The treatment of late-stage prostate cancer is shifting. With the approval of two new oral agents, abiraterone acetate (Zytiga) in April 2011 and enzalutamide (Xtandi) in August 2012, there are now options for men with metastatic prostate cancer who have progressed after chemotherapy treatment with docetaxel where there were none just two years ago. Since its initial approval, abiraterone has also been approved by the FDA for the use of abiraterone in chemotherapy-naïve patients with metastatic prostate cancer. Enzalutamide is also being tested in this patient population; a phase III trial is ongoing.

	Next-Generation Androgen Receptor Signaling Agents

The reason for the shift? Research over the past 10 years has shown that metastatic prostate cancer tumors that are resistant to hormonal (androgen)- deprivation therapies still rely on androgen receptor (AR) pathways for growth. “Until this decade, we had assumed that tumors from [surgically or medically castrated patients who stopped responding to hormonal treatments] were no longer reliant on hormones for their growth and progression,” said Joshi J. Alumkal, MD, assistant professor of Medicine at the Oregon Health & Science University in Portland.

There are several mechanisms by which prostate tumors hijack androgen signaling to fuel cancer growth. Some castration-resistant prostate cancer (CRPC) tumors are able to make testosterone and androgen precursors. These tumors also amplify ARs on prostate cancer cells or develop mutations in AR genes. The next-generation androgen-targeting therapies, abiraterone and enzalutamide, target these mechanisms.

“Abiraterone and enzalutamide are proof that at least in some patients, male hormones still matter and they are promoting prostate cancer growth. Those are the 50% of patients who respond [to these new agents], at least temporarily, and who may derive an overall survival benefit,” said Alumkal.

The two drugs have different mechanisms of action. Abiraterone works by inhibiting CYP17, an enzyme necessary to make a precursor of testosterone in the testes, adrenal glands, and within the prostate tumor itself. Enzalutamide is a second-generation oral antiandrogen that binds to the androgen receptor, inhibiting the interaction of testosterone to its receptor.

“Enzalutamide is selective—it works particularly well in tumors in which the androgen receptor is overactive, such as through amplification,” said Andrew J. Armstrong, MD, MSc, co-leader of the Genitourinary Oncology Research program at Duke University School of Medicine in Durham, North Carolina.

Other novel hormonal agents in development include orteronel (TAK700), another oral nonsteroidal selective inhibitor of androgen synthesis that targets the same enzyme as abiraterone. The oral drug is being tested in phase III trials in patients with metastatic CRPC both before and after treatment with chemotherapy.

	Management of Prostate Cancer in Urology Practices

Another novel oral agent, ODM-201, has the same mechanism of action as enzalutamide, and thus interacts with the AR. The drug has shown high response rates in a phase I/II first-in-human trial presented at this year’s European Society for Medical Oncology (ESMO) Congress.

As abiraterone, enzalutamide, and other oral androgen-targeting therapies become the standard of care, it is likely that more urologists will be treating patients with advanced prostate cancer and that these patients will remain in the care of their urologists longer, through the progression of their cancer.

This trend of prostate cancer management within urology practices will likely continue as these newer agents move into the nonmetastatic setting. “As we see the data emerge in the nonmetastatic setting, you may see more urologists consider using these drugs because they appear quite safe,” said Armstrong.

Armstrong emphasized that there are serious side effects of these agents that urologists may not wish to manage, such as heart failure, liver toxicity, muscle fatigue, risk of seizure, and drug interactions with other medications. But with proper training, he believes urologists can manage the toxicities.

“One of the differences between medical oncologists and urologists is that medical oncologists have learned how to recognize and handle side effects of cancer therapies because of their experience in handling chemotherapy side effects,” said Stanley A. Brosman, MD, a urologist in Santa Monica, California. Brosman emphasizes that while easy to administer, the new agents are not without side effects. “It is not just prescribing a pill, but educating a patient of potential side effects and learning how to deal with them.”

		Table. Selected Oral Androgen-Affecting Agents for the Treatment

					Selective inhibitor of androgen biosynthesis by the adrenal glands, testes, and prostate cancer (inhibits CYP17 enzyme, necessary for androgen biosynthesis), dosed in combination with prednisone

					Approved April 2011 for metastatic CRPC post-docetaxel with prednisone

					Approved December 2012 for metastatic CRPC chemotherapy- naïve patients who have failed ADT

					Phase III COUAA- 301 trial: 14.8 months median OS on abiraterone vs 10.9 months on placebo

					Phase III COU-AA-302 trial: 16.5 months median rPFS on abiraterone vs 8.3 months in control

					Phase II neoadjuvant abiraterone + leuprolide trial (NCT00924469)

					Phase II abiraterone + enzalutamide combo trial (NCT01650194)

					Androgen receptor signaling inhibitor

					Approved August 2012 for metastatic CRPC post-docetaxel

					Phase III AFFIRM trial: 5-month longer median OS benefit vs placebo (18.4 months in MDV3100 arm vs 13.6 months for placebo arm)

					Phase III PREVAIL chemotherapy-naïve metastatic CRPC trial (NCT01212991)

					Phase II neoadjvuant MDV3100 prior to prostatectomy trial (NCT01547299)

					Phase II Hormone-naïve prostate cancer trial (NCT01302041)

					Phase II TERRAIN trial vs the antiandrogen bicalutamide in asymptomatic CRPC patients who have progressed on hormone therapy (NCT01288911)

					Reversible nonsteroidal inhibitor of androgen synthesis (CYP17 inhibitor)

					Preliminary phase II activity in nonmetastatic CRPC

					Preliminary phase II antitumor activity of 41% to 63% of metastatic CRPC patients with more than 50% decline in PSA in 97 patients

					Phase III TAK700 maintenance therapy post-first-line docetaxel in metastatic CRPC (NCT01707966)

					Phase III TAK700 in chemotherapy-naïve metastatic CRPC trial (NCT01193244)

					Phase III TAK700 in metastatic CRPC post-docetaxel trial (NCT01193257)

					Phase III TAK700 + hormone therapy + radiotherapy in high-risk patients (NCT01546987)

					Preliminary antitumor activity of nearly 90% of patients with more than 50% decline in PSA in 15 patients

					Phase I/II metastatic CRPC safety and pharmacokinetics trial (NCT01317641)

		ADT indicates androgen-deprivation therapy; CRPC, castration-resistant prostate cancer; MOA, mechanism of action; N/A, not applicable; OS, overall survival;

		PFS, progression-free survival; PSA, prostate-specific antigen.

Despite the improvement in overall survival with both abiraterone and enzalutamide, resistance and disease progression is still inevitable. “These drugs have really not shown cures yet for patients in the metastatic setting—all patients eventually progress, and we need to understand how this occurs,” said Armstrong.

What are the escape mechanisms of tumors exposed to these new androgen receptor pathway agents? “That is the million dollar question,” said Alumkal. “With cancer therapy, anything that doesn’t kill a cancer makes it stronger. Tumor cells that can survive the treatment and evolve have activated bypass mechanisms.”

The entire range of resistance mechanisms to these new agents has not been identified, but research is ongoing. “The side effect of these drugs may be to activate other critical survival pathways to sustain these tumors. But that remains to be proven,” said Alumkal. One pathway that may be important when the AR pathway is inhibited is phosphoinositide 3-kinase (PI3K)/AKT. So far the evidence for this resistance mechanism comes from preclinical research, but the combination of a PI3K inhibitor with enzalutamide may not be far off.

The goal is to find new, rational combinations to prevent resistance— or at least to prolong responses or increase response rates. Another goal is to understand why approximately half of patients with metastatic CRPC do not respond to either abiraterone or enzalutamide.

	Combinations and Treating Earlier-Stage Prostate Cancer

Alumkal and colleagues are starting their own effort with funding from a Prostate Cancer Dream Team Award sponsored by the Stand Up to Cancer Foundation, the Prostate Cancer Foundation, and the American Association for Cancer Research, using genomic sequencing to categorize tumors before and during treatment with enzalutamide and at time of progression on enzalutamide to understand the differences between patients who respond and those who do not.

“My hope is that, for all of these new and promising hormonal agents, we will develop combinations that will work better,” said Alumkal.

One potential combination is abiraterone plus enzalutamide. A pilot phase I study is in progress, testing whether the two drugs are more potent when given in parallel and to understand the toxicities of the combination.

Another approach to boost overall survival for patients with prostate cancer is to study these new hormonal agents in earlierstage prostate cancer. Because cancer becomes increasingly more complex as it progresses, treating patients in the adjuvant or neoadjuvant setting or in combination with surgery or radiation has the potential to improve cure rates, similar to adjuvant hormonal therapy in breast cancer, according to Armstrong.

“The earlier you use these drugs in the metastatic setting, the more active they appear to be. Perhaps if we use them even earlier in presumed micro-metastatic disease, the absolute survival benefit would be better. Trials should be conducted in these settings to address these critical questions,” said Armstrong.

Armstrong also advocates for a trial to compare abiraterone and enzalutamide. There is currently little evidence for which agent should be used first for metastatic disease that has progressed after chemotherapy; however, such a trial by the US Cooperative groups (ALLIANCE) is being planned.

As new research probes the genomic pathways of resistance and examines optimal combinations, there is no doubt that these next-generation androgen-targeting therapies are changing the way urologists treat patients with late-stage prostate cancer.

Articles

The treatment of late-stage prostate cancer is shifting; with the approval of two new oral agents there are now more options for men with metastatic prostate cancer then just two years ago. 

New Oral Androgen Receptor Pathway Agents Are Changing the Way Prostate Cancer Is Treated

		Thomas B. Smyth, MD, chats with a patient at Chesapeake Urology Associates.

When the founding partners of Chesapeake Urology Associates (CUA) in Maryland decided to merge their practices, Sanford J. Siegel, MD, CUA’s president and CEO, drew inspiration from another consolidation process.

“I read a lot about American history and I looked at the birth of this country,” Siegel explained. “If you look at this country under the Articles of Confederation, each state was very autonomous, which led to a weak central government. It wasn’t until the states came together under the Constitution and had a single purpose that the United States started to blossom.”

With that vision in mind, Siegel, then running a smaller version of CUA, joined forces with Thomas B. Smyth, MD, of Maryland Urology Associates, and Brad D. Lerner, MD, of Urologic Surgical Associates to form the current version of CUA in 2006.M

The practice now has 14 urology centers and 16 surgical centers in the state, and is staffed by 43 urologists, one urologic pathologist, four radiation oncologists, a dozen physician assistants, two nurse practitioners, and 400 additional employees. Smyth is CUA’s vice president, while Lerner is the clinical director of the CUA-affiliated Summit Ambulatory Surgical Centers.

Looking back, Smyth called the full-scale merger “the most important decision we made as a group... to fully integrate our practices, financially, operationally, and even culturally. We could have said, ‘You need to adopt all of Chesapeake Urology’s methods while you need to take on Maryland Urology’s way of doing things.’ But we made a decision to take a risk...we didn’t merge incrementally.”

The idea of integration has continued to be one of the keys to the practice’s success. 

 talked with Siegel and Smyth about the challenges they faced making CUA into a unified practice, some obstacles they’ve overcome, and what the next stage is for the group in the post—Affordable Care Act [ACA] era. Our editors also spoke with one of newest members of the practice about the future of urologic cancer care.

It’s become trendy for business entities to refer to their employees as “family,” but Siegel doesn’t see it that way. “I don’t call them employees or family members; they are caregivers. Our strength is in the fact that everyone believes in our vision, which is to provide a superior patient experience.”

While the CUA physicians no doubt agreed with that vision in theory, obtaining buy-in to some of the practicalities of becoming a large group practice was another matter. One of the main challenges was getting the physicians—a group Siegel described as “healthy skeptics” who prefer to be their own bosses&mdash;to accept a new professional framework.

For instance, Smyth recalled that within a year of the merger, the physicianleaders realized that they needed to invest in administration to manage operations, finance, marketing, and human resources.

“That was tough for our physicians to swallow initially,” he said. “They said, ‘You [physician-leaders] are doing great. We are about to turn a corner, why do we need to invest in all these new people?’ It was huge leap of faith for all of us.” That leap paid off as it freed up the physicians to focus on their goal of superlative patient care. CUA is “first and foremost, a business, and we run it like one with a strong infrastructure that can support the growth, which is a part of our ongoing strategy,” Siegel said.

The group experienced the unpleasant side of doing business when a series of newspaper articles suggested that CUA had significantly boosted the number of Medicare prostate cancer patients it referred for intensity-modulated radiation therapy (IMRT) after investing in its own IMRT machine (

 Siegel categorically denied the allegations made against the practice, and responded to the criticism by pointing out that the number of prostate cancer patients who received IMRT in 2010 at CUA was “dramatically lower than the national average for utilization of radiation therapy for prostate cancer treatment.” In addition, “it is actually 56% more expensive for a patient with prostate cancer to be treated with radiation therapy in a Maryland hospital than in a medical practice such as Chesapeake Urology” (

While the issue of self-referral in medicine is a serious one, Siegel drew attention to the fact that the majority of practicing physicians, and especially the ones at CUA, don’t have the time to dream up elaborate financial schemes.

“We wake up every day and think about providing the best patient care,” he said. “We do not wake up and think, ‘How many tests can I run today? How may CT scans can I order? How many patients can I send for radiation?’ We keep the needs of our patients front and center, which is what guides us in everything we do as an organization.”

Still, Siegel cautioned his fellow urologists that between the government’s closer scrutiny of potential Medicare fraud and a news cycle that feeds on scandal, even the most dominant urology practice in its area cannot afford to ignore controversy.

“It is a real mistake for doctors to put their heads in the sand as challenges continue to surface on many fronts,” he said. “Urologists are quickly beginning to realize that they must be constantly vigilant in defending their right to practice in a way that they believe is best for their patients. I think organizations such as the Large Urology Group Practice Association [LUGPA] has really helped raise awareness about independent urology issues. They are a strong voice for urology.”

	Full-Spectrum Care: Patients to Physicians

Holistic, integrated patient care has become a go-to concept in modern medicine, and CUA has embraced it. As the director of physician practice development, Smyth explained how CUA has its own take on the idea.

“Integrated care for us means taking a look at our common medical conditions and asking, ‘How can we better integrate these medical conditions with increasingly complex diagnostic and treatment algorithms within the scope of our practice?’ We recognize that, within the next five to ten years, we are going to be paid very differently than we are paid now. Because of that, we need to understand what it costs to take care of common diseases: benign prostate hyperplasia, kidney stones, erectile dysfunction, prostate cancer.”

The goal is to move patients along the entire continuum of care until their medical condition is treated to their satisfaction, Smyth added. This will require a shift away from the traditional idea of transactional medicine.

“A patient comes in for a transaction, the physician addresses or resolves that transaction, but no relationship is built and the patients often don’t ever come back,” Smyth said. “We believe that in order to better care for the patient, we need to change our system into one that builds relationships in which patients are able to discuss a variety of their health issues with the urologist.”

Finally, in another unique move toward integration, CUA has a formal program to ensure the well-being of its own staff, including discounted fees for exercise classes, gym memberships, and tobacco use cessation programs.

“We may be one of the only practices in the country that is doing a physician wellness program,” Smyth said. “If we keep our physicians and staff healthy, then our patients can see that we practice what we preach in terms of living a healthy lifestyle.”

Full-spectrum, superior patient care often means offering investigational treatments. To that end, CUA has Chesapeake Urology Research Associates, under the direction of Ronald F. Tutrone, Jr, MD. Current urologic cancer clinical trials at CUA include:

		A phase III, randomized, active-controlled open-label study on the efficacy and safety of EN3348 (MCC) as compared with mitomycin C for intravesical treatment of subjects with recurrent or refractory nonmuscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG) therapy.

		A randomized, parallel-arm, controlled study of a system that creates space between the rectum and prostate during image-guided IMRT for localized stage T1- T2 prostate cancer.

“It’s imperative that we offer our patients access to that science,” Siegel said. “It’s also important to our doctors that they are involved in making ongoing advances in medical care.”

In addition to offering patients access to advances in medical care, CUA also keeps an eye on the future of urologic care by recruiting and mentoring new physicians. Rian J. Dickstein, MD, joined CUA in August 2012 after completing a fellowship at The University of Texas MD Anderson Cancer Center in Houston.

CUA appealed to Dickstein in part because of its mentorship program. “They align you to another physician who has been in practice for a number of years,” he said. Dickstein’s mentor is Geoffrey N. Sklar, MD, CUA’s chief medical officer. “I think it’s important for physicians who are coming out of training to have that support system.”

Dickstein was also attracted by the chance to join a large group practice. “I didn’t see a solo practice as a feasible and desirable lifestyle,” he said. “That wasn’t even a consideration for me. I was interested in the camaraderie of the group in terms of patient care, financial models, etc. A large group practice made perfect sense to me.”

Dickstein’s time at MD Anderson gave him a chance to compare cancer care at a major center with care at a urology practice—a difference that fits in with the CUA philosophy of promising a superior patient experience.

“What we can offer is a similar level of care as a major cancer center, but do it closer to home,” he said. “Also, I think we offer a mode of care that is more personalized than a bigger institution.”

Since starting at CUA, Dickstein said he has mostly treated kidney, prostate, and bladder cancer cases. It’s in the last disease state that Dickstein would like to see more public health focus.

“When it comes to smoking, most people focus on lung cancer. But they don’t realize that smoking is a major risk factor for bladder cancer. Furthermore, smoking affects cardiovascular health, which can in turn affect urologic health, specifically in the form of erectile dysfunction,” he said.

“For the most part, any of the risk factors that affect other diseases affect urologic health: Tobacco exposure, obesity, cardiovascular diseases, all of these increase the risk for urologic cancers, as well as how a patient will respond to treatment and their prognosis for recovery,” he added.

Between those population-based health issues and the potential for more than 30 million new Medicare patients under the ACA, the practice has an eye toward “organic growth,” Siegel said, such as expanding their geographic footprint and continuing to build relationships with their hospital partners.

Of course, they are looking to add new physicians who can share in CUA’s vision of fully integrated patient care.

“When we started in 2006, probably 65% of our doctors were over 50 years of age; now, 65% of our physicians are under 50,” he said. “So we have great promise for the future as we continue to build our physician base. We expect all of our people to have a strong commitment to patient care and to their social responsibilities. Our core values drive everything we do at CUA.”

When the founding partners of Chesapeake Urology Associates (CUA) in Maryland decided to merge their practices, Sanford J. Siegel, MD, CUA's president and CEO, drew inspiration from another consolidation process.

A United Front: Chesapeake Urology Associates Puts Its Singular Spin on Integrative Care

New clinical models are emerging for the delivery of prostate cancer care. Some large urology group practices are expanding to offer cancer care and instituting bone health clinics to treat patients throughout the entire course of their disease. In some academic settings, the concept of multidisciplinary prostate cancer care has been adopted, in line with a model that has become routine in breast and lung cancer assessment. In both the academic and group practice settings, new drugs are offering efficacy along with good tolerability, and the promise for a significant impact on patient care may be close at hand.

, Judd W. Moul, MD, professor of Surgery and director of the Duke Prostate Center, Duke Cancer Institute, Durham, North Carolina, commented on practice trends in urologic cancer care and the advantages and disadvantages of his institution’s multidisciplinary prostate cancer clinic. He highlighted a few of the new treatments on the horizon for prostate cancer, and elaborated on the rationale behind the urology community’s disagreement with the recent US Preventive Services Task Force (USPSTF) recommendation against PSAbased prostate cancer screening.

: Some urology practices, especially large groups, are expanding to provide cancer care, and establishing additional onsite services such as bone clinics. Could you reflect on this trend from an academic medical center perspective?

 I think this offers a great opportunity for some of the large urology groups to find at least one partner or one member of the group who has a special interest in advanced prostate cancer. There are a number of new agents, either available now or in the pipeline. If urology groups do not embrace some of the new prostate cancer treatments, I am afraid they are going to lose out to medical oncology and some of the academic centers that are offering these services and treatments.

It has been said that the availability of more prostate cancer drugs with good tolerability and easy regimens such as oral administration also helps to make the case for urology practices to provide ongoing prostate cancer care.

I completely embrace urologists’ maintaining their role as the key physicians for men with prostate cancer—early and advanced. While I am enthusiastic about our continued role in pushing the technology envelope with early-stage prostate cancer, I am worried that many young urologists have focused so much on early-stage technology, such as the robot, and have not kept up or embraced the equally exciting new treatments for advanced prostate cancer.

Many LUGPA [Large Urology Group Practice Association] groups have adopted subspecialty expertise, such as having only one or two partners per group as robotic surgeons. In the same vein, I feel these groups need to embrace one or two partners as champions for new therapy for advanced disease—such as sipuleucel- T infusions, abiraterone use, or denosumab expertise. Urology remains a wonderful specialty because we can be surgeons and also be medical experts in our key diseases.

MDV3100 (enzalutamide) has been described as a “gamechanger” in the treatment of prostate cancer, having shown a significant survival benefit in men with prostate cancer post-docetaxel. Can you comment on these results and whether you agree with the claims about this oral drug’s potential?

MDV3100 has to be placed in the context of other products that have been FDA-approved in the last year or two years, such as sipuleucel-T, which is another treatment that large urology groups should embrace because of its low side-effect profile and evidence for increased survival in advanced prostate cancer. An advantage to MDV3100 is that it is an oral agent with a low sideeffect profile. It does not have to be administered with steroid medications and does not seem to have as many toxicities as some of the other oral agents that are currently being utilized.

You are an author of a recent paper that reports phase III results for zibotentan (ZD4054), an endothelin A receptor antagonist, in patients with castration-resistant prostate cancer [CRPC] that has metastasized to bone.

 Can you comment on the results and the drug’s possible future in the expanding treatment armamentarium for CRPC?

This is a good news-bad news story. I was fortunate to be one of the global principal investigators on the trials for ZD4054, which was given the generic name of zibotentan by AstraZeneca, its developer. Unfortunately, those trials were all essentially negative and did not meet the endpoint of increasing survival in men with advanced prostate cancer. Currently the ZD4054 program has been discontinued, and the drug, at least currently, is not moving forward in advanced prostate cancer. I admire AstraZeneca for its commitment, with three global randomized studies, to determine if the drug would increase overall survival for advanced prostate cancer.

One of the ZD4054 trials was in men who had biochemical CRPC. These were men who had evidence of progression despite androgendeprivation therapy [ADT] but who still had a negative bone scan. When the patients were imaged for entry into the trial, fully one-third had bone metastases.

 This finding teaches us that we need to reimage men to look for bone metastases when they have a rising PSA while on ADT. By detecting metastases, more men will be candidates for novel therapies including sipuleucel-T and denosumab.

Duke is one of a few medical centers with a multidisciplinary prostate cancer clinic, following from earlier examples of this type of service such as the one at Walter Reed Army Medical Center. You are among the authors of a recent report highlighting Duke’s utilization trends for its clinic over a five-year period.

 What would you cite as some of the advantages and disadvantages of the multidisciplinary clinic, and what did your study learn about utilization trends?

I am very fortunate to be at a medical center where we have embraced the concept of multidisciplinary care for advanced prostate cancer. We’ve had a multidisciplinary program since 2004. We are now celebrating our eighth year offering this service. We offer multidisciplinary care in two ways, including a “true” multidisciplinary clinic in which once per week, in one visit, patients will see a urologist, a medical oncologist, and radiation oncologist. After we all have seen the patient, we meet as a group to discuss the patient’s case in a kind of tumor board setting, then go back to the patient and give him our recommendations and options for treatment. Typically we see about a half-dozen patients in a five-hour morning session/clinic where all three specialists see and interact with the patients. Each takes a history and conducts a physical.

The patients and their families love this. The down side it that it takes three specialists much time out of their weekly practice, and I am not sure that it is a financially rewarding exercise. But certainly it is a great thing to offer and tremendous value-added service. And it may pay dividends in word-of-mouth recommendations, bringing a lot more patients to the center.

We also offer a pseudo-multidisciplinary option, where doctors are in their individual clinics but our new-patient coordinator lines up patients to see all three specialists the same day: urology, radiation oncology, and, in some cases, medical oncology.

		Figure. Baseline Characteristics of Patients Who Received Care at Duke's Multidisciplinary Clinic Versus the Duke Urology Clinic

		BMI indicates body mass index; IQR, interquantile range.

		Stewart SB, Banez LL, Robertson CN, et al. Utilization trends at a multidisciplinary prostate cancer clinic: initial 5-year experience from the Duke Prostate Center. 

The utilization trends from our true multidisciplinary prostate cancer clinic were published in the 

 We looked at the first approximately 700 patients who went through the true multidisciplinary clinic between the years 2004 to 2011, comparing utilization determinants with the urology prostate cancer clinic (

). We identified the factors that were associated with pursuing treatment at the university medical center for multidisciplinary clinic patients. We found that about 60% of men who attended the multidisciplinary clinic ended up getting their primary treatment at Duke. For these Duke-treated men, about 52% went on to radical prostatectomy, 33% had primary radiation, and 9% elected active surveillance. High-risk men (PSA > 20, or Gleason score 8-10, or clinical stage T2c-T3) were more likely to decide on staying at Duke for their initial treatment. For the 40% of men who came to Duke for the multidisciplinary clinic but who did not stay at Duke for primary therapy, those living more than 100 miles from Duke, and those with higher socioeconomic status were less likely to be retained for care

Does the clinic setting—either or both the multidisciplinary and the pseudo-multidisciplinary&mdash;result in recruitment of more patients into clinical trials?

The clinic has increased the clinical trial participation rate because we have more time to speak to the patients about trials. Since patients are so happy otherwise because they got such good education, they appear to be more inclined to participate in clinical trials, perhaps as a result this “high-touch environment.”

We are involved in a large number of trials in local and advanced prostate cancer, and are trying to do a better job of informing our patients about clinical trial opportunities and trying to incorporate clinical trials into our practices on a daily basis. Some of the large urology group practices have done a great job with clinical trials. Dr Neil Shore and his partners in Myrtle Beach, South Carolina, immediately come to mind. They have embraced the concept of clinical trials embedded into a large community urology private practice and generally are better positioned to attract many trials compared to major academic centers. While we in academics do a great job as well, we sometimes take too long to approve trials and are more expensive due to our complex structure.

You and your colleagues have published several recent articles on chemoprevention with finasteride—cost-effectiveness, age at start of therapy, duration of therapy, quality of life.

 Could you speak to this issue and to the findings?

Prostate cancer chemoprevention with finasteride or dutasteride remains extremely controversial. On the one hand, these drugs have some tremendous benefits: they will shrink the prostate. They will improve a patient’s symptoms (lower urinary tract symptoms), and they typically will cut the PSA level by about one-half. They also have the benefit of being approved to treat benign prostatic hyperplasia [BPH]. Finasteride is generic as well, so it is not expensive. For the patient with BPH, and in our practices, the drugs have made a huge impact. Those are the good things.

The challenge is that some experts, including the FDA, feel that the drugs might slightly increase the rate of high-grade cancers. So, the FDA was thumbs down on dutasteride for a pure chemoprevention indication, noting a slight chance of increasing the risk of high-grade cancer. Right now, neither finasteride nor dutasteride is approved for chemoprevention. On the other hand, urologists commonly prescribe these drugs for BPH. I personally think that the benefit may outweigh the risk for chemoprevention. There are also other data to suggest that the drugs might delay prostate cancer progression in men who are on active surveillance for low-grade, low-stage prostate cancer as well.

What new data from the American Urological Association [AUA] or American Society of Clinical Oncology [ASCO] this year were especially exciting and potentially meaningful to the urology community in the treatment of prostate cancer?

One of the things I thought was really a bombshell revelation at ASCO in June was reported by Maha Hussain, MD, an investigator with the Southwest Oncology Group [SWOG], who presented long-term follow-up results on the intermittent versus continuous hormone therapy trial.

 In patients with traditional metastatic prostate cancer, intermittent hormone therapy was inferior to continuous hormone therapy. That was quite interesting and probably something that many urologists may not be aware of.

The practical implications of this are significant. For patients with traditional advanced prostate cancer who are initiated on hormone therapy, the new standard may return to continuous androgen-deprivation therapy, away from intermittent hormone therapy. This suggests that some of the more potent hormone therapies such as degarelix or abiraterone or enzalutamide may make sense. For a while we were wondering what it all means, that if intermittent was just as good as continuous hormone therapy, then what is the big deal about keeping the testosterone level low? With this new intermittent data, at least for traditional advanced prostate cancer patients with bone metastasis, continuous hormone therapy appears to be better, and perhaps some of the newer agents that keep the testosterone levels really low may be better.

Significant controversy has erupted over the recent US Preventive Services Task Force [USPSTF] recommendation against PSA testing. A number of professional groups representing urologists, such as the AUA, men’s health groups, and LUGPA, have issued strong statements of disagreement—even rejection&mdash;of the USPSTF recommendation. What are your and your colleagues’ views on the issue of PSA testing for asymptomatic men, and how might it affect your clinical decision-making?

I was very fortunate to be part of a group of authors that published a rebuttal to the US Preventive Services Task Force. My views were put in writing in the

I think the biggest reason that urologists are frustrated is the fact that the USPSTF really did not recognize PSA as having any value in any man. They did not take into account some newer data suggesting that a baseline PSA level at age 40 is a powerful tool to stratify men for future risk of prostate cancer. They didn’t take into consideration African-American men, whom we know to be at much higher risk for prostate cancer. And they did not take into account men who have a strong family history of prostate cancer. They made a blanket statement that PSA should not be used in anyone.

While I agree that PSA is probably overutilized in elderly men, I disagree in that they threw the baby out with the bath water, and did not recognize PSA to be of value in high-risk groups nor its role in risk stratification. With a D recommendation, the Medicare program will not pay for PSA screening. We can code for diagnostic PSA or to follow patients. In North Carolina, if a Medicare patient comes in and if I code for “screening PSA,” patients must pay $205 out of pocket.

			Nelson JB, Fizazi K, Miller K, et al. Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castrate-resistant prostate cancer metastatic to bone [published online ahead of print July 11, 2012]. 

			Yu EY, Miller K, Nelson J, et al. Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer [published online ahead of print May 12, 2012]. 

			Stewart SB, Banez LL, Robertson CN, et al. Utilization trends at a multidisciplinary prostate cancer clinic: initial 5-year experience from the Duke Prostate Center. 

			Stewart SB, Scales CD, Moul JW, Reed, SD. Does variation in either age at start of therapy or duration of therapy make chemoprevention with finasteride cost-effective? [published online ahead of print July 10, 2012]. 

			Reed SD, Scales CD, Stewart SB et al. Effects of family history and genetic polymorphism on the cost-effectiveness of chemoprevention with finasteride for prostate cancer. 

			Hussain M, Tangen CM, Higano CS, et al. Intermittent versus continuous androgen deprivation in hormone sensitive metastatic prostate cancer patients: results of S9346 (INT-0162), an international phase III trial. 

			Catalano WJ, D’Amico AV, Fitzgibbons WF, et al. What the U.S. Preventive Services Task Force missed in its prostate cancer screening recommendation. 

Judd W. Moul, MD, from the Duke Cancer Institute, comments on practice trends in urologic cancer care and the advantages and disadvantages of his institution's multidisciplinary prostate cancer clinic.

Multidisciplinary Prostate Cancer Care at Duke Cancer Institute: An Interview With Judd W. Moul, MD

As many of us are keenly aware, the coming 12 months present some very challenging times in the medical community. Having just returned from the 4th Annual Meeting of the Large Urology Group Practice Association (LUGPA), the issues that confront our specialty, and society, were made painfully clear to all who were in attendance.

Economically, we are moving quickly toward the fiscal cliff that Federal Reserve System Chairman Ben S. Bernanke warned of earlier this year. Due to pending legislative events expected to hit in January, there will be a projected 50% reduction in the 2013 budget deficit (from $1.2 trillion to $560 billion) and potential flattening of the debt curve for the next decade. Many economists predict that this may result in a short-term recession, slowing of economic recovery, and more than likely an increased tax burden for all Americans.

Even more sobering is our current national debt–running around $17 trillion as I type and increasing with every key stroke. The first keynote speaker at the LUGPA meeting, Robert Laszewski, president of Health Policy and Strategy Associates, Inc, in Alexandria, Virginia, noted that although entitlement spending is the major driver of our runaway deficit, the Medicare program has the pole position. If Medicare continues to go unchecked without significant payment reform, it will for all intents and purposes consume our resources and bankrupt the country in the years to come. As a result, alternative methodologies to pay providers will be developed, and the likely intent of those methodologies will be to pay all of us less. Not redistribute, not keep things even–less.

My good friend and colleague, Neil D. Shore, MD, of Carolina Urologic Research Center in Myrtle Beach, South Carolina, moderated a program at the LUGPA meeting on advances in the management of patients with castration-resistant prostate cancer (CRPC). The session provided a comprehensive overview of the advances and complexities that currently confront the practicing urologist. The good news for our patients is that there are many new therapies already available, and more on the horizon, that provide hope and the potential for long-term survival. However, there are no existing data on sequencing or combinatorial therapy.

One of the problems with obtaining these data is that in most trials, the FDA still requires a primary endpoint of overall survival. This hampers our ability to gather data quickly, since such trials take years to complete.

Another difficulty that we all face is the rising cost of oncologic care. While the drug component is the fastest-rising element within that sector, it does not actually represent the largest cost to the healthcare system. With all of our medical advances, we now simply have more cancer patients to manage. And with every patient comes the associated costs of therapy, including monitoring (lab, advanced imaging, etc), procedures, office visits, and hospitalizations. The challenge, given the economic landscape, is how to pay for these new therapies that clearly have a survival advantage and better side-effect profile, but individually carry a high price tag. Patients and their doctors face a difficult conundrum, given the economic downturn and loss of personal and corporate income versus trying to obtain/deliver quality care.

As physicians, we take the Hippocratic Oath on completion of our medical school training to always try to do what is best for our patients and do no harm. It is a lifetime plan that we try to formulate for those who come to us for help and medical expertise. Given the many obstacles in the way of providing quality care for cancer patients, it is disappointing to me that many of our leaders in government–in either party–seem to only have a two-, four-, or six-year commitment and will do whatever it takes to get them to the next election. They may win elections, but their constituents, patients, and our country end up losing by this short-sighted strategy.

As many of us are keenly aware, the coming 12 months present some very challenging times in the medical community.

The Challenges That Lie Ahead

In May 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA screening for prostate cancer in men regardless of age, citing evidence of a very small potential benefit from screening and significant potential harms.

In the aftermath of this recommendation, a number of medical organizations issued formal statements of disagreement, including the American Urological Association (AUA), which stated in part that “…the PSA test provides important information in the diagnosis, pretreatment staging or risk assessment and monitoring of prostate cancer patients….”

Editor-in-Chief of Urologists in Cancer Care, Raoul S. Conception, MD, Director of Clinical Research at Urology Associates, PC, in Nashville, Tennessee, moderated a panel discussion with physicians (see sidebar for the full list of panelists) as part of a video series from the 

Urologists in Cancer Care Peer Exchange program

As part of a more extensive discussion about clinical and practice management issues that urologists face, Concepcion asked panel members for their thoughts on the USPSTF recommendations, and how this widely publicized health message has impacted their urology practices.

: Let’s talk about prostate cancer screening. We know that the United States Preventive Services Task Force came out recently with a very controversial recommendation regarding PSA screening for prostate cancer. Dr Crawford, let’s start with you.

: My short answer is that there is a lot of truth in what they say. In 1989, we started one of the biggest organized national prostate cancer screening events, Prostate Cancer Awareness Week, which has been in place ever since. Millions of men have been screened, and we have learned a lot. Where we got into trouble was by diagnosing people who maybe did not need to be diagnosed and treated. The bottom line is that we need to separate diagnosis from treatment. Not everyone who is diagnosed needs to be treated.

If you don’t believe in overdiagnosis and overtreatment…I can say that I see it all the time. Patients come in with a PSA of 45 and Gleason score of 6 in one core, and they get a robotic prostatectomy or IMRT [intensity-modulated radiation therapy]. Does this person really need to be treated?

I am not sure that we should be attacking the USPSTF. We should find some common ground and work on better ways to identify who needs to be screened.

: Dr Austenfeld, like most of us, you wear multiple hats. Could you comment with your American Association of Clinical Urologists (AACU) hat as well as your clinician’s hat as a key part of a large urology group?

: I think most of urologists in this country feel that the USPSTF overstepped its bounds and didn’t listen to some of the expert opinion and advisory groups, particularly the AUA and experts who were able to break down some of the studies. They only used two studies primarily, and the follow-up was short.

And, as we know, there were neither oncologists nor urologists on the panel. It is true that they may have some biases, but there are a great number of researchers in urology in this country who can give a good and unbiased professional opinion about this. Also, the Task Force had a chance to go back and revise its recommendation and didn’t. I think most people feel they plowed ahead without really good data, or at least [interpreted] the data incorrectly.

I agree with David that we probably diagnose too many men with prostate cancer, and some are overtreated. But we can’t ignore the fact that the death rate from prostate cancer has declined from the early days of PSA screening. We also can’t deny the fact that many men who suffer from prostate cancer live for many years before they die from the disease. So, death from prostate cancer as an endpoint is probably not very good.

The last thing I would say is that men I have seen in my practice are confused by this recommendation. I think it’s going to be our role to come up with a little more balanced assessment of prostate cancer screening or case-finding.

: The egregious thing about this is that the USPSTF tied together early diagnosis and over-treatment, and these are two separate entities. Just because there is overtreatment, it doesn’t mean that the patient does not have the right to know that he has prostate cancer at a very early stage.

: That’s what we’ve been saying at Prostate Cancer Awareness Week for two decades. Know what you have so you can choose a treatment, or maybe choose to do nothing. The unfortunate thing is that a lot of time when men are diagnosed, the “train has left the station.” We give a lot of lip service to active surveillance, but if you look at the numbers of men who go onto active surveillance, it’s way less than 10%, and it’s decreasing rather than increasing.

: Dr Shore, since the USPSTF recommendation, tell us a little bit about how this has impacted your practice—with referring doctors and how they have responded, and what patients say when they come in to see you and your partners in Myrtle Beach.

: The Task Force gives its recommendation a “D” rating. And, based on the news that went out into the mass media, the interpretation by many of my patients was that “I don’t really need to have PSA testing; it is really unnecessary. No one dies from prostate cancer.” We all know that this is not the situation. So I think it’s created terrible misinformation in the public mind. I don’t think the Task Force wanted to do that; I think they were trying to address issues of overdiagnosing and perhaps overtreatment, which are very valid issues, and I wouldn’t argue with that. I don’t think that any of us would. But it’s created terrible misinformation in my clinic population.

We have also seen a decline in our referrals from our primary care base. And, as someone who is very involved in treating systemic prostate cancer in patients who fail localized therapy, I am concerned that a future trend could be that we will see more patients who are not appropriately diagnosed, and not appropriately screened but who are at high-risk for prostate cancer (eg, positive family history, African-American individuals, those who have had industrial chemical exposure, rapid PSA elevation). We may end up seeing more patients presenting to our clinics with advanced disease. As we all know, prostate cancer is the second leading cause of cancer mortality in men in the United States, after lung cancer. So, I have real concerns about it. We need to more judiciously know whom to screen, whom to diagnose, and whom to biopsy. But it’s not a one-size- fits-all [situation], and the Task Force recommendation, at least for my patient population, has presented this as a one-size-fits-all concept.

From a legislative standpoint, we are also concerned that with this type of a recommendation, there could be a failure to pay for PSA testing in the future. Although Department of Health and Human Services Secretary Kathleen Sebelius has said that this is not the case right now, she or her successor has the option to no longer pay for it. This is very disconcerting.

: I would echo Neal’s comment: I spend more time each day explaining—even in patients with prostate cancer&mdash;that the PSA test is not invalid. [The task of communicating this] is an overwhelming burden. The gripe I have with the Task Force is that I don’t think they understand the weight of what they said in terms of how the average man is going to see a front-page headline and interpret it. This has led to a significant burden in our office to talk to our patients. 

A panel of experts provides their thoughts on the USPSTF PSA screening recommendations, and how this widely publicized health message has impacted their urology practices.

December 2012 | Oncology Live Urologists in Cancer Care®

New Oral Androgen Receptor Pathway Agents Are Changing the Way Prostate Cancer Is Treated

A United Front: Chesapeake Urology Associates Puts Its Singular Spin on Integrative Care

Multidisciplinary Prostate Cancer Care at Duke Cancer Institute: An Interview With Judd W. Moul, MD

The Challenges That Lie Ahead

The USPSTF Prostate Cancer Screening Recommendations: Urologists Discuss Its Message and Impact on Their Practices