decades. The first radical prostatectomy, in fact, was conducted more than 100 years ago, and the importance of chemotherapy in advanced — especially high-burden – disease has persisted for half a century. Yet progress is regularly being made in these areas, and newer techniques are being added to our toolbox.

In the surgical realm, there’s a growing trend toward the less invasive: robotassisted laparoscopic prostatectomy is growing in popularity, and experimental strategies include a newer form of laparoscopy known as LESS and a urethral prostatectomy called NOTES. Radiation techniques are also evolving, with a focus on higher doses that are given in shorter courses and cause less damage to surrounding tissue. And since 2010, six new medical treatments for prostate cancer have been approved, including hormonal treatments Zytiga (abiraterone) and Xtandi (enzalutamide), immunotherapy Provenge (sipuleucel-T) and the chemotherapies Taxotere (docetaxel) and Jevtana (cabazitaxel). Just in the last year, there has been evidence that earlier use of chemotherapy may be better for certain patients than waiting until hormonal therapies are no longer effective.

While we certainly can’t answer all the questions about how best to screen, diagnose and treat prostate cancer, we have endeavored to fill this special issue of CURE with a wide array of information about state-of-the-art screening and care for all phases of the disease, as well as a look at what’s on the horizon. We hope this information will help you ask the most relevant questions and make informed decisions as you determine how to live with, and fight, prostate cancer.

Chair, Department of Breast Medical Oncology

The University of Texas MD Anderson Cancer Center

Editor's Page

Medical and scientific communities continue to weigh the value of PSA screening

Resolving a Controversy: The Value of PSA Screening

"Linda, I'm going to die!" The strained voice was that of my former husband, Michael, in a message left on my work phone. I had not expected to hear from him during the day since he was undergoing a prostatectomy; my son and I planned to visit him in the hospital after work. I certainly didn’t expect to hear those words.

It was 2008, and weeks earlier Michael’s prostate biopsy finally showed cancer. I say finally, as it was one of many biopsies performed in the face of a rising PSA (prostate-specific antigen) level. The surgery was to be “routine,” and a good outcome was anticipated. He was likely to be one of those men who did well following surgery and perhaps radiation. Unfortunately, the prostatectomy was never completed.

At the hospital that evening, Michael relayed the surgeon’s message: metastatic cancer, stage 4 disease and a prognosis of two years on the average. What? This was shocking news, and a strong sense of failure followed for not having caught this earlier.

As an oncology nurse for more than 20 years, I knew the majority of men with early prostate cancer did very well. My own father was a classic example, having been diagnosed and treated with leuprolide for the last three years with hardly a break in his stride.

Michael proceeded with the usual next steps: radiation and androgen ablation treatment. His PSA never went to zero. Within one to two months following completion of radiation, his PSA began to rise, suggesting disease progression. It never seemed to really stop much. The addition of bicalutamide (a drug that blocks the effects of testosterone, which feeds prostate cancer) had little effect. Referral to medical oncology followed.

In the back of my mind, I had a nagging thought and eventually mentioned it to Michael. Could he have a genetic mutation, namely 

, which was playing a role in the aggressiveness of this cancer?

A few years prior, in 2003, we had been contacted by an agency that assists adopted people in finding their biological families. I received a phone call from a woman asking unusual questions about the whereabouts of Michael’s parents (both deceased). The memory of suspicions by one of Michael’s sisters came to mind: She recalled as a child that their mother had gone to the hospital pregnant and returned without a baby. Was that baby given up for adoption?

The answer, as it turned out, was yes, and a new sister, Ann, joined the group of five siblings. Ann had grown up in a very loving and caring family, yet her drive to find her biological family came from an unfortunate discovery.

Michael Penwarden shared a BRCA2 mutation with his sister, Ann Hanson; both developed cancer. [Photo courtesy of Linda Penwarden]

At age 40, Ann was diagnosed with breast cancer. Having been adopted, she had no family history with which to evaluate hereditary risk. Wisely, her surgeon recommended genetic testing, and the results — positive for the 

 mutation — were the driving force behind the search for her biological family. In Ann’s words, “A bolt of energy shot me out of my chair and I knew exactly what I needed to do. It was no longer just about me or curiosity.”

In our first meeting with the medical oncologist, I explained the situation and asked if it was reasonable to test Michael. Having a copy of Ann’s results, the testing would be specifically for that mutation. The oncologist agreed, and Michael subsequently underwent testing. We were aware that the testing would not benefit Michael, but the implications for our 11-yearold son were clear.

The results came back: “positive for a deleterious mutation” of 

. We were both devastated knowing that our son had a 50/50 chance of inheriting this mutation. We were also informed that Michael’s prostate cancer was likely more aggressive as a result of this mutation. That was certainly clear by this point.

Multiple treatments followed: the hormone-suppressing drug ketoconazole, the chemotherapy docetaxel and Zytiga (abiraterone), a hormone therapy that inhibits a protein called CYP17A1, which helps in producing testosterone. These are all therapies used to treat progressive disease when others have failed. Palliative radiation was used to treat bone metastases, which seemed to crop up every few weeks or so. Sadly, Michael succumbed to his prostate cancer in September 2011.

I placed the results of his genetic testing in a safe along with my will. There were instructions for my sister to divulge this information to my son if I hadn’t already done so, should something happen to me. I had numerous conversations with the genetic counselor about how and when to inform him.

For men, it’s recommended that testing be offered in their mid- 20s, since early screening isn’t necessary until age 35. However, in 2014, at age 17, my son was headed off to college, and it seemed reasonable to begin discussing this before he gained his independence.

My son felt he could have been told of this possible risk sooner. He didn’t hesitate. “Of course I want to be tested.” I was prepared to support any decision he made. It was reasonable to wait and decide later. With a full life ahead of him I felt there was such a burden in knowing, and yet there is power in knowledge.

I can’t explain why I knew what the results would be, and as I sat listening to the genetic counselor tell him that he had indeed tested positive for the 

 mutation, I felt déjà vu hearing this for a second time.

My son asked very intelligent questions about level of risk and listened to her recommendations. It seems to be that there’s much less that men, compared with women, can actively do to mitigate this elevated threat. Cancers related to the 

 mutation in men include prostate, pancreatic and breast cancers, as well as melanoma.

 mutations came alive with actress Angelina Jolie’s revelation in 2013 of her own 

 positivity. The “Angelina Jolie Effect” has resulted in greatly increased screening for this mutation in women. But where are the men? Are there an equivalent number of men and women carrying these mutations? Isn’t the impact on them just as important? Risk of inheritance is 50/50 regardless of gender.

Michael Penwarden, whose nickname was “Mad Dog,” posed with relatives who participated in a triathlon in his honor. [Photo courtesy of Linda Penwarden]

Consider the labeling of this mutation — 

ancer; this can be misleading, even for women. The mutation elevates the risk for ovarian cancer as well. Men are rarely recognized in the literature or public commentary when it comes to awareness and discussion about the influence of this unfortunate mutation. While 

 mutations are associated with an elevated risk of prostate cancer in male carriers, it is not yet clear if this is the case for 

In addition to the effect this gene had on Michael and Ann, other family members have been affected. Ann’s daughter, Rachel, tested positive for the mutated gene at age 19. She was advised to wait until her mid-20s to pursue “vigilant monitoring.” When her cousin was diagnosed with breast cancer, Rachel made contact with a high-risk breast clinic and underwent extensive genetic counseling, gathering current and evidence-based information about her options. Subsequently, at age 25, she chose to have a bilateral mastectomy and reconstruction to reduce her risk of breast cancer.

Mollie, Rachel’s cousin and another of Michael’s nieces, was unfortunately diagnosed with breast cancer at age 27 in 2013. Mollie has completed surgery and adjuvant treatment for her breast cancer and is actively considering fertility treatment along with preimplantation genetic diagnosis (PGD). This procedure would allow for testing of the embryos for the 

 mutation and the selection of those without the gene.

As for my son, he is now well informed about the importance of cancer prevention, being aware of his body and reporting changes. He has adhered to healthy habits for years, such as going to the gym, maintaining a healthy weight and using sunscreen regularly. He may need to begin prostate cancer screening earlier than usual, but that is still years away. He is also aware of the implications for a family in the future.

 mutations, we need to remember that men matter. Clinicians and the public need to be aware that being positive for 

 mutations has consequences for men and their families, too. It’s time to start talking about — and including &mdash; men in these discussions.

Linda Penwarden, a nurse for more than 27 years, is an oncology clinical nurse specialist at Mountain States Tumor Institute in Boise, Idaho. Penwarden is also a mom and a member of a family in which cancer genetics have played a significant role. She wants to get the word out to others affected by this genetic mutation.

BRCA mutations can lead to prostate and other cancers, and men are as likely as women to inherit them. Yet male awareness is lagging.

Where Are the Men? BRCA Mutations and Male Awareness

For localized disease, guidelines state that both surgery and radiation are acceptable forms of treatment, and men in this category make up a large number of cases. According to data from the Surveillance, Epidemiology, and End Results (SEER) program, localized disease accounts for about 80 percent of the nearly 221,000 new cases projected for 2015 in the United States.

“It’s mostly early-stage cancers in which radiation therapy is competing with surgery,” says Dorin Todor, director of the brachytherapy program at Virginia Commonwealth University’s Massey Cancer Center in Richmond. “Surgery doesn’t make much sense for anything but early-stage prostate cancer, because if more than the prostate is involved, you’ll need some form of systemic approach.”

To help make a sound decision, patients should consider the following factors.

Younger patients can better tolerate the general anesthesia that’s used in the vast majority of surgical cases, but new minimally invasive techniques (such as robot-assisted surgery) have made surgery a broader option, says James B. Yu, assistant professor of therapeutic radiology at Yale University School of Medicine in New Haven, Conn.

 Insurance coverage varies, but external beam radiation therapy of any type might be more expensive than surgery, according to a 2013 study in the British Journal of Urology International. Researchers found that the costs ranged from about $20,000 for a robot-assisted prostatectomy for low-risk cancer to approximately $50,000 for combined radiation therapy for high-risk cancer. Brachytherapy, however, may be cheaper than surgery. Patients should always discuss the cost of treatment with their health care providers.

 Any side effects from surgery — even the nerve-sparing type &mdash; tend to show up immediately, whereas radiation takes time to produce some of the same changes, experts say. (Which side effects occur and their frequencies vary from patient to patient, regardless of the choice.) For example, about half the men who had normal erections prior to EBRT became impotent within five years, and about one-third of the men who received brachytherapy experienced incontinence.

“We’ve made great strides over the past couple of decades, and prostate cancer remains a very curable disease for the most part,” Yu says. “That’s why we’re focusing so much on side effects and cost. In a way, focusing on these subtle questions is a good problem to have, since so many of these men go on to live such good, long lives.”

Whether to opt for surgery or radiation to treat localized prostate cancer depends mainly on the stage and grade of disease.

Surgery or Radiation for Prostate Cancer: What Determines the Choice?

The course of Jim Kiefert’s life took an unexpected turn 26 years ago during a routine physical examination. Along with the usual blood work, his doctor offered to perform a test that was new back then, the prostate-specific antigen (PSA) test, which measures the PSA level in the blood and can, if the level is high, indicate the presence of prostate cancer.

His test revealed a serum PSA concentration of 39 nanograms per milliliter (ng/mL); most healthy men have a PSA level below 4.

“Not only did they find out that I had prostate cancer, but it had also spread to the seminal vesicles,” Kiefert says. “So I began to do research on what to do from that point.”

Jim Kiefert had a PSA test when the screening measure was brand-new, and it led to his diagnosis with prostate cancer. [Photo by Shauna Bittle]

Kiefert, of Olympia, Wash., had surgery to remove his prostate gland and underwent 35 sessions of external beam radiation therapy. But his PSA level was still high. “At that point, the doctor called me and my wife into his office and told us that the major treatments for prostate cancer had failed, and it had spread,” Kiefert recalls. “He said that I probably had one to three years left to live, and I should go home and get my life in order.”

Kiefert decided to not follow his doctor’s advice. “Instead,” he says, “I started my journey of becoming an informed and empowered patient.”

More than two decades later, Kiefert, who will turn 77 in September, still has not gotten his affairs in order. Instead, the retired school superintendent has defied his initial diagnosis. In addition to using standard medical therapies and entering clinical trials, he has made changes to his lifestyle and diet.

Less than 10 years ago, the cupboard was relatively bare when it came to treating advanced prostate cancer. But new drug strategies have been developed, including immunotherapy, hormone therapy and chemotherapy. Biologically targeted agents are in development. Although these agents are generally not curative, studies have shown they can slow disease progression, improve quality of life and extend overall survival.

“For a man with advanced prostate cancer who has been through a gamut of therapies, the moment when he sees a rise in his PSA can be one of the scariest times in his life,” says Edwin Posadas, medical director of the urologic oncology program at Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute in Los Angeles. “There was a time when we didn’t have anything with known efficacy to offer. It wasn’t until 2004 that oncologists had the first FDA-approved drug that impacted survival after progression through initial hormone therapy.”

Since 2010, the U.S. Food and Drug Administration (FDA) has approved six new agents for prostate cancer. Five of these approvals were based on an improvement in survival.

Male hormones, known as androgens, which include testosterone, play a pivotal role in the development, growth and pathology of prostate cancer. As most cases of prostate cancer are fueled by androgens, hormone therapy, also known as androgen deprivation therapy, has long been a component of treatment. Simply put, the goal of hormone therapy is to lower the levels of androgens, which in turn can shrink the cancer and put the brakes on its growth.

Hormone therapy is generally used if surgery and radiation are not options or if the cancer remains or returns following those treatments. In addition, hormone therapy combined with radiation is used as a first-line therapy for men who have a high risk of their cancer recurring or if it has metastasized. Sometimes hormone therapy is used before radiation to shrink the tumor, potentially making the treatment more effective.

The collection of drugs in this class is expanding, and now patients have several options.

Luteinizing hormone—releasing hormone (LHRH) agonists, or analogs, block release of LHRH, a key hormone released by the pituitary gland that stimulates the testicles to produce testosterone. These agents, which are injected or placed as small implants under the skin, include Lupron (leuprolide), Zoladex (goserelin), Vantas (histrelin) and Trelstar (triptorelin).

LHRH antagonists are a newer class of drugs that can reduce testosterone levels more quickly without causing a “flare,” an initial short-term rise in testosterone, as the agonists do. Firmagon (degarelix), the only approved therapy in this class, is administered monthly by injection.

Anti-androgens, such as Eulexin or Drogenil (flutamide), Casodex (bicalutamide) and Nilandron (nilutamide), can block the action of androgens made by the testicles and/or adrenal glands. When paired with an LHRH agonist, these daily pills can help prevent testosterone flare.

Ketoconazole, an anti-fungal, also blocks the production of androgen (and the steroid cortisol) in men with prostate cancer, and is sometimes administered to those who haven’t responded well to other hormonal therapies — although it’s not approved by the FDA for that indication, or for the treatment of any cancer, for that matter.

Newer therapies that work by a different mechanism have recently become available, and they could prove to be more effective than older drugs. Zytiga (abiraterone) inhibits enzymes produced by the adrenal glands — selectively those enzymes that are responsible for making androgens. Zytiga received FDA approval in 2012 to be used for metastatic disease that has become resistant to other treatments. This is known as castration-resistant prostate cancer (CRPC).

“One of the most significant developments has been the recognition that, even in castration-resistant prostate cancer, testosterone is still driving growth,” says Bruce Roth, an oncologist at the Washington University School of Medicine in St. Louis, Mo. “We now know that testosterone is coming from a number of sources, one being the adrenal gland, and recognize that prostate cancer can make its own testosterone.”

Another drug, Xtandi (enzalutamide), is a newer type of anti-androgen that works by a different mechanism than others in its class. It blocks androgen receptor signaling and has been shown to have a significant effect on median overall survival in men with CRPC whose disease has progressed after chemotherapy. In 2014, the FDA approved expanded use of this oral medication when a study showed that it also delayed tumor progression and prolonged lives in men who used the drug before receiving chemotherapy.

On the horizon, new therapies are undergoing clinical trials. Among these are galeterone (TOK-001) and ARN-509, which interfere with the androgen signaling pathway. Early results are promising. The clinical trial for another drug, orteronel (TAK-700), was stopped early because although this drug, along with prednisone, extended the period before cancer progression, it did not improve overall survival.

But some researchers still see the potential of TAK-700, and are testing it in a different combination. SWOG, formerly the Southwest Oncology Group, is conducting a large, phase 3 study comparing an LHRH agonist and an anti-androgen medication (bicalutamide) with an LHRH agonist and TAK-700. This study is still in its early stages.

Even though prostate cancer tumors generally respond to hormone therapy, resistance to these agents typically develops, occurring over a wide range of time among individual patients. Hormone therapy also carries some unwanted side effects, which can include hot flashes, loss of bone density, weight gain, erectile dysfunction and fatigue. One potential method of minimizing these side effects is a strategy known as intermittent therapy, which stops and restarts treatment depending on the levels of PSA in the blood.

Several studies have shown that intermittent therapy might give patients some relief from side effects but is not as effective in controlling cancer and may be more suitable for those without metastases. As a result, continuous therapy remains the standard of care for those with metastatic disease. Intermittent therapy needs to be adjusted to the individual patient.

Kiefert eventually chose intermittent therapy following his initial treatment. He also made significant changes in his lifestyle: He modified his diet and no longer eats red meat or dairy. Instead, he opts for fresh fruits and vegetables. Kiefert also exercises regularly, biking, gardening and playing in the lake at his home with his grandkids and great-grandkids.

Realizing that his emotional outlook and stress levels also contribute to his health, Kiefert learned mind-body techniques to keep negative thoughts at bay. He left his job and went to one that “he looked forward to going to each morning,” a move that helped make his life less stressful.

Kiefert stayed off of therapy for about seven years, and when his PSA level began to rise, he looked into hormone therapies. “There wasn’t a protocol for intermittent therapy at that time,” Kiefert says. “But that was the way I wanted to do it. I monitored my own testosterone.”

It wasn’t until his PSA level began to rise a little too much that he decided to resume therapy. “The best advice I received as to when to start therapy again was when I reached the panic point,” Kiefert says. “When that happened, I did what I had to do.”

Amid all of the buzz about personalized medicine and genomic therapy, chemotherapy is often considered “old school.” But prostate cancer treatment is one area where the old methods are finding new success.

The chemotherapy drug docetaxel (known as Taxotere, but also available as a generic) has become a treatment for patients with CRPC, but recently researchers questioned whether it improved survival if it was given earlier, during hormone therapy and before the cancer became resistant. The CHAARTED trial showed that using docetaxel early, along with hormonal therapy, resulted in better overall survival, especially in patients who had more extensive metastases. These findings were supported by the STAMPEDE study, sponsored by Cancer Research UK and presented at the 2015 American Society of Clinical Oncology annual meeting, which found that combining docetaxel early in treatment with standard hormone therapy improved survival by 10 months, specifically in men with newly diagnosed advanced prostate cancer that had not previously been treated with hormone therapy.

If docetaxel proves ineffective for patients with CRPC or stops working, a second chemotherapy agent, Jevtana (cabazitaxel), is another option. Jevtana was approved in 2010 for the treatment of patients with CRPC in combination with prednisone, but only after patients had been previously treated with docetaxel.

“Chemotherapy is not going away in prostate cancer,” Posadas says. “It is a viable and important strategy, and we are going to keep coming back to it because it helps patients.” Despite the concerns about chemotherapy toxicity, treatment with drugs such as docetaxel has been shown to improve quality of life as well as survival for symptomatic patients.

Immunotherapy boosts the ability of the body’s immune system to identify and target cancer cells.

Several approaches to immunotherapy for prostate cancer have shown promise in clinical trials in recent years, with the most notable being Provenge (sipuleucel-T). Indicated for the treatment of metastatic CRPC, it is the first therapeutic vaccine approved for any type of cancer.

Each dose is manufactured specifically for the individual patient using his own immune cells. The process involves the removal of a certain type of white blood cell, called a dendritic cell, from the patient. These cells are then exposed to an antigen specific to prostate cancer cells, along with a stimulatory molecule to activate their immunity. The final step is injecting the white blood cells, now “programmed” to attack the prostate cancer, into the patient.

The pivotal study that led to FDA approval found that Provenge increased median survival by about four months in men who had advanced disease. But not everyone is a candidate for this treatment. Those most likely to benefit from this therapy are relatively free from symptoms and have not had extensive treatment for advanced disease.

Roth points out that even though the study showed a survival benefit, it didn’t really show “objective” responses, such as a delay in tumor progression.

“I think some healthy skepticism about what patients get in terms of their treatment is reasonable,” Roth says. “And now there are other drugs like Zytiga and Xtandi that provide survival benefits that weren’t available when Provenge was approved. They also have objective responses and are in pill forms and easier for the patients. So it is something to consider when patients are choosing their different options.”

After a prostate cancer diagnosis, Jim Kiefert decided to research potential treatment strategies and drive decisions about his medical care. [Photo by Shauna Bittle]

According to Mark Stein, a medical oncologist at Rutgers Cancer Institute of New Jersey, additional research looking at Provenge combined with other therapies is indicated. Currently, two such studies are under way.

Other immunotherapy agents are nearing clinical application. Pending are results from a large, multicenter phase 3 trial to determine whether Prostvac, a series of vaccines that uses pox viruses to stimulate the immune system, contributes to overall survival in men with advanced prostate cancer. The trial is designed to investigate whether the vaccine alone or in combination with a growth factor can be effective in prolonging overall survival in men with few or no symptoms from CRPC. The treatment is administered by injection under the skin and does not involve blood collections.

A third vaccine showing promise is based on a Listeria bacterium platform. It combines the Listeria monocytogenes immunotherapy agent ADXS-PSA, which has been modified to target a prostate-specific antigen, with the checkpoint inhibitor Keytruda (pembrolizumab), which works by “releasing the brakes” on the immune system. Stein noted that Listeria-based vaccines seem to be very immunogenic, safe and able to overcome some of the mechanisms that tumors use to hide from the immune system.

Unlike standard chemotherapy, targeted agents act by blocking essential biochemical pathways or proteins that are required for tumor cell growth and survival. Therefore, the development of targeted therapies requires the identification of good targets — those that are known to play a part in the growth and survival of cancer cells.

One targeted agent, custirsen (OGX-011), in combination with docetaxel and prednisone, did not extend survival, a finding that was unexpected. Previous evidence had shown that custirsen targets a protein, clusterin, which is produced in elevated levels in advanced cancers, including prostate cancer, and protects cancer cells from programmed cell death (known as apoptosis).

In a different clinical trial, custirsen is being tested in combination with Jevtana as a second-line treatment for men with CRPC. This phase 3 trial is ongoing.

Some of the newer drugs are being tested in combination with established therapies. “We do see combinations of nonmedical therapies, and we’ve gone beyond the one-trick pony,” Posadas says. “The idea of being able to combine in a systemic fashion is intriguing — such as androgen deprivation and immunotherapy.”

However, Roth cautions that, with so many new drugs available, there is little existing data about the sequencing of these agents, although trials are currently under way to answer this question. “The standard approach,” says Roth, “is to use these single agents sequentially. The use of combinations of these agents should be restricted to clinical trials.”

As for personalized medicine, the goal of being able to tailor therapy to the individual is one that has not yet been fully realized. “We are not there yet for prostate cancer,” says Roberto Pili, director of genitourinary oncology at the Indiana University Melvin and Bren Simon Cancer Center. “There is research left to do. However, we have made significant advances in genetics and we are getting closer to sequencing a tumor. For example, we are learning about the type of alteration in the androgen receptor, and then telling the patient with prostate cancer which treatment will likely either work or not.”

Kiefert has proven that long-term survival is possible, using what is currently available. He participated in clinical trials for both Provenge and Xtandi, and since Xtandi’s FDA approval in 2014, he is now taking this medication. His PSA level has gone up a bit, but is holding at 8.

“I’m doing great now,” he says. “I have stayed on top of prostate cancer. Information is power, and patients need the information so that they can make the right decisions. Of course they want to listen to their physicians, but they have to realize that they are in the driver’s seat for their care.”

New drug treatments are helping patients with advanced prostate cancer to live longer.

Marathon Men: Living Longer With Prostate Cancer

When Jon Spelman, 73, was diagnosed with prostate cancer six years ago, he didn’t have any trouble deciding on a course of treatment. “I was not going to live with cancer in my body,” says Spelman. “I opted for surgery, the sooner the better.”

Spelman’s cancer was confined to the prostate gland, and according to the American Cancer Society, nearly half the men who receive that diagnosis choose surgery.

During the procedure, called a radical prostatectomy (RP), the surgeon removes the entire prostate and some surrounding tissue, including the seminal vesicles and nearby lymph nodes if warranted. Although RP carries the risk of incontinence and impotence, it is nonetheless a common treatment for prostate cancer. Newer surgical techniques and technologies, however, are providing men with additional options, and they come with the possibility of fewer damaging side effects.

The traditional approach to RP is open surgery, which requires surgeons to make a large incision (4 to 10 inches) to access the prostate, either retropubically (through the lower abdomen) or, less commonly, perineally (through the skin between the anus and the scrotum). These approaches can mean that the patient risks blood loss, the possibility of developing blood clots and a recovery time of six weeks or so. Although open RP has come to be accepted as the gold standard, this procedure is giving way to newer surgical methods.

At the beginning of the 21st century, the medical community started making the shift toward laparoscopic surgery, a less invasive technique. The surgeon makes a small incision near the belly button and then inserts a laparoscope, a thin, tube-like instrument with a light and a lens for viewing the prostate. Then more incisions are usually made in the same area to expedite removal of the prostate.

For cancer confined to his prostate gland, Jon Spelman chose laparoscopic prostatectomy, and has no regrets. [Photo courtesy of Jon Spelman]

Laparoscopic surgery has many advantages. It is a minimally invasive method, so there is less bleeding and pain, and hospital stays can be shortened. However, learning the techniques of pure laparoscopic surgery can be challenging for many clinicians.

Spelman’s procedure was done laparoscopically. Although he has experienced the common side effects of incontinence and erectile dysfunction, he has no regrets. A recent suburethral sling procedure has helped alleviate many of his incontinence issues, providing welcome relief.

The next development in prostate surgery in the U.S. was the use of advanced robotic systems equipped with laparoscopic tools, according to Mitchell Humphreys of the Mayo Clinic in Phoenix. When performed by an experienced surgeon, robot-assisted surgery can result in lower rates of blood loss and complications, less pain and quicker recovery times. Research is ongoing to determine the advantages and disadvantages of the different techniques.

With the availability of these new techniques, open surgery might not be widely available in the future. Furthermore, according to Wesley White, an assistant professor in the Division of Urology at the University of Tennessee Graduate School of Medicine in Knoxville, Tenn., surgeons familiar with that approach will be retiring, and younger surgeons are selecting robotics.

Although surgeons may be moving toward robotics, the research is by no means clear that it is a big improvement over other methods. Like open prostatectomy, laparoscopic and robotic prostatectomies can be performed with the goal of sparing some or all of the nerves that control erections in eligible patients; nerve-sparing surgery was introduced by urologist Patrick Walsh in 1982, before the advent of robotic surgery. But a review of the literature published in 2010 in 

 showed that, to date, neither laparoscopic nor robot-assisted surgery is better than open surgery at preventing the common side effects of incontinence and erectile dysfunction. The research does, however, show a trend toward improved outcomes in both areas when robot-assisted surgery is used, compared with the laparoscopic approach. For this reason, both Humphreys and White agree that, in the long run, robot-assisted techniques will result in better outcomes.

“The clarity with which you can see the anatomy is so much better,” White says. “Instead of standing at the operating room table staring down at someone’s pelvis and reaching behind the pelvic bone, sort of fishing around for things, you are actually looking at it on a huge screen that enhances your vision.” White and other experts also note that the robot allows surgeons to make smaller, more precise incisions.

One way to improve care for patients with prostate cancer would be to achieve the benefits of removing the prostate gland without damaging surrounding structures. Even with the currently used laparoscopic and robot-assisted techniques, those structures are affected.

Natural orifice transluminal endoscopic surgery (NOTES) and laparoendoscopic single-site (LESS) surgery are two new techniques that have the potential to make prostate cancer surgery even less traumatic. They are both under investigation.

With the NOTES technique, surgeons can remove the prostate without making an incision by using the urethra as the entry point, Humphreys explains.

“There are some limitations right now on the technique and the technology, but where it is today is not where it is going to be two years from now,” he adds. His hope is that companies that produce instruments for NOTES will see the potential benefits for patients with prostate cancer, and “true innovation can take over.” One barrier, though, is that the medical device companies already have a large share of the urology market, so they have little financial incentive to improve urology applications. Their focus now is on equipping robots for other types of surgery.

“After my diagnosis, my first reactions were ‘How soon am I going to die and what am I going to do about it?’ With the love and support of my family, and the opportunity to talk with other men who had similar experiences, I got through it.” — Jon Spelman [Photo courtesy of Jon Spelman]

Humphreys explains that, in the future, it might be possible to use NOTES for focal removal, which means locating and removing the cancer from the prostate instead of removing the entire gland. “Focal removal now is limited by the ability of imaging to discern disease from normal prostate tissue. At this point, what is working best is treatment with ablative technology, often with a laser.”

Although small clinical trials have shown that this procedure is effective, some researchers question its safety and efficacy. The reason is that prostate cancer is often a multifocal disease, and there is concern that some cancerous cells will be left behind.

LESS, an alternative form of laparoscopy, has shown promise as a surgical technique. It uses the belly button as a single entry point, as well as specially designed flexible instruments. In 2007, surgeons from the Cleveland Clinic used this approach on four patients. All the patients had early-stage prostate cancer and came through the surgery successfully. Between 2010 and 2011, surgeons in China performed prostatectomies on six patients with the LESS technique. According to the surgeons, their work points to the feasibility of this approach in selected cases.

Prostate surgery using the LESS approach has also been done with a robotic system, but the currently available robot is not ideal for this type of surgery. This issue is one of many yet to be resolved, largely because the technology has not caught up with the concept.

“Someday they may build a robot that allows us to do everything we want to do, that allows us to do an entire procedure inside the space of a pencil eraser, but we’re not there yet,” White says.

In the meantime, many men are satisfied with surgery using the tried-and-true methods. That has been the case for Spelman, a writer and performer, who has developed a theatrical production based on his experience with prostate cancer. Called “Facing the Bull,” the show has had runs in Washington, D.C., New York, Seattle and Indianapolis. In each venue, the performance has helped educate men and their families about prostate cancer, as well as pointing to the ways that humor can help men cope with their diagnosis and treatment.

“After my diagnosis, my first reactions were ‘How soon am I going to die and what am I going to do about it?’” recalls Spelman. “With the love and support of my family, and the opportunity to talk with other men who had similar experiences, I got through it.”

Innovative approaches offer more surgical options with potentially fewer side effects.

Delicate Difference: More Surgical Options for Prostate Cancer

Tom’s annual physical was all but done, and all systems were go when his doctor thought he detected a lump on his prostate. Then the trap door opened, and from referral to biopsy, the news grew rapidly worse: A specialist found a sizable tumor that was aggressive and inoperable.

Decisions had to be made quickly. The oncologist wanted to radiate and begin testosterone suppression immediately. Swimming upstream through the mass of new medical information, Tom says he knows he asked whether he would still be able to make love with his wife. The doctor asked if Tom was having problems now. Tom said no. The doctor turned to Tom’s wife and asked again: any erection problems? She confirmed, no. The doctor assured him he would be fine.

Tom, who requested anonymity, credits his doctors with giving him a chance to survive a brutal cancer, but wishes they had been straightforward about the fine print. Although he was able to get erections throughout his radiation treatment, after a few months the treatment and the missing testosterone brought his libido to a halt. Depression ensued. It wasn’t until Tom saw his fifth therapist that he found someone who didn’t blush when he talked about his inability to get an erection. With help, he was able to begin to heal himself. He fired his health care team and found a new doctor who spent more time talking with him about risk versus reward.

Sexual activity after prostate cancer therapy might be different, but still possible.

Despite the fact that he is a 56- year-old working professional in a mid-sized, Midwestern town, Tom didn’t have access to someone like Sharon Bober. She directs the sexual health program at Dana-Farber Cancer Institute in Boston, using an integrative and optimistic approach, addressing body and mind. “There are certain things that are never going to be the same,” Bober says frankly about prostate cancer. But she adds that sexual problems are rarely just physical; that it’s possible to “re-engineer your sex life so that it’s really satisfying. But it might look really different.”

First, the bad news: Prostate cancer treatment often affects sexual function, and medical progress in this area has been slow.

“The patient education literature gives a very inaccurate idea of how many men recover good sexual function after prostate cancer,” says Leslie Schover, a clinical psychologist specializing in sexual health at the MD Anderson Cancer Center in Houston. “If you look at radical prostatectomy, it doesn’t matter if it’s done with a robot or if it’s done laparoscopically, the results are basically the same across the board. Fewer than one-fourth of men have erections afterward that resemble the ones they had before — if they had good function. And that applies overwhelmingly to the men who are under 60, with very good erections before treatment.”

Robot-assisted surgery and new radiation regimens claim better outcomes, but, Schover says, there is little difference five years after treatment. Even watchful waiting has its problems, possibly because of tumor progression, repeated prostate biopsies or other factors, she says. “The bottom line is nobody does very well.” In other words, very few men get off scot-free.

Prostate Cancer Special Issue | CURE